Box2Mask: Box-Supervised Instance Segmentation via Level-Set Evolution.

In contrast to fully supervised methods using pixel-wise mask labels, box-supervised instance segmentation takes advantage of simple box annotations, which has recently attracted increasing research attention. This paper presents a novel single-shot instance segmentation approach, namely Box2Mask, which integrates the classical level-set evolution model into deep neural network learning to achieve accurate mask prediction with only bounding box supervision. Specifically, both the input image and its deep features are employed to evolve the level-set curves implicitly, and a local consistency module based on a pixel affinity kernel is used to mine the local context and spatial relations. Two types of single-stage frameworks, i.e., CNN-based and transformer-based frameworks, are developed to empower the level-set evolution for box-supervised instance segmentation, and each framework consists of three essential components: instance-aware decoder, box-level matching assignment and level-set evolution. By minimizing the level-set energy function, the mask map of each instance can be iteratively optimized within its bounding box annotation. The experimental results on five challenging testbeds, covering general scenes, remote sensing, medical and scene text images, demonstrate the outstanding performance of our proposed Box2Mask approach for box-supervised instance segmentation. In particular, with the Swin-Transformer large backbone, our Box2Mask obtains 42.4% mask AP on COCO, which is on par with the recently developed fully mask-supervised methods.

Modified aortic root anastomosis and the frozen elephant trunk technique using an integrated tetra-furcate graft to repair type A aortic dissection.

BACKGROUND: Surgery is the preferred treatment for acute Stanford type A aortic dissection (STAAD); however, due to the complexity of the procedure, cardiac ischaemia and cardiopulmonary bypass (CPB) time are longer than general heart surgery, leading to complications. In this present study, we used an integrated tetra-furcate graft for both modified aortic root and distal arch anastomoses (frozen elephant trunk technique, [FET]), and investigated postoperative outcomes associated with this technique in patients with STAAD. METHODS: We included a total of 140 patients who underwent total arch replacement and FET between January 2019 and June 2022 in the present study, 41 patients who underwent the modified technique, and 99 who underwent the graft eversion technique. We subsequently analyzed the perioperative outcomes to compare the differences between the two techniques. RESULTS: There were no statistically significant differences between the two groups in regards to the preoperative characteristics; however, the intraoperative CPB, cardiac ischaemia, and operation times of the modified technique group were significantly shorter than those of the eversion technique group (P = 0.02, P = 0.01, and P = 0.04, respectively), as were postoperative hypoxaemia, intensive care unit (ICU) stay, and ventilation times (P = 0.04, P = 0.03, and P = 0.04, respectively). Additionally, the degree of postoperative bilirubin elevation was milder in the modified technique group (P = 0.002 for direct bilirubin and P = 0.01 for indirect bilirubin). CONCLUSIONS: The modified anastomosis technique can significantly shorten CPB, cardiac ischemia, and operation times, and reduce the intraoperative FFP transfusion and postoperative hypoxemia times. This modified technique, therefore, is worth utilizing for patients with STAAD.

Pseudolaric acid B triggers ferritinophagy and ferroptosis via upregulating NCOA4 in lung adenocarcinoma cells.

BACKGROUND: Ferroptosis is a novel subtype of programmed cell death caused by iron-dependent lipid peroxidation and excessive reactive oxygen species (ROS) production. Small-molecule ferroptotic drugs have the probability of selectively targeting the specific features of aggressive tumor cells. In particular, pseudolaric acid B (PAB) triggered ferroptosisin breast cancer cells. The aim of this study is to explore the antitumor effect of PAB on A549 cells and provide a theoretical basis for the further development and clinical application of PAB. METHODS: First, relevant databases were used to predict of target genes related to PAB, Then, EdU proliferation assay, colony formation and wound-healing assays were applied to calculate A549 cells proliferative abilities. Measurement of ferrous iron, lipid peroxidation, ROS, malondialdehyde (MDA) and glutathione (GSH) were utilized to explore the relevant mechanism. RESULTS: We showed that PAB decreased the viability of lung adenocarcinoma cells in vitro, which was accompanied by abnormally elevated levels of intracellular ferrous iron and overproduction of lipid reactive oxidate species (L-ROS). In turn, deferoxamine (DFO) significantly rescued PAB-induced lipid peroxidation. PAB also improved the intracellular labile iron pool by promoting ferritin autophagy via the upregulation of the nuclear receptor coactivator 4 (NCOA4). Moreover, silencing of NCOA4 alleviated PAB-inducedferroptotic death and reduced the levels of intracellular ferrous iron. CONCLUSIONS: In summary, PAB-triggered ferroptosis in lung adenocarcinoma cells by enhancing ferritinophagy. thus, PAB is a potential therapeutic agent for lung adenocarcinoma.

Effect of minimally invasive versus conventional aortic root replacement on transfusion and postoperative wound complications in patients: A meta-analysis.

We examined whether small incision aortic root replacement could reduce the amount of blood transfusion during operation and the risk of postoperative complications. An extensive e-review of the 4 main databases (PubMed, Cochrane, Web of Science and EMBASE) was carried out to determine all the published trials by July 2023. The search terms used were associated with partial versus full sternotomy and aortic root. This analysis only included the study articles that compared partial and full sternotomy. After excluding articles based on titles or abstracts, selected full-text articles had reference lists searched for any potential further articles. We analysed a total of 2167 subjects from 10 comparable trials. The minimally invasive aortic root graft in breastbone decreased the duration of hospitalization (MD, -2.58; 95% CI, -3.15, -2.01, p < 0.0001) and intraoperative red blood cell transfusion (MD, -1.27; 95% CI, -2.34, -0.19, p = 0.02). However, there were no significant differences in wound infection (OR, 0.88; 95% CI, 0.16, 4.93, p = 0.88), re-exploration for bleeding (OR, 0.96; 95% CI, 0.60, 1.53, p = 0.86), intraoperative blood loss (MD, -259.19; 95% CI, -615.11, 96.73, p = 0.15) and operative time (MD, -7.39; 95% CI, -19.10, 4.32, p = 0.22); the results showed that the microsternotomy did not differ significantly from that of the routine approach. Small sternotomy may be an effective and safe substitute for the treatment of the aorta root. Nevertheless, the wide variety of data indicates that larger, well-designed studies are required to back up the current limited literature evidence showing a benefit in terms of complications like postoperative wound infections or the volume of intraoperative red blood cell transfusion.

Analysis of the genetic contribution to thoracic aortic aneurysm or dissection in a prospective cohort of patients with familial and sporadic cases in East China.

BACKGROUND: Thoracic aortic aneurysm or dissections (TAADs) represent a group of life-threatening diseases. Genetic aetiology can affect the age of onset, clinical phenotype, and timing of intervention. We conducted a prospective trial to determine the prevalence of pathogenic variants in TAAD patients and to elucidate the traits related to harbouring the pathogenic variants. One hundred and one unrelated TAAD patients underwent genetic sequencing and analysis for 23 TAAD-associated genes using a targeted PCR and next-generation sequencing-based panel. RESULTS: A total of 47 variants were identified in 52 TAAD patients (51.5%), including 5 pathogenic, 1 likely pathogenic and 41 variants of uncertain significance. The pathogenic or likely pathogenic (P/LP) variants in 4 disease-causing genes were carried by 1 patient with familial and 5 patients with sporadic TAAD (5.9%). In addition to harbouring one variant causing familial TAAD, the FBN1 gene harboured half of the P/LP variants causing sporadic TAAD. Individuals with an age of onset less than 50 years or normotension had a significantly increased genetic risk. CONCLUSIONS: TAAD patients with a younger age at diagnosis or normotension were more likely to carry a P/LP variant; thus, routine genetic testing will be beneficial to a better prognosis through genetically personalized care prior to acute rupture or dissection.

Supramolecular Nanozyme System Based on Polydopamine and Polyoxometalate for Photothermal-Enhanced Multienzyme Cascade Catalytic Tumor Therapy.

The advent of enzyme-facilitated cascade events in which endogenous substrates within the human body are used to generate reactive oxygen species (ROS) has spawned novel cancer treatment possibilities. In this study, a supramolecular cascade catalytic nanozyme system was successfully developed, exhibiting photothermal-enhanced multienzyme cascade catalytic and glutathione (GSH) depletion activities and ultimately triggering the apoptosis-ferroptosis synergistic tumor therapy. The nanozyme system was fabricated using ß-cyclodextrin-functionalized polydopamine (PDA) as the substrate, which was then entangled with polyoxometalate (POM) via electrostatic forces and assembled with adamantane-grafted hyaluronic acid and glucose oxidase (GOx) via host-guest supramolecular interaction for tumor targeting and GOx loading. The catalytic function of GOx facilitates the conversion of glucose to H2O2 and gluconic acid. In turn, this process affirms the propitious generation of hydroxyl radical (•OH) through the POM-mediated cascade catalysis. Additionally, the POM species actively deplete the intracellular GSH pool, initiating a cascade catalytic tumor therapy. In addition, the PDA-POM-mediated photothermal hyperthermia boosted the cascade catalytic effect and increased ROS production. This confers considerable promise for photothermal therapy (PTT)/nanocatalytic cancer therapy on supramolecular nanozyme systems. The in vitro and in vivo antitumor efficacy studies demonstrated that the supramolecular cascade catalytic nanozyme system was effective at reducing tumor development while maintaining an acceptable level of biocompatibility. Henceforth, this study is to widen the scope of cascade catalytic nanoenzyme production using supramolecular techniques, as well as endeavor to delineate a prospective pathway for the application of PTT-enhanced nanocatalytic tumor therapy.

Arginine methyltransferases PRMT2 and PRMT3 are essential for biosynthesis of plant-polysaccharide-degrading enzymes in Penicillium oxalicum.

Many filamentous fungi produce plant-polysaccharide-degrading enzymes (PPDE); however, the regulatory mechanism of this process is poorly understood. A Gal4-like transcription factor, CxrA, is essential for mycelial growth and PPDE production in Penicillium oxalicum. Its N-terminal region, CxrAΔ207-733 is required for the regulatory functions of whole CxrA, and contains a DNA-binding domain (CxrAΔ1-16&Δ59-733) and a methylated arginine (R) 94. Methylation of R94 is mediated by an arginine N-methyltransferase, PRMT2 and appears to induce dimerization of CxrAΔ1-60. Overexpression of prmt2 in P. oxalicum increases PPDE production by 41.4-95.1% during growth on Avicel, compared with the background strain Δku70;hphR+. Another arginine N-methyltransferase, PRMT3, appears to assist entry of CxrA into the nucleus, and interacts with CxrAΔ1-60 in vitro under Avicel induction. Deletion of prmt3 resulted in 67.0-149.7% enhanced PPDE production by P. oxalicum. These findings provide novel insights into the regulatory mechanism of fungal PPDE production.

Kinase POGSK-3ß modulates fungal plant polysaccharide-degrading enzyme production and development.

The filamentous fungus Penicillium oxalicum secretes integrative plant polysaccharide-degrading enzymes (PPDEs) applicable to biotechnology. Glycogen synthase kinase-3ß (GSK-3ß) mediates various cellular processes in eukaryotic cells, but the regulatory mechanisms of PPDE biosynthesis in filamentous fungi remain poorly understood. In this study, POGSK-3ß (POX_c04478), a homolog of GSK-3ß in P. oxalicum, was characterised using biochemical, microbiological and omics approaches. Knockdown of POGSK-3ß in P. oxalicum using a copper-responsive promoter replacement system led to 53.5 - 63.6%, 79.0 - 92.8% and 76.8 - 94.7% decreases in the production of filter paper cellulase, soluble starch-degrading enzyme and raw starch-degrading enzyme, respectively, compared with the parental strain ΔKu70. POGSK-3ß promoted mycelial growth and conidiation. Transcriptomic profiling and real-time quantitative reverse transcription PCR analyses revealed that POGSK-3ß dynamically regulated the expression of genes encoding major PPDEs, as well as fungal development-associated genes. The results broadened our understanding of the regulatory functions of GKS-3ß and provided a promising target for genetic engineering to improve PPDE production in filamentous fungi. KEY POINTS: • The roles of glycogen synthase kinase-3ß were investigated in P. oxalicum. • POGSK-3ß regulated PPDE production, mycelial growth and conidiation. • POGSK-3ß controlled the expression of major PPDE genes and regulatory genes.

Aortic arch branch-prioritized reconstruction for type A aortic dissection surgery.

Background: Acute Stanford type A aortic dissection (STAAD) is a fatal condition requiring urgent surgical intervention. Owing to the complexity of the surgical process, various complications, such as neurological disorders, are common. In this study, we prioritized the reconstruction of aortic arch branches during surgery and investigated the association between prioritizing the branches and the postoperative outcomes of patients with STAAD. Methods: Ninety-seven patients were included in the observational study and underwent total arch replacement and frozen elephant trunk technique between January 2018 and June 2021. Of these, 35 patients underwent the branch-priority technique, and 62 patients underwent the classic technique. By analyzing the perioperative outcomes, we compared the differences between the two techniques. Results: The branch priority group had significantly shorter cardiopulmonary bypass and ventilator times and earlier postoperative wake-up times than the classic group. Additionally, the ICU stay time was shorter, with a significant decrease in neurological complications and 24 h drainage in the branch priority group compared to the classic group. Conclusion: The branch priority technique can effectively provide better brain protection, resulting in earlier awakening of patients after surgery, reduced neurological complications, shorter ventilation time and decreased ICU hospitalization time. Therefore, it is recommended for use in aortic dissection surgeries.

Leveraging Nanodrug Delivery System for Simultaneously Targeting Tumor Cells and M2 Tumor-Associated Macrophages for Efficient Colon Cancer Therapy.

Tumor-associated macrophages (TAMs) widely exist in the solid tumors, which participate in the entire course of tumor development and execute momentous impacts. Therefore, manipulating TAMs has been identified as an expecting strategy with immense potential for cancer therapy. Herein, a nanodrug delivery system was leveraged for simultaneously targeting tumor cells and M2-type TAMs for efficient colon cancer therapy. The broad-spectrum anticancer chemotherapeutic drug doxorubicin (DOX) was hitchhiked in a mannose-modified bovine serum albumin (MAN-BSA) carrier. The DOX@MAN-BSA nanodrug delivery system was verified to possess feasible physical performances for unhindered systemic circulation and active targeting on colon tumors. DOX@MAN-BSA nanoparticles could be preferentially swallowed by colon tumor cells and M2 TAMs through mannose receptor-mediated endocytosis. Further in vivo antitumor therapy in CT26 colon tumor-bearing mice has achieved remarkable suppression efficacy with satisfactory biosafety. Leveraging the nanodrug delivery system for simultaneously targeting tumor cells and M2 TAMs has contributed a feasible strategy to collaboratively repress the malignant tumor cells and the collusive M2 TAMs for efficient cancer therapy.

The role of ferroptosis in the development of acute and chronic kidney diseases.

Ferroptosis, a novel form of regulated cell death, is characterized by imbalance of intracellular iron and redox systems, resulting from overgeneration of toxic lipid peroxidation products. In recent years, the verified crucial role of ferroptosis has been widely concerned in rudimentary pathogenesis and development of various acute and chronic kidney disease (CKD), comprehending the potential patterns of cell death can afford more reliable bases and principles for treatment and prevention of renal disease. In this review, the regulatory mechanisms of ferroptosis were introduced and the important roles of ferroptosis in diverse renal diseases such as acute kidney injury, CKD, and renal fibrosis were outlined to illuminate the potential of restraining ferroptosis in treatment and prevention of kidney disease.

Buffet-style Cu(II) for enhance disulfiram-based cancer therapy.

Studies have shown that disulfiram (DSF) can combine with Cu2+ to form bis(N, N-diethyldithiocarbamate) copper(II) complex (CuET) as antitumor drugs. However, there is insufficient endogenous Cu2+ dose to eradicate cancer cells selectively. Inspired by the buffet, we use Cu2+ doped hollow zeolitic imidazolate framework nanoparticles (HZIFCu) as the carrier and equipped with DSF and indocyanine green (ICG) and targeted by folic acid (FA) (D&I@HZIFCu-FA) to enhance DSF-based cancer therapy. D&I@HZIFCu-FA could effectively supply Cu2+ by a buffet-style, assisting the "DSF-to-CuET" transformation in the tumor. Additionally, self-supply Cu2+ could convert H2O2 into ·OH by triggering a Fenton-like reaction for chemo-dynamic therapy, and ICG achieves photothermal therapy for tumors under laser irradiation. This work provides a buffet-style for Cu2+ to make DSF a strong candidate for cancer treatment by combining chemotherapy, chemo-dynamic therapy, and photothermal therapy and inspires more research about its applications in tumor therapy.

Co-loaded lapatinib/PAB by ferritin nanoparticles eliminated ECM-detached cluster cells via modulating EGFR in triple-negative breast cancer.

Cancer stem cell (CSC) cluster of triple-negative breast cancer (TNBC) is suggested to be responsible for therapy resistance, metastatic process and cancer recurrence, yet the sensitivity of CSC clusters of TNBC to ferroptosis remains elusive in a great measure. Current research revealed that epidermal growth factor receptor (EGFR) reinforced CD44-mediated TNBC cell clustering, whether blockade of EGFR has synergistic effects on erastin-induced tumor inhibition of CSC clusters is still poorly understood. Here, we found that fraction of CD24lowCD44high cells and size of tumor spheres clearly decreased following EGFR inhibition in TNBC cells. Inhibition of EGFR promoted expression of LC3B-II via YAP/mTOR signaling pathway, indicating that EGFR-mediated autophagy which contributed to ferroptosis. In order to further verify the protective effects of EGFR on ferroptosis induced by small molecules in TNBC cells, pseudolaric acid B (PAB) which led to ferroptosis of malignant cells was selected. In our experiment, lapatinib and PAB cotreatment inhibited TNBC cells viability and restrained formation of tumor spheres, accompanied with a high level of intracellular ROS. To target delivery lapatinib and PAB to TNBC cells, lapatinib/PAB@Ferritin (L/P@Ferritin) nanoparticles were prepared; results of in vitro and in vivo showed a higher tumor suppression efficiency of L/P@Ferritin, highlighting that it might provide a new perspective for treatment of CSC clusters of TNBC.

CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability.

BRCA1 is frequently down-regulated in breast cancer, the underlying mechanism is unclear. Here we identified DCAF8L1, an X-linked gene product, as a DDB1-Cullin associated Factor (DCAF) for CUL4 E3 ligases to target BRCA1 and BARD1 for proteasomal degradation. Forced expression of DCAF8L1 caused reduction of BRCA1 and BARD1, and impaired DNA damage repair function, conferring increased sensitivity to irradiation and DNA damaging agents, as well as Olaparib, a PARPi anticancer drug; while depletion of DCAF8L1 restored BRCA1 and suppressed the growth of its xenograft tumors. Furthermore, the expression of DCAF8L1 was induced in human H9 ES cells during transition from primed to naïve state when Xi chromosome was reactivated. Aberrant expression of DCAF8L1 was observed in human breast fibroadenoma and breast cancer. These findings suggest that CRL4DCAF8L1 is an important E3 ligase that may participate in the development of breast cancer, probably through regulating the stability of BRCA1 and BARD1 tumor suppressor, linking BRCA1 and X chromosome inactivation to breast carcinogenesis.

Simultaneous manipulation of transcriptional regulator CxrC and translational elongation factor eEF1A enhances the production of plant-biomass-degrading enzymes of Penicillium oxalicum.

Genetic engineering is an efficient approach to improve fungal bioproducts, but the specific targets are limited. In this study, it was found that the key transcription repressor CxrC of Penicillium oxalicum could physically interact with the translational elongation factor eEF1A that positively regulated the production of plant-biomass-degrading enzymes by the fungus under Avicel induction. Simultaneously deletion of the cxrC and overexpression of the eEF1A in the strain Δku70 resulted in 55.4%-314.6% higher production of cellulase, xylanase and raw-starch-degrading enzymes than that of the start strain Δku70. Transcript abundance of the genes encoding predominant cellulases, xylanases and raw-starch-degrading enzymes were significantly upregulated in the mutant ΔcxrC::eEF1A. The ΔcxrC::eEF1A enhanced saccharification efficiency of raw cassava flour by 9.3%-15.5% at early-middle stage of hydrolysis in comparison with Δku70. The obtained knowledges expanded the sources used as effective targets for increased production of plant-biomass-degrading enzymes by fungi.

CREB1 transcription-activated lncRNA PVT1 promotes cardiac fibrosis via miR-145/HCN1 axis.

BACKGROUND: Cardiac fibrosis is a common pathological process of most cardiac diseases, which may result in cardiac function impairment. Long noncoding RNAs (lncRNAs) have been verified as crucial regulators of cardiac fibrosis. This study explored the function and molecular mechanism of PVT1 in cardiac fibrosis. METHODS: TGF-ß1-exposed human cardiac fibroblasts (HCF-a) and isoproterenol (ISO)-treated mice were used as the in vitro and in vivo cardiac fibrosis models. PVT1, miR-145, and HCN1 expression was determined by quantitative RT-PCR. Cell proliferation was evaluated by CCK-8 and EdU fluorescence staining. α-SMA and collagen I expression was assessed by immunohistochemical staining and immunofluorescence staining. Protein levels of fibrosis-related factors were assessed by Western blotting. The interaction between miR-145 and PVT1/HCN1 was evaluated by dual luciferase assay. ChIP assay was used to validate the binding of CREB1 to the promoter of PVT1. Cardiac fibrosis in mice was observed by H&E and Masson's trichrome staining. RESULTS: PVT1 and HCN1 were up-regulated, while miR-145 was down-regulated in the cardiac fibrosis models. PVT1 knockdown restrained TGF-ß1-induced proliferation and activation of HCF-a cells. CREB1 bound to the promoter of PVT1 and activated its transcription. Mechanistically, PVT1 enhanced HCN1 expression via sponging miR-145. Finally, silencing of PVT1 attenuated cardiac fibrosis via regulating miR-145/HCN1 axis in mice in vivo. CONCLUSION: PVT1 contributed to cardiac fibrosis by increasing HCN1 expression via sponging miR-145, which suggested that targeting PVT1 may be a therapeutic option for cardiac fibrosis and cardiac diseases.

The Apolipoprotein C1 is involved in breast cancer progression via EMT and MAPK/JNK pathway.

Apolipoprotein C1 (APOC1) is a member of the apolipoprotein family. In recent years, more and more studies have shown that APOC1 participates in the occurrence and development of cancer. However, there is no systematic study about the specific functions and underlying mechanisms of APOC1 in breast carcinogenesis. The APOC1 was found significantly over-expressed in breast cancer tissues. The correlation of APOC1 expression with the prognosis and the clinicopathological characteristics were subsequently analyzed. APOC1 overexpression was correlated with higher TNM stage and positive lymph node metastasis. APOC1 enhanced the proliferation, invasion, and migration ability of breast cancer cell lines (MDA-MB-231 and MCF-7) in vitro. APOC1 inhibited E-cadherin expression and promoted Vimentin's expression, which suggested that APOC1 played a crucial role in the epithelial-mesenchymal transition (EMT) process of the breast cancer cell. Moreover, APOC1 participated in the progression of breast cancer by regulating the JNK/MAPK pathway. Thus, our results demonstrated that APOC1 might be used as a novel biomarker for prognosis and diagnostic in breast cancer patients.

Resveratrol against Cardiac Fibrosis: Research Progress in Experimental Animal Models.

Cardiac fibrosis is a heterogeneous disease, which is characterized by abundant proliferation of interstitial collagen, disordered arrangement, collagen network reconstruction, increased cardiac stiffness, and decreased systolic and diastolic functions, consequently developing into cardiac insufficiency. With several factors participating in and regulating the occurrence and development of cardiac fibrosis, a complex molecular mechanism underlies the disease. Moreover, cardiac fibrosis is closely related to hypertension, myocardial infarction, viral myocarditis, atherosclerosis, and diabetes, which can lead to serious complications such as heart failure, arrhythmia, and sudden cardiac death, thus seriously threatening human life and health. Resveratrol, with the chemical name 3,5,4'-trihydroxy-trans-stilbene, is a polyphenol abundantly present in grapes and red wine. It is known to prevent the occurrence and development of cardiovascular diseases. In addition, it may resist cardiac fibrosis through a variety of growth factors, cytokines, and several cell signaling pathways, thus exerting a protective effect on the heart.

Death-Associated Protein Kinase 1 Regulates Oxidative Stress in Cardiac Ischemia Reperfusion Injury.

To investigate the role of death-associated protein kinase 1 (DAPK1) in cardiac ischemia reperfusion (I/R) in vivo, and to determine whether the process is regulated by nuclear factor E2-associated factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (keap1). Western blot analysis was used to analyze the expression level of DAPK1 at different time points. The hemodynamic parameters and apoptosis of cardiac I/R injury in vivo were observed using DAPK1 knockdown lentivirus. The oxidative stress of I/R in vivo was observed. Nrf2-IN-1 was applied to determine whether the role of DAPK was regulated by Nrf2/keap1. Results show that the DAPK1 expression increased to a peak after 12 h of I/R. Moreover, the level of DAPK1 expression decreased, as determined by Western blot, after DAPK1 knockdown lentivirus administration. In addition, the hemodynamic parameters of the DAPK1-shRNA group were improved. The apoptosis level (Bax, Bcl-2, cleaved caspase-3, and TUNEL staining) increased in the I/R group, and the DAPK1 knockdown lentivirus could reverse the injury. The oxidative stress indices (CK, cTn-1, CAT, LDH, GSH-PX, MDA, and SOD) also improved in the DAPK1-shRNA group. Finally, Nrf2-IN-1 inhibited tNrf2, nNrf2, and Bcl-2 expression and boosted keap1, Bax, and cleaved caspase-3 expression after DAPK1 lentivirus administration. These findings suggest that DAPK1 may regulate the oxidative stress in cardiac I/R, and Nrf2/keap1 may be the downstream target factor of DAPK1.

Fe(II) and Tannic Acid-Cloaked MOF as Carrier of Artemisinin for Supply of Ferrous Ions to Enhance Treatment of Triple-Negative Breast Cancer.

Suppression of tumor development by inducing ferroptosis may provide a potential remedy for triple-negative breast cancer, which is sensitive to intracellular oxidative imbalance. Recently, artemisinin (ART) and its derivatives have been investigated as potential anticancer agents for the treatment of highly aggressive cancers via the induction of ferroptosis by iron-mediated cleavage of the endoperoxide bridge. Owing to its poor water solubility and limited intracellular iron content, it is challenging for further application in antitumor therapy. Herein, we developed ferrous-supply nano-carrier for ART based on tannic acid (TA) and ferrous ion (Fe(II)) coated on the zeolitic imidazolate framework-8 (ZIF) with ART encapsulated (TA-Fe/ART@ZIF) via coordination-driven self-assembly. Drug release experiments showed that ART was not nearly released in pH 7.4, while 59% ART was released in pH 5.0 after 10 h, demonstrating the excellent pH-triggered release. Meanwhile, a high level of intracellular ROS and MDA, accompanied with decreasing GSH and GPX4, displayed a newly developed nano-drug system displayed markedly enhanced ferroptosis. Compared with monotherapy, in vitro and vivo tumor inhibition experiments demonstrated higher efficiency of tumor suppression of TA-Fe/ART@ZIF. This work provides a novel approach to enhance the potency of ferroptotic nano-medicine and new directions for TBNC therapy.