Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis.

Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.

Versatile Landscape of Low-k Polyimide: Theories, Synthesis, Synergistic Properties, and Industrial Integration.

The development of microelectronics and large-scale intelligence nowadays promotes the integration, miniaturization, and multifunctionality of electronic and devices but also leads to the increment of signal transmission delays, crosstalk, and energy consumption. The exploitation of materials with low permittivity (low-k) is crucial for realizing innovations in microelectronics. However, due to the high permittivity of conventional interlayer dielectric material (k ∼ 4.0), it is difficult to meet the demands of current microelectronic technology development (k < 3.0). Organic dielectric materials have attracted much attention because of their relatively low permittivity owing to their low material density and low single bond polarization. Polyimide (PI) exhibits better application potential based on its well permittivity tunability (k = 1.1-3.2), high thermal stability (>500 °C), and mechanical property (modulus of elasticity up to 3.0-4.0 GPa). In this review, based on the synergistic relationship of dielectric parameters of materials, the development of nearly 20 years on low-k PI is thoroughly summarized. Moreover, process strategies for modifying low-k PI at the molecular level, multiphase recombination, and interface engineering are discussed exhaustively. The industrial application, technological challenges, and future development of low-k PI are also analyzed, which will provide meaningful guidance for the design and practical application of multifunctional low-k materials.

Highly oxidized guaiane 12(8),15(6)-dilactones with neuroprotective activities from the roots of Lindera aggregata (Sims) Kosterm.

In our search for neuroprotective agents, six previously undescribed highly oxidized guaiane sesquiterpenes, linderaggrols A-F (1-6), together with three known sesquiterpenes, were isolated from the roots of Lindera aggregata (Sims) Kosterm. Their structures including absolute configurations were established by a combination of NMR spectroscopic techniques and single crystal X-ray diffraction experiments. Compounds 1-6 represented the first instances of guaiane 12(8),15(6)-dilactones. Additionally, compound 6 possessed a rare 1,8-O-bridge. Neuroprotective effects against erastin-induced ferroptosis on HT-22 cells showed that some compounds demonstrated neuroprotective effects at 20.0 µM.

Risk factors for postpartum posttraumatic stress disorder after emergency admission.

BACKGROUND: Postpartum posttraumatic stress disorder (PTSD) can occur in women who give birth after emergency admission. The identification of risk factors for this condition is crucial for developing effective preventive measures. This retrospective study aimed to explore the incidence and risk factors for postpartum PTSD in women who give birth after emergency admission. METHODS: Medical records of women who gave birth after emergency admission were collected between March 2021 and April 2023. The patients' general conditions and perinatal clinical indicators were recorded. The puerperae were divided into PTSD group and control group based on symptom occurrence at six weeks postpartum. Multivariate logistic regression analysis was performed to identify risk factors. RESULTS: A total of 276 puerperae were included, with a PTSD incidence of 20.3% at six weeks postpartum. Multivariate logistic regression analysis identified emergency cesarean section (odds ratio [OR]=2.102; 95% confidence interval [CI]: 1.114-3.966, P=0.022), admission to the emergency department after midnight (12:00 AM) (OR=2.245; 95%CI: 1.170-4.305, P<0.001), and cervical dilation (OR=3.203; 95%CI: 1.670-6.141, P=0.039) as independent risk factors for postpartum PTSD. Analgesia pump use (OR= 0.500; 95%CI: 0.259-0.966, P=0.015) was found to be a protective factor against postpartum PTSD. CONCLUSION: Emergency cesarean section, admission to the emergency department after midnight, and cervical dilation were identified as independent risk factors for postpartum PTSD, while analgesic pump use was a protective factor. These findings provide insights for developing more effective preventive measures for women who give birth after emergency admission.

Advanced Dielectric Materials for Triboelectric Nanogenerators: Principles, Methods, and Applications.

Triboelectric nanogenerator (TENG) manifests distinct advantages such as multiple structural selectivity, diverse selection of materials, environmental adaptability, low cost, and remarkable conversion efficiency, which becomes a promising technology for micro-nano energy harvesting and self-powered sensing. Tribo-dielectric materials are the fundamental and core components for high-performance TENGs. In particular, the charge generation, dissipation, storage, migration of the dielectrics, and dynamic equilibrium behaviors determine the overall performance. Herein, a comprehensive summary is presented to elucidate the dielectric charge transport mechanism and tribo-dielectric material modification principle toward high-performance TENGs. The contact electrification and charge transport mechanism of dielectric materials is started first, followed by introducing the basic principle and dielectric materials of TENGs. Subsequently, modification mechanisms and strategies for high-performance tribo-dielectric materials are highlighted regarding physical/chemical, surface/bulk, dielectric coupling, and structure optimization. Furthermore, representative applications of dielectric materials based TENGs as power sources, self-powered sensors are demonstrated. The existing challenges and promising potential opportunities for advanced tribo-dielectric materials are outlined, guiding the design, fabrication, and applications of tribo-dielectric materials.

High-toughness, extensile and self-healing PDMS elastomers constructed by decuple hydrogen bonding.

Elastomers are widely used in traditional industries and new intelligent fields. However, they are inevitably damaged by electricity, heat, force, etc. during the working process. With the continuous improvement of reliability and environmental protection requirements in human production and living, it is vital to develop elastomer materials with good mechanical properties that are not easily damaged and can self-heal after being damaged. Nevertheless, there are often contradictions between mechanical properties and self-healing as well as toughness, strength, and ductility. Herein, a strong and dynamic decuple hydrogen bonding based on carbon hydrazide (CHZ) is reported, accompanied with soft polydimethylsiloxane (PDMS) chains to prepare self-healing (efficiency 98.7%), recyclable, and robust elastomers (CHZ-PDMS). The strategy of decuple hydrogen bonding will significantly impact the study of the mechanical properties of elastomers. High stretchability (1731%) and a high toughness of 23.31 MJ m-3 are achieved due to the phase-separated structure and energy dissipation. The recyclability of CHZ-PDMS further supports the concept of environmental protection. The application of CHZ-PDMS as a flexible strain sensor exhibited high sensitivity.

Electrochemical Reductive Cross-Coupling of Vinyl Bromides for the Synthesis of 1,3-Dienes.

An electroreductive cross-electrophile coupling protocol was developed for the construction of valuable 1,3-dienes from vinyl bromides. Furthermore, this scalable method can also be used to forge complex [4 + 2] cycloadducts in a one-pot manner. One of the most important advantages of this green and sustainable protocol is the in situ release of nickel catalyst from the inexpensive electrodes without the addition of extra harmful metal catalysts and reductant.

Natural product-derived ferroptosis mediators.

It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future.

Dual-Effect Coupling for Superior Dielectric and Thermal Conductivity of Polyimide Composite Films Featuring "Crystal-Like Phase" Structure.

To match the increasing miniaturization and integration of electronic devices, higher requirements are put on the dielectric and thermal properties of the dielectrics to overcome the problems of delayed signal transmission and heat accumulation. Here, a 3D  porous thermal conductivity network is successfully constructed inside the polyimide (PI) matrix by the combination of ionic liquids (IL) and calcium fluoride (CaF2 ) nanofillers, motivated by the bubble-hole forming orientation force. Benefiting from the 3D thermal network formed by IL as a porogenic template and "crystal-like phase" structures induced by CaF2 - polyamide acid charge transfer, IL-10 vol% CaF2 /PI porous film exhibits a low permittivity of 2.14 and a thermal conductivity of 7.22 W m-1 K-1 . This design strategy breaks the bottleneck that low permittivity and high thermal conductivity in microelectronic systems are difficult to be jointly controlled, and provides a feasible solution for the development of intelligent microelectronics.

Rare 7,9'-dinorlignans with neuroprotective activity from the roots of Lindera aggregata (Sims) Kosterm.

Linderagatins C-F (1-4), the first examples of naturally occurring diaryltetrahydrofuran-type 7,9'-dinorlignans, were characterized from the roots of Lindera aggregata (Sims) Kosterm. The structures of these dinorlignans were elucidated by extensive spectroscopic analysis. The absolute configurations were determined based on calculated and experimental ECD data. A biosynthetic pathway for these dinorlignans was hypothetically proposed. Compounds 2 and 3 showed significant neuroprotective effects on erastin-induced ferroptosis in HT-22 cells with EC50 values of 23.4 and 21.8 µM, respectively.

Anisodamine hydrobromide in the treatment of critically ill patients with septic shock: a multicenter randomized controlled trial.

BACKGROUND: Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. METHODS: This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. RESULTS: Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. CONCLUSION: Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

Intrinsic-designed polyimide dielectric materials with large energy storage density and discharge efficiency at harsh ultra-high temperatures.

Polymer dielectric materials with excellent temperature stability are urgently needed for the ever-increasing energy storage requirements under harsh high-temperature conditions. In this work, a novel diamine monomer (bis(2-cyano-4-aminophenyl)amine) was successfully synthesized to prepare a series of cyano-containing polyimides (CPI-1-3), which possessed excellent dielectric properties and high thermostability. The maximum dielectric permittivity was up to 5.5 at 102 Hz for CPI-3, being 2.5 times higher than that of commercially used BOPP. In comparison, the CPI-1 exhibited an outstanding breakdown strength of 433 MV m-1 and a high energy density of 2.5 J cm-3 even at 250 °C, which was the highest value reported under the same conditions. The synthesized CPIs through such an intrinsic approach are potential candidate materials for energy storage and even other applications under simultaneously harsh electrical and thermal conditions.

Structurally Diverse Sesquiterpenoids from the Genus of Ainsliaea.

The genus of Ainsliaea embraces approximately 70 recognized species, many of which have been used to treat various diseases in folklore medicines. As the main metabolites of Ainsliaea plants, Ainsliaea sesquiterpenoids have drawn considerable attention in related scientific communities due to their intriguing structures and a variety of bioactivities. In this review, we intend to provide a full-aspect coverage of sesquiterpenoids reported from the genus of Ainsliaea, including 145 monomeric sesquiterpenoids and 30 oligomeric ones. Multiple aspects will be summarized, including their classification, distributions, structures, bioactivities, and biomimetic syntheses. In addition, their possible biosynthetic pathway will be discussed in detail.

An imaging-based machine learning model outperforms clinical risk scores for prognosis of cirrhotic variceal bleeding.

OBJECTIVES: To develop and validate a machine learning model based on contrast-enhanced CT to predict the risk of occurrence of the composite clinical endpoint (hospital-based intervention or death) in cirrhotic patients with acute variceal bleeding (AVB). METHODS: This retrospective study enrolled 330 cirrhotic patients with AVB between January 2017 and December 2020 from three clinical centers. Contrast-enhanced CT and clinical data were collected. Centers A and B were divided 7:3 into a training set and an internal test set, and center C served as a separate external test set. A well-trained deep learning model was applied to segment the liver and spleen. Then, we extracted 106 original features of the liver and spleen separately based on the Image Biomarker Standardization Initiative (IBSI). We constructed the Liver-Spleen (LS) model based on the selected radiomics features. The performance of LS model was evaluated by receiver operating characteristics and calibration curves. The clinical utility of models was analyzed using decision curve analyses (DCA). RESULTS: The LS model demonstrated the best diagnostic performance in predicting the composite clinical endpoint of AVB in patients with cirrhosis, with an AUC of 0.782 (95% CI 0.650-0.882) and 0.789 (95% CI 0.674-0.878) in the internal test and external test groups, respectively. Calibration curves and DCA indicated the LS model had better performance than traditional clinical scores. CONCLUSION: A novel machine learning model outperforms previously known clinical risk scores in assessing the prognosis of cirrhotic patients with AVB CLINICAL RELEVANCE STATEMENT: The Liver-Spleen model based on contrast-enhanced CT has proven to be a promising tool to predict the prognosis of cirrhotic patients with acute variceal bleeding, which can facilitate decision-making and personalized therapy in clinical practice. KEY POINTS: • The Liver-Spleen machine learning model (LS model) showed good performance in assessing the clinical composite endpoint of cirrhotic patients with AVB (AUC ≥ 0.782, sensitivity ≥ 80%). • The LS model outperformed the clinical scores (AUC ≤ 0.730, sensitivity ≤ 70%) in both internal and external test cohorts.

Dynamic Covalent Adaptable Polyimide Hybrid Dielectric Films with Superior Recyclability.

Polyimides (PIs) used in advanced electrical and electronic devices can be electrically/mechanically damaged, resulting in a significant waste of resources. Closed-loop chemical recycling may prolong the service life of synthetic polymers. However, the design of dynamic covalent bonds for preparing chemically recyclable crosslinked PIs remains a challenging task. Herein, new crosslinked PI films containing a PI oligomer, chain extender, and crosslinker are reported. They exhibit superior recyclability and excellent self-healable ability owing to the synergistic effect of the chain extender and crosslinker. The produced films can be completely depolymerized in an acidic solution at ambient temperature, leading to efficient monomer recovery. The recovered monomers may be used to remanufacture crosslinked PIs without deteriorating their original performance. In particular, the designed films can serve as corona-resistant films with a recovery rate of approximately 100%. Furthermore, carbon fiber reinforced composites (CFRCs) with PI matrices are suitable for harsh environments and can be recycled multiple times at a non-destructive recycling rate up to 100%. The preparation of high-strength dynamic covalent adaptable PI hybrid films from simple PI oligomers, chain extenders, and crosslinkers may provide a solid basis for sustainable development in the electrical and electronic fields.

[Research progress on chemical structures and pharmacological effects of natural cytisine and its derivatives].

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.

Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy.

Myocardial fibrosis is the characteristic pathology of diabetes-induced cardiomyopathy. Therefore, an in-depth study of cardiac heterogeneity and cell-to-cell interactions can help elucidate the pathogenesis of diabetic myocardial fibrosis and identify treatment targets for the treatment of this disease. In this study, we investigated intercellular communication drivers of myocardial fibrosis in mouse heart with high-fat-diet/streptozotocin-induced diabetes at single-cell resolution. Intercellular and protein-protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells revealed critical changes in ligand-receptor interactions such as Pdgf(s)-Pdgfra and Efemp1-Egfr, which promote the development of a profibrotic microenvironment during the progression of and confirmed that the specific inhibition of the Pdgfra axis could significantly improve diabetic myocardial fibrosis. We also identified phenotypically distinct Hrchi and Postnhi fibroblast subpopulations associated with pathological extracellular matrix remodeling, of which the Hrchi fibroblasts were found to be the most profibrogenic under diabetic conditions. Finally, we validated the role of the Itgb1 hub gene-mediated intercellular communication drivers of diabetic myocardial fibrosis in Hrchi fibroblasts, and confirmed the results through AAV9-mediated Itgb1 knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers involved in pathological extracellular matrix remodeling during diabetic myocardial fibrosis.

Predicting Microvascular Invasion in Hepatocellular Carcinoma Using CT-based Radiomics Model.

Background Prediction of microvascular invasion (MVI) may help determine treatment strategies for hepatocellular carcinoma (HCC). Purpose To develop a radiomics approach for predicting MVI status based on preoperative multiphase CT images and to identify MVI-associated differentially expressed genes. Materials and Methods Patients with pathologically proven HCC from May 2012 to September 2020 were retrospectively included from four medical centers. Radiomics features were extracted from tumors and peritumor regions on preoperative registration or subtraction CT images. In the training set, these features were used to build five radiomics models via logistic regression after feature reduction. The models were tested using internal and external test sets against a pathologic reference standard to calculate area under the receiver operating characteristic curve (AUC). The optimal AUC radiomics model and clinical-radiologic characteristics were combined to build the hybrid model. The log-rank test was used in the outcome cohort (Kunming center) to analyze early recurrence-free survival and overall survival based on high versus low model-derived score. RNA sequencing data from The Cancer Image Archive were used for gene expression analysis. Results A total of 773 patients (median age, 59 years; IQR, 49-64 years; 633 men) were divided into the training set (n = 334), internal test set (n = 142), external test set (n = 141), outcome cohort (n = 121), and RNA sequencing analysis set (n = 35). The AUCs from the radiomics and hybrid models, respectively, were 0.76 and 0.86 for the internal test set and 0.72 and 0.84 for the external test set. Early recurrence-free survival (P < .01) and overall survival (P < .007) can be categorized using the hybrid model. Differentially expressed genes in patients with findings positive for MVI were involved in glucose metabolism. Conclusion The hybrid model showed the best performance in prediction of MVI. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Summers in this issue.

Rising of Dynamic Polyimide Materials: A Versatile Dielectric for Electrical and Electronic Applications.

Polyimides (PIs) are widely used in circuit components, electrical insulators, and power systems in modern electronic devices and large electrical appliances. Electrical/mechanical damage of materials are important factors that threaten reliability and service lifetime. Dynamic (self-healable, recyclable and degradable) PIs, a promising class of materials that successfully improve electrical/mechanical properties after damage, are anticipated to solve this issue. The viewpoints and perspectives on the status and future trends of dynamic PI based on a few existing documents are shared. The main damage forms of PI dielectric materials in the application process are first introduced, and initial strategies and schemes to solve these problems are proposed. Fundamentally, the bottleneck issues faced by the development of dynamic PIs are indicated, and the relationship between various damage forms and the universality of the method is evaluated. The potential mechanism of the dynamic PI to deal with electrical damage is highlighted and several feasible prospective schemes to address electrical damage are discussed. This study is concluded by presenting a short outlook and future improvements to systems, challenges, and solutions of dynamic PI in electrical insulation. The summary of theory and practice should encourage policy development favoring energy conservation and environmental protection and promoting sustainability.