Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization.

BACKGROUND: The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. METHODS: VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [18F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [11C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography. RESULTS: In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. CONCLUSIONS: Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.

Doubly Spiro-Conjugated Chiral Carbocycles Exhibiting SOMO-HOMO Inversion in Persistent Radical Cations.

Persistent chiral organic open-shell systems have captured growing interest due to their potential applications in organic spintronic and optoelectronic devices. Nevertheless, the integration of configurationally stable chirality into an organic open-shell system continues to pose challenges in molecular design. The π-extended skeleton incorporated in spiro-conjugated carbocycles can provide robust chiroptical properties and a significant stabilization of the excited and ionic radical states. However, this approach has been relatively less explored in the design of persistent organic open-shell systems. We report here the (S,S)-, (R,R)-, and meso-isomers of doubly spiro-conjugated carbocycles featuring flat and rigid carbon-bridged para-phenylenevinylene (CPV) of different conjugation lengths connected by two spiro-carbon centers, which we denote D-spiro-CPV for its quasi-dimeric structure. Our synthetic method based on a double lithiation cyclization approach enables facile production of D-spiro-CPV. D-spiro-CPVs exhibit circularly polarized luminescence (CPL) with high fluorescence quantum yields (ΦFL) resulting in a high CPL brightness of 21 M-1 cm-1 and also exhibit high thermal and photostability. The monoradical cation of D-spiro-CPV absorbing near-infrared light is notably persistent, exhibiting a half-life of 570 h under ambient conditions due to doubly spiro-conjugative stabilization. Theoretical and electrochemical studies indicate the radical cation of D-spiro-CPVs presents a non-Aufbau electron filling, exhibiting inversion of the energy level of the singly occupied molecular orbital (SOMO) and the highest (doubly) occupied molecular orbitals with the SOMO level even below the HOMO-1 level (double SHI effect). Our discoveries provide valuable insights into non-Aufbau molecules and the development of configurationally stable, optically active persistent radicals.

Robust, Self-Healing, and Multi-Use Poly(Urethane-Urea-Imide) Elastomer as a Durable Adhesive for Thermal Interface Materials.

Currently, research on thermal interface materials (TIMs) is primarily focused on enhancing thermal conductivity. However, strong adhesion and multifunctionality are also important characteristics for TIMs when pursing more stable interface heat conduction. Herein, a novel poly(urethane-urea-imide) (PUUI) elastomer containing abundant dynamic hydrogen bonds network and reversible disulfide linkages is successfully synthesized for application as a TIM matrix. The PUUI can self-adapt to the metal substrate surface at moderate temperatures (80 °C) and demonstrates a high adhesion strength of up to 7.39 MPa on aluminum substrates attributed its noncovalent interactions and strong intrinsic cohesion. Additionally, the PUUI displays efficient self-healing capability, which can restore 94% of its original mechanical properties after self-healing for 6 h at room temperature. Furthermore, PUUI composited with aluminum nitride and liquid metal hybrid fillers demonstrates a high thermal conductivity of 3.87 W m-1 K-1 while maintaining remarkable self-healing capability and adhesion. When used as an adhesive-type TIM, it achieves a low thermal contact resistance of 22.1 mm2 K W-1 at zero pressure, only 16.7% of that of commercial thermal pads. This study is expected to break the current research paradigm of TIMs and offers new insights for the development of advanced, reliable, and sustainable TIMs.

Inhibition of Wnt Signaling by Atovaquone Inhibits Gastric Cancer and Enhances Chemotherapy Effectiveness Through Activation of Casein Kinase 1α.

Abnormal activation of the Wnt/ß-catenin signaling pathway is a driving force behind the progression of gastric cancer. Atovaquone, known as an antimalarial drug, has emerged as a potential candidate for anti-cancer therapy. This study investigated atovaquone's effects on gastric cancer and its underlying mechanisms. Using gastric cancer cell lines, we found that atovaquone, at concentrations relevant to clinical use, significantly reduced their viability. Notably, atovaquone exhibited a lower effectiveness in reducing the viability of normal gastric cells compared to gastric cancer cells. We further demonstrated that atovaquone inhibited gastric cancer growth and colony formation. Mechanism studies revealed that atovaquone inhibited mitochondrial respiration and induced oxidative stress. Experiments using ρ0 cells, deficient in mitochondrial respiration, indicated a slightly weaker effect of atovaquone on inducing apoptosis compared to wildtype cells. Atovaquone increased phosphorylated ß-catenin at Ser45 and Ser33/37/Thr41, elevated Axin, and reduced ß-catenin. The inhibitory effects of atovaquone on ß-catenin were reversed upon depletion of CK1α. Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer.

Lipoprotein lipase as a target for obesity/diabetes related cardiovascular disease.

Worldwide, the prevalence of obesity and diabetes have increased, with heart disease being their leading cause of death. Traditionally, the management of obesity and diabetes has focused mainly on weight reduction and controlling high blood glucose. Unfortunately, despite these efforts, poor medication management predisposes these patients to heart failure. One instigator for the development of heart failure is how cardiac tissue utilizes different sources of fuel for energy. In this regard, the heart switches from using various substrates, to predominantly using fatty acids (FA). This transformation to using FA as an exclusive source of energy is helpful in the initial stages of the disease. However, over the progression of diabetes this has grave end results. This is because toxic by-products are produced by overuse of FA, which weaken heart function (heart disease). Lipoprotein lipase (LPL) is responsible for regulating FA delivery to the heart, and its function during diabetes has not been completely revealed. In this review, the mechanisms by which LPL regulates fuel utilization by the heart in control conditions and following diabetes will be discussed in an attempt to identify new targets for therapeutic intervention. Currently, as treatment options to directly target diabetic heart disease are scarce, research on LPL may assist in drug development that exclusively targets fuel utilization by the heart and lipid accumulation in macrophages to help delay, prevent, or treat cardiac failure, and provide long-term management of this condition during diabetes.

RACGAP1 drives proliferation, migration and invasion and suppresses autophagy of gastric cancer cells via inhibiting SIRT1/Mfn2.

Objective: Gastric cancer is the most frequent gastrointestinal malignancy with a poor prognosis. Rac GTPase activation protein 1 (RACGAP1) is a novel tumor promotor, whose detailed effect on gastric cancer remains to be further elucidated. Hence, this study identifies the action of RACGAP1 on gastric cancer and investigates the potential mechanism. Methods: RACGAP1 expression in gastric cancer was analyzed based on the data of The Cancer Genome Atlas (TCGA) database. Cell proliferation was measured by CCK-8 and colony formation assay. Cell migration and invasion were evaluated by transwell assay. Cell apoptosis was assessed by flow cytometry. Cell autophagy was evaluated via determining LC3. Results: RACGAP1 presented at high level in gastric cancer cells. Overexpressed RACGAP1 potentiated gastric cancer cell proliferation, migration, and invasion. Besides, silenced RACGAP1 induced cell apoptosis and autophagy. Furthermore, RACGAP1 suppressed the expression of SIRT1 and Mfn2. Conclusion: RACGAP1 was overexpressed in gastric cancer. RACGAP1 potentiated aggressive behaviors of gastric cancer, and suppressed cell apoptosis and autophagy via modulating SIRT1/Mfn2. RACGAP1 may be a valuable target in the treatment of gastric cancer.

Galvanic replacement synthesis of PtPdAu hollow nanorods as peroxidase mimic with high specific activity for colorimetric detection.

Noble metal nanomaterials have been widely demonstrated to possess intrinsic enzyme-like properties and have been increasingly applied in the fields of analysis and biomedicine. However, current exploration of high-activity noble metal nanozymes is still far from adequate. The construction of hollow structures and adjustment of their elemental composition are effective ways to improve the specific activity (SA) of nanozymes. In this study, trimetallic PtPdAu hollow nanorods (HNRs) were developed using a galvanic replacement reaction and Kirkendall effect. The catalytic experiment showed that the PtPdAu HNRs possessed outstanding peroxidase-like performance and their SA value was up to 563.71 U mg-1, which is remarkable among various previously reported nanozymes and higher than that of monometallic or bimetallic counterparts with similar structure and size prepared in this study. Electron paramagnetic resonance (EPR)measurements showed that the PtPdAu HNRs could contribute to the formation of hydroxyl radicals (˙OH) in catalyzing hydrogen peroxide. When using PtPdAu HNRs as a nanozyme in the colorimetric detection of H2O2 and ascorbic acid (AA), the limits of detection were as low as 1.8 µM and 0.068 µM, respectively. This study demonstrates that PtPdAu HNRs are high-activity nanozymes and have the potential to be applied in the field of analysis.

Current and future trends of acupuncture as an adjuvant therapy in cancer: A bibliometric and visual analysis.

BACKGROUND: Acupuncture, as one of the representatives of complementary therapies, is often used as an adjunctive therapy in the treatment of cancer and related complications with beneficial results. METHODS: We selected the Web of Science Core Collection (WOSCC) database as the data source and searched to obtain relevant literatures on the application of acupuncture in cancer treatment. The relevant literature was analyzed using CiteSpace (version 6.1.R6) and VOSviewer (version 1.6.20). RESULTS: A total of 592 publications were included, with an overall upward trend in the number of publications. There were 135 countries or institutions involved, with China as the most published country. There were 1888 related institutions, and Memorial Sloan Kettering Cancer Center was the institution with the most publications. A total of 3067 authors were involved, and there were obvious collaborations between authors. There were 190 related journals, and J Clin Oncol was the most cited journal. The most frequently occurring keywords were breast cancer and management, but also other related topics such as quality of life, chemotherapy, and complementary. CONCLUSION: Acupuncture is gaining increasing attention as an adjunctive therapy in cancer treatment programs. Currently, relevant research focuses on acupuncture to alleviate cancer-induced comorbid symptoms, such as pain and insomnia. Future research is gradually shifting toward spiritual care, Colorectal Cancer Surgery, and systematic review.

C-F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres.

Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements in synthetic methodologies have enabled the rapid adoption of this strategy into drug discovery programs. Consequently, conceptionally innovative practices would be appreciated by the medicinal chemistry community. Here we report an expeditous synthetic method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere of the benzophenone core. This approach involves the merger of light-driven C-F bond activation and strain-release chemistry under the catalysis of a newly designed N-anionic-based organic photocatalyst. This defluorinative coupling methodology enables the direct conversion of a wide variety of commercially available trifluoromethylaromatic C-F bonds (more than 70 examples) into the corresponding difluoromethyl bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates in a single step. The strategy can also be applied to [3.1.1]and [4.1.1]propellane systems, providing access to analogues with different geometries. Moreover, we have successfully used this protocol to rapidly prepare ADB-substituted analogues of the bioactive molecule Adiporon. Biological testing has shown that the ADB scaffold has the potential to enhance the pharmacological properties of benzophenone-type drug candidates.

Structural engineering of Pt-on-Rh hollow nanorods with high-performance peroxidase-like specific activity for colorimetric detection.

The preparation of nanozymes with high specific activity is highly important for various applications. However, only a few nanozymes have specific activities comparable to natural enzymes. Herein, novel Pt-on-Rh hollow nanorods (PtRh HNRs) were developed, in which surface Pt exhibited adjustable dispersity and interior Rh served as the support. The optimized PtRh HNRs demonstrated high-performance peroxidase (POD)-like activity, with a specific activity as high as 1352 U mg-1, which was 3.86 times that of their monometallic Pt counterparts. Density functional theory (DFT) calculations illustrated that the presence of Rh decreased the energy barrier of the rate-determining step. When PtRh HNRs were used as nanozymes in the colorimetric detection of hydrogen peroxide (H2O2) and ascorbic acid (AA), the limits of detection (LODs) were as low as 9.97 µM and 0.039 µM, respectively. The current work highlights a facile and powerful strategy for manufacturing nanozymes with high specific activity and demonstrates that the prepared PtRh HNRs have the potential for analysis and determination.

Efficacy of endovascular therapy for cerebral vasospasm following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

Background: Cerebral vasospasm (CV) is a common complication of aneurysmal subarachnoid hemorrhage (aSAH), leading to increased morbidity and mortality rates. Endovascular therapy, particularly intra-arterial vasodilator infusion (IAVI), has emerged as a potential alternative treatment for CV. Methods: A systematic review and meta-analysis were conducted to compare the efficacy of endovascular therapy with standard treatment in patients with CV following aSAH. The primary outcomes assessed were in-hospital mortality, discharge favorable outcome, and follow-up favorable outcome. Secondary outcomes included major infarction on CT, ICU stay duration, and total hospital stay. Results: Regarding our primary outcomes of interest, patients undergoing intervention exhibited a significantly lower in-hospital mortality compared to the standard treatment group, with the intervention group having only half the mortality risk (RR = 0.49, 95% CI [0.29, 0.83], p = 0.008). However, there were no significant differences between the two groups in terms of discharge favorable outcome (RR = 0.99, 95% CI [0.68, 1.45], p = 0.963) and follow-up favorable outcome (RR = 1.09, 95% CI [0.86, 1.39], p = 0.485). Additionally, there was no significant difference in major infarction rates (RR = 0.79, 95% CI [0.34, 1.84], p = 0.588). It is important to note that patients undergoing endovascular treatment experienced longer stays in the ICU (MD = 6.07, 95% CI [1.03, 11.12], p = 0.018) and extended hospitalization (MD = 5.6, 95% CI [3.63, 7.56], p < 0.001). Subgroup analyses based on the mode of endovascular treatment further supported the benefits of IAVI in lowering in-hospital mortality (RR = 0.5, 95% CI [0.27, 0.91], p = 0.023). Conclusion: Endovascular therapy, particularly IAVI, holds promising potential in reducing in-hospital mortality for patients with CV following aSAH. However, it did not show significant improvement in long-term prognosis and functional recovery. Further research with larger sample sizes and randomized controlled trials is necessary to validate these findings and optimize the treatment strategy for cerebral vasospasm in aSAH patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42023451741.

Multi-Functional Spirobifluorene Phosphonate Based Exciplex Interface Enables Voc Reaching 95% of Theoretical Limit for Perovskite Solar Cells.

Metal halide perovskite solar cells (PSCs) show significant advancements in power conversion efficiency (PCE). However, the open-circuit voltage (VOC) of PSCs is limited by interfacial factors such as defect-induced recombination, energy band mismatch, and non-intimate interface contact. Here, an exciplex interface is first developed based on the strategically designed and synthesized two spirobifluorene phosphonate molecules to mitigate VOC loss in PSCs. The exciplex interface constructed by the intimate contact between the multi-functional molecules and hole transport layer takes the roles to promote the hole extraction by donor-acceptor interaction, passivate coordination-unsaturated Pb2+ defects by equipped phosphonate groups, and optimize the energy level alignment. As a result, a record VOC of 1.26 V with a perovskite bandgap of 1.61 eV is achieved, representing over 95% of theoretical limit. This advancement leads to an increase in PCE from 21.29% to 24.12% and improved stability. The exciplex interface paves the way for addressing the long-standing challenge of VOC loss and promotes the wider application of PSCs.

Characterization of key aroma compounds in a novel Chinese rice wine Xijiao Huojiu during its biological-ageing-like process by untargeted metabolomics.

Xijiao Huojiu (Xijiao), an ancient Chinese rice wine (ACRW), is produced using traditional methods, which involve biological-ageing-like process and result in distinctive sensory profiles. However, its aroma composition is still unclear. In this study, the aroma characteristics of three samples with varying ageing times were examined. Xijiao_SCT, with a short cellar time, exhibited a strong fruity and floral aroma and a less grain-like aroma. Conversely, Xijiao_LCT, which had a long cellar time, had a deep cocoa- and caramel-like aroma. A total of 27 key odorants that greatly influenced the aroma characteristics of Xijiao were identified. Comparative studies were used to identify 12 key odorants that distinguish Xijiao from modern Chinese rice wine (MCRW) and grape wines (GW). Additionally, 13 dominant latent ageing markers differentiated Xijiao_SCT from Xijiao_LCT. Our results suggested that ACRW and MCRW have overlapping but distinct volatile metabolomic profiles, highlighting the characteristics of ACRW during ageing process.

Heparanase Stimulation of Physiologic Cardiac Hypertrophy Is Suppressed After Chronic Diabetes, Resulting in Cardiac Remodeling and Dysfunction.

In addition to controlling smooth muscle tone in coronary vessels, endothelial cells also influence subjacent cardiomyocyte growth. Because heparanase, with exclusive expression in endothelial cells, enables extracellular matrix remodeling, angiogenesis, metabolic reprogramming, and cell survival, it is conceivable that it could also encourage development of cardiac hypertrophy. Global heparanase overexpression resulted in physiologic cardiac hypertrophy, likely an outcome of HSPG clustering and activation of hypertrophic signaling. The heparanase autocrine effect of releasing neuregulin-1 could have also contributed to this overexpression. Hyperglycemia induced by streptozotocin-induced diabetes sensitized the heart to flow-induced release of heparanase and neuregulin-1. Despite this excess secretion, progression of diabetes caused significant gene expression changes related to mitochondrial metabolism and cell death that led to development of pathologic hypertrophy and heart dysfunction. Physiologic cardiac hypertrophy was also observed in rats with cardiomyocyte-specific vascular endothelial growth factor B overexpression. When perfused, hearts from these animals released significantly higher amounts of both heparanase and neuregulin-1. However, subjecting these animals to diabetes triggered robust transcriptome changes related to metabolism and a transition to pathologic hypertrophy. Our data suggest that in the absence of mechanisms that support cardiac energy generation and prevention of cell death, as seen after diabetes, there is a transition from physiologic to pathologic cardiac hypertrophy and a decline in cardiac function.