Targeting Macrophage Phenotypes and Metabolism as Novel Therapeutic Approaches in Atherosclerosis and Related Cardiovascular Diseases.

PURPOSE OF THE REVIEW: Macrophage accumulation and activation function as hallmarks of atherosclerosis and have complex and intricate dynamics throughout all components and stages of atherosclerotic plaques. In this review, we focus on the regulatory roles and underlying mechanisms of macrophage phenotypes and metabolism in atherosclerosis. We highlight the diverse range of macrophage phenotypes present in atherosclerosis and their potential roles in progression and regression of atherosclerotic plaque. Furthermore, we discuss the challenges and opportunities in developing therapeutic strategies for preventing and treating atherosclerotic cardiovascular disease. RECENT FINDINGS: Dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypealters the immuno-inflammatory response during atherosclerosis progression, leading to plaque initiation, growth, and ultimately rupture. Altered metabolism of macrophage is a key feature for their function and the subsequent progression of atherosclerotic cardiovascular disease. The immunometabolism of macrophage has been implicated to macrophage activation and metabolic rewiring of macrophages within atherosclerotic lesions, thereby shifting altered macrophage immune-effector and tissue-reparative function. Targeting macrophage phenotypes and metabolism are potential therapeutic strategies in the prevention and treatment of atherosclerosis and atherosclerotic cardiovascular diseases. Understanding the precise function and metabolism of specific macrophage subsets and their contributions to the composition and growth of atherosclerotic plaques could reveal novel strategies to delay or halt development of atherosclerotic cardiovascular diseases and their associated pathophysiological consequences. Identifying biological stimuli capable of modulating macrophage phenotypes and metabolism may lead to the development of innovative therapeutic approaches for treating patients with atherosclerosis and coronary artery diseases.

Pd(II)-Catalyzed C4-Selective Alkynylation of Indoles by a Transient Directing Group.

With alanine as a transient directing group, Pd-catalyzed regioselective alkynylation at the indole C4-position was successfully established in a good yield. The total synthesis of the PAF antagonist demonstrated the synthetic utility of this protocol. The regioselectivity was explicitly proven by the prepared C4-selective palladacycle intermediate in the catalytic process and the DFT calculation of the energy barriers of C4- and C2-site-selective C-H activation of indole.

The fusion of vegetation indices increases the accuracy of cotton leaf area prediction.

Introduction: Rapid and accurate estimation of leaf area index (LAI) is of great significance for the precision agriculture because LAI is an important parameter to evaluate crop canopy structure and growth status. Methods: In this study, 20 vegetation indices were constructed by using cotton canopy spectra. Then, cotton LAI estimation models were constructed based on multiple machine learning (ML) methods extreme learning machine (ELM), random forest (RF), back propagation (BP), multivariable linear regression (MLR), support vector machine (SVM)], and the optimal modeling strategy (RF) was selected. Finally, the vegetation indices with a high correlation with LAI were fused to construct the VI-fusion RF model, to explore the potential of multi-vegetation index fusion in the estimation of cotton LAI. Results: The RF model had the highest estimation accuracy among the LAI estimation models, and the estimation accuracy of models constructed by fusing multiple VIs was higher than that of models constructed based on single VIs. Among the multi-VI fusion models, the RF model constructed based on the fusion of seven vegetation indices (MNDSI, SRI, GRVI, REP, CIred-edge, MSR, and NVI) had the highest estimation accuracy, with coefficient of determination (R2), rootmean square error (RMSE), normalized rootmean square error (NRMSE), and mean absolute error (MAE) of 0.90, 0.50, 0.14, and 0.26, respectively. Discussion: Appropriate fusion of vegetation indices can include more spectral features in modeling and significantly improve the cotton LAI estimation accuracy. This study will provide a technical reference for improving the cotton LAI estimation accuracy, and the proposed method has great potential for crop growth monitoring applications.

Fc receptor-like A promotes malignant behavior in renal cell carcinoma and correlates with tumor immune infiltration.

BACKGROUND: Our study aims to investigate the mechanisms through which Fc receptor-like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration. MATERIALS AND METHODS: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein-protein interaction (PPI) network analyses were performed for FCRLA and its co-expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy. RESULTS: Fc receptor-like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1-3- and 5-year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA-RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/-MMP2 pathway and was associated with tumor immune microenvironment in RCC. CONCLUSION: Fc receptor-like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2-MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.

Water-soluble biodegradable polyesters with pH and ionic responsivity.

The synthesis of novel water-soluble polymers with biodegradability is an effective way to mitigate their negative environmental impacts. In this study, semi-aromatic copolyester poly(butylene succinate-co-butylene terephthalate) (PBST) with exceptional biodegradability is used as the resin matrix. Anionic sodium 1-3-isophthalate-5-sulfonate (SIPA) is introduced as a fourth monomer to prepare random poly(butylene succinate-co-butylene terephthalate-co-butylene 5-sodiosulfoisophthalate) (PBSTS) copolyesters by melt copolymerization. The incorporation of ionic groups enhances the hydrophilicity and water absorption of the copolyesters, resulting in water-soluble materials that exhibit ionic and temperature responsivity. Furthermore, the ionized biodegradable copolyesters demonstrate distinct pH-dependent degradation, which is accelerated at pH = 5.5 and 8.5 but inhibited at pH = 7.2. Degradation assessments in simulated body fluids reveal that the PBSTS copolyesters exhibit significant degradation in gastric fluids at pH = 1.5 with minimal degradation in intestinal fluids at pH = 6.8 and in body fluids at pH = 7.0. This unique degradation performance highlights the potential of these materials for addressing the challenges associated with selective drug delivery and localized controlled release in the human body.

Superalloys fracture process inference based on overlap analysis of 3D models.

Superalloy materials exhibit susceptibility to fracture failures stemming from the influence of thermomechanical factors. To comprehensively understand the fracture mechanisms, material properties, root causes of failure, and the subsequent optimization of alloys, a detailed analysis of the internal fracture process and the morphological traits of the fracture surface is imperative. Traditional analysis of fracture surfaces solely relies on 2D images, thus lacking crucial 3D information. Although in situ experiments can capture the fracture process, their effectiveness is confined to the specimen's surface, precluding insight into internal changes. Here we introduce an integrated framework encompassing the process of 3D reconstruction of fracture surfaces, aiming to enhance the visual information obtained with micron-level accuracy, visual intuitiveness and sense of depth. Additionally, this framework also facilitates the scrutiny and inference of internal fracture processes. These results demonstrate that under specific service conditions, material deformation fracture probably stems from a combination of surface cracking and internal cracking rather than exclusively one or the other. Overall, our description and analysis of internally initiated cracking due to defects within the specimens can be beneficial in guiding future alloy design and optimization efforts.

An innovative anti-rotation tension band wiring for treating transverse patellar fractures: finite element analysis and mechanical testing.

BACKGROUND: The displacement and rotation of the Kirschner wire (K-wire) in the traditional tension band wiring (TBW) led to a high rate of postoperative complications. The anti-rotation tension band wiring (ARTBW) could address these issues and achieve satisfactory clinical outcomes. This study aimed to investigate the biomechanical performance of the ARTBW in treating transverse patellar fracture compared to traditional TBW using finite element analysis (FEA) and mechanical testing. METHODS: We conducted a FEA to evaluate the biomechanical performance of traditional TBW and ARTBW at knee flexion angles of 20°, 45°, and 90°. Furthermore, we compared the mechanical properties under a 45° knee flexion through static tensile tests and dynamic fatigue testing. The K-wire pull-out test was also conducted to evaluate the bonding strength between K-wires and cancellous bone of two surgical approaches. RESULTS: The outcome of FEA demonstrated the compression force on the articular surface of ARTBW was 28.11%, 27.32%, and 52.86% higher than traditional TBW at knee flexion angles of 20°, 45°, and 90°, respectively. In mechanical testing, the mechanical properties of ARTBW were similar to the traditional TBW. In the K-wire pull-out test, the pull-out strength of ARTBW was significantly greater than the traditional TBW (111.58 ± 2.38 N vs. 64.71 ± 4.22 N, P < 0.001). CONCLUSIONS: The ARTBW retained the advantages of traditional TBW, and achieved greater compression force of articular surface, and greater pull-out strength of K-wires. Moreover, ARTBW effectively avoided the rotation of the K-wires. Therefore, ARTBW demonstrates potential as a promising technique for treating patellar fractures.

Coherence-controlled chaotic soliton bunch.

Controlling the coherence of chaotic soliton bunch holds the promise to explore novel light-matter interactions and manipulate dynamic events such as rogue waves. However, the coherence control of chaotic soliton bunch remains challenging, as there is a lack of dynamic equilibrium mechanism for stochastic soliton interactions. Here, we develop a strategy to effectively control the coherence of chaotic soliton bunch in a laser. We show that by introducing a lumped fourth-order-dispersion (FOD), the soliton oscillating tails can be formed and generate the potential barriers among the chaotic solitons. The repulsive force between neighboring solitons enabled by the potential barriers gives rise to an alleviation of the soliton fusion/annihilation from stochastic interactions, endowing the capability to control the coherence in chaotic soliton bunch. We envision that this result provides a promising test-bed for a variety of dynamical complexity science and brings new insights into the nonlinear behavior of chaotic laser sources.

Effect of carbon nanoparticle suspension injection versus indocyanine green tracer in guiding lymph node dissection during radical gastrectomy (FUTURE-01): a randomized clinical trial.

BACKGROUND: Carbon nanoparticle suspension injection (CNSI) and indocyanine green (ICG) have both been applied intraoperatively to facilitate lymphatic mapping and postoperatively to sort lymph nodes (LNs) in gastric cancer patients. However, no study has compared the two tracers in gastric cancer patients. MATERIALS AND METHODS: This prospective randomized controlled trial was conducted from January 2022 to March 2023. Patients with potentially resectable gastric cancer (cT1-4a N0/+ M0) were randomized to the CNSI or ICG group. RESULTS: This study enrolled 96 patients. Ninety patients were in the modified intention-to-treat population, including 46 patients (32 males and 14 females; mean [SD] age, 57.4 [9.4] years) in the CNSI group and 44 patients (31 males and 13 females; mean [SD] age, 60.8 [8.8] years) in the ICG group. The mean (SD) number of retrieved LNs was 69.8 (21.9) and 53.6 (17.2) in the CNSI and ICG groups, respectively (P<0.001). The mean (SD) number of retrieved micro-LNs was 19.9 (13.3) and 11.6 (9.9) in the CNSI and ICG groups, respectively (P=0.001). The mean (SD) number of metastatic LNs was 8.1 (11.9) and 5.2 (9.2) in the CNSI and ICG groups, respectively (P=0.19). CONCLUSIONS: Compared with ICG, CNSI can increase the number of LNs detected, especially micro-LNs. Both tracers have high diagnostic value for detecting metastatic LNs. CNSI-guided lymphography may be a superior method for improving the accuracy of LN dissection.

IGF2 promotes the differentiation of chicken embryonic myoblast by regulating mitochondrial remodeling.

Skeletal muscle is crucial for animal movement and posture maintenance, and it serves as a significant source of meat in the livestock and poultry industry. The number of muscle fibers differentiated from myoblast in the embryonic stage is one of the factors determining the content of skeletal muscle. Insulin-like growth factor 2 (IGF2), a well-known growth-promoting hormone, is crucial for embryonic and skeletal muscle growth and development. However, the specific molecular mechanism underlying its impact on chicken embryonic myoblast differentiation remains unclear. To elucidate the molecular mechanism by which IGF2 regulates chicken myoblast differentiation, we manipulated IGF2 expression in chicken embryonic myoblast. The results demonstrated that IGF2 was upregulated during chicken skeletal muscle development and myoblast differentiation. On the one hand, we found that IGF2 promotes mitochondrial biogenesis through the PGC1/NRF1/TFAM pathway, thereby enhancing mitochondrial membrane potential, oxidative phosphorylation, and ATP synthesis during myoblast differentiation. This process is mediated by the PI3K/AKT pathway. On the other hand, IGF2 regulates BNIP3-mediated mitophagy, clearing dysfunctional mitochondria. Collectively, our findings confirmed that IGF2 cooperatively regulates mitochondrial biogenesis and mitophagy to remodel the mitochondrial network and enhance mitochondrial function, ultimately promoting myoblast differentiation.

Pulsed Laser-Bleaching Semiconductor and Photodetector.

Pulsed lasers alter the optical properties of semiconductors and affect the photoelectric function of the photodetectors significantly, resulting in transient changes known as bleaching. Bleaching has a profound impact on the control and interference of photodetector applications. Experiments using pump-probe techniques have made significant contributions to understanding ultrafast carrier dynamics. However, there are few theoretical studies to the best of our knowledge. Here, carrier dynamic models for semiconductors and photodetectors are established, respectively, employing the rectified carrier drift-diffusion model. The pulsed laser bleaching effect on seven types of semiconductors and photodetectors from visible to long-wave infrared is demonstrated. Additionally, a continuous bleaching method is provided, and the finite-difference time-domain (FDTD) method is used to solve carrier dynamic theory models. Laser parameters for continuous bleaching of semiconductors and photodetectors are calculated. The proposed bleaching model and achieved laser parameters for continuous bleaching are essential for several applications using semiconductor devices, such as infrared detection, biological imaging, and sensing.

Highly flexible yet strain-insensitive conjugated polymer.

Imparting excellent electrical properties, mechanical robustness, suppleness, conduction stability during deformation, and self-healing to intrinsic conducting polymers is a challenging endeavor. The reversibly interlocked macromolecular networks (RILNs) approach is utilized to tackle this problem. Specifically, poly(3,4-ethylenedioxythiophene) (PEDOT) is mixed with flexible polysulfonic acid networks crosslinked by reversible Diels-Alder bonds, while rigid polyaniline networks crosslinked by reversible Schiff base bonds act as molecular staples. Owing to the joint actions of the doping effect of polyaniline on PEDOT, the specific interlocking architecture and synergy between the component materials, the electrical conductivity (59.3-980.5 S cm-1), tensile strength (8.4-81.6 MPa) and elongation at break (44.5-411.0%) of the resultant PEDOT/RILNs films is significantly tunable according to different usage scenarios by adjusting the PEDOT content from 1.48 to 22.24 wt%. More importantly, the electrical resistance of PEDOT/RILNs remains constant during not only a single large extension and deflection but also repeated stretching (up to 1500 cycles) and bending (up to 106 cycles). The built-in reversible covalent bonds enable the PEDOT/RILNs to autonomously restore damaged mechanical and electrical performance. These record-breaking results and the demonstration of self-powered sensor made of PEDOT/RILNs suggest that the proposed approach successfully satisfies various conflicting requirements of flexible electronics regarding the properties of conducting polymers.

In situ SEM fatigue testing technology for metallic materials: a review.

Fatigue failure is one of the most common fracture modes of structural materials in the industrial field. The study of material fatigue mechanisms and methods for predicting fatigue life has always been of significant interest to researchers due to the abrupt and catastrophic failure mode. In recent decades, the performance and functionality of scanning electron microscopy (SEM) have been continuously improved and expanded. Based on this, the development of in situ fatigue testing in SEM has been rapidly developed. This technology plays a crucial role in providing insights into the deformation behavior of materials under fatigue. Keeping this in view, a comprehensive review of the development and application methods of in situ SEM fatigue testing technology is provided here. The development of in situ SEM fatigue testing devices is provided in brief overview, and the application and research progress of this technology in some representative metal structural materials (nickel-based single-crystal superalloys, steel, aluminum alloys and additive manufacturing materials) are analyzed in detail. Moreover, the perspectives on evaluating fatigue damage, particularly about small cracks and the plastic accumulations fatigue behavior, are presented in this study, utilizing the latest advancements in in situ SEM fatigue testing. Remarks about the present and outlook for future work to be done are then provided.

Enhanced fluorescence properties of polyfluorene-based polymer dots through an ascorbic acid-photoaging treatment for living cell imaging.

The polymer dots (Pdots) prepared by the conjugated polymer (PFO, poly (9,9-dihexylfluorene-2,7-diyl)) have high fluorescence intensity and are often used in biological fluorescence imaging. However, due to the chain defects, the PFO Pdots suffer from stability issues such as photoinactivation and photobleaching. To solve this problem, we drew inspiration from the preparation process of organic planar light-emitting devices and added an optimization processing after Pdots was prepared. We used illumination as the driving force to activate defects on its chain, and ascorbic acid as a reducing substance to restore the chain defects of the polymer to a more stable state. Through this method, we increased the fluorescence intensity by nearly 1.9 times, and significantly improving their long and short-term stability. In addition, it ensures other properties remain unchanged. This optimization scheme is also fully compatible with the entire biological imaging process, ensuring that other important properties such as cytotoxicity do not undergo unnecessary changes. Furthermore, we conducted material characterization and theoretical simulation, revealing that the optimization scheme mainly serves to repair C-9 alkyl defects on the polyfluorene unit. This study has improved and enhanced the fluorescence performance of PFO Pdots, and also provides a way to optimize the treatment of other similar conjugated polymer material systems.

Mechanism of action of the Banxia-Xiakucao herb pair in sleep deprivation: New comprehensive evidence from network pharmacology, transcriptomics and molecular biology experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herb pairs are the most basic and compressed examples of Chinese herbal combinations and can be used to effectively explain the fundamental concepts of traditional Chinese medicine prescriptions. These pairings have gained significant interest due to their subtle therapeutic benefits, minimal side effects, and efficacy in treating complicated chronic conditions. The Banxia-Xiakucao Chinese herb pair (BXHP) consists of Pinellia ternata (Thunb.) Breit. (Banxia) and Prunella vulgaris L. (Xiakucao). This formula was documented in The Medical Classic of the Yellow Emperor approximately 2000 years ago，and clinical research has demonstrated that BXHP effectively treats insomnia. AIM OF THE STUDY: This study aimed to evaluate the efficacy and therapeutic mechanism of the BXHP through a comprehensive strategy involving network pharmacology, molecular docking, transcriptomics, and molecular biology experimental validation. MATERIALS AND METHODS: The composition of BXHP was characterized using the UPLC-Q-TOF-MS. The active compounds were screened to find drug-likeness compounds by analyzing the ADME data. To predict the molecular mechanism of BXHP in sleep deprivation (SD) by network pharmacology and molecular docking. We established a rat model of SD and the in vivo efficacy of BXHP was verified through the pentobarbital sodium righting reflex test, behavioral assays, enzyme-linked immunosorbent assay, transmission electron microscopy, HE staining, and Nissl staining, and the underlying molecular mechanism of BXHP in SD was revealed through transcriptomic and bioinformatic analyses in conjunction with quantitative real-time PCR, Western blot, and immunofluorescence staining. RESULTS: In the present study, we showed for the first time that BXHP reduced sleep latency, prolongs sleep duration, and improves anxiety; lowered serum CORT, IL6, TNF-α and MDA levels; decreased hypothalamic Glu levels; and elevated hypothalamic GABA and 5-HT levels in SD rats. We found 16 active compounds that acted on 583 targets, 145 of which are related to SD. By modularly dissecting the PPI network, we discovered three critical targets, Akt1, CREB1, and PRKACA, all of which play important roles in the effects of BXHP on SD. Molecular docking resulted in the identification of 16 active compounds that strongly bind to key targets. The results of GO and KEGG enrichment analyses of network pharmacology and transcriptomics focused on both the regulation of circadian rhythm and the cAMP signaling pathway, which strongly demonstrated that BXHP affects SD via the cAMP-PKA-CREB-Circadian rhythm pathway. Molecular biology experiments verified this hypothesis. Following BXHP administration, PKA and CREB phosphorylation levels were elevated in SD rats, the cAMP-PKA-CREB signaling pathway was activated, the expression levels of the biological clock genes CLOCK, p-BMAL1/BMAL1, and PER3 were increased, and the rhythmicity of the biological clock was improved. CONCLUSIONS: The active compounds in BXHP can activate the cAMP-PKA-CREB-Circadian rhythm pathway, improve the rhythmicity of the biological clock, promote sleep and ameliorate anxiety, which suggests that BXHP improves SD through a multicomponent, multitarget, multipathway mechanism. This study is important for the development of herbal medicines and clinical therapies for improving sleep deprivation.

Quinic acid alleviates high-fat diet-induced neuroinflammation by inhibiting DR3/IKK/NF-κB signaling via gut microbial tryptophan metabolites.

With the increasing of aging population and the consumption of high-fat diets (HFD), the incidence of Alzheimer's disease (AD) has skyrocketed. Natural antioxidants show promising potential in the prevention of AD, as oxidative stress and neuroinflammation are two hallmarks of AD pathogenesis. Here, we showed that quinic acid (QA), a polyphenol derived from millet, significantly decreased HFD-induced brain oxidative stress and neuroinflammation and the levels of Aß and p-Tau. Examination of gut microbiota suggested the improvement of the composition of gut microbiota in HFD mice after QA treatment. Metabolomic analysis showed significant increase of gut microbial tryptophan metabolites indole-3-acetic acid (IAA) and kynurenic acid (KYNA) by QA. In addition, IAA and KYNA showed negative correlation with pro-inflammatory factors and AD indicators. Further experiments on HFD mice proved that IAA and KYNA could reproduce the effects of QA that suppress brain oxidative stress and inflammation and decrease the levels of of Aß and p-Tau. Transcriptomics analysis of brain after IAA administration revealed the inhibition of DR3/IKK/NF-κB signaling pathway by IAA. In conclusion, this study demonstrated that QA could counteract HFD-induced brain oxidative stress and neuroinflammation by regulating inflammatory DR3/IKK/NF-κB signaling pathway via gut microbial tryptophan metabolites.

Epinephelus coioides Sec3 promotes Singapore grouper iridovirus infection by negatively regulates immune response.

Exocyst, a protein complex, plays a crucial role in various cellular functions, including cell polarization, migration, invasion, cytokinesis, and autophagy. Sec3, known as Exoc1, is a key subunit of the Exocyst complex and can be involved in cell survival and apoptosis. In this study, two subtypes of Sec3 were isolated from Epinephelus coioides, an important marine fish in China. The role of E. coioides Sec3 was explored during Singapore grouper iridovirus (SGIV) infection, an important pathogen of marine fish which could induce 90 % mortality. E. coioides Sec3 sequences showed a high similarity with that from other species, indicating the presence of a conserved Sec3 superfamily domain. E. coioides Sec3 mRNA could be detected in all examined tissues, albeit at varying expression levels. SGIV infection could upregulate E. coioides Sec3 mRNA. Upregulated Sec3 significantly promoted SGIV-induced CPE, and the expressions of viral key genes. E. coioides Sec3 could inhibit the activation of NF-κB and AP-1, as well as SGIV-induced cell apoptosis. The results illustrated that E. coioides Sec3 promotes SGIV infection by regulating the innate immune response.

Two new types of structures from soft coral-associated epiphytic fungus Aspergillus versicolor CGF9-1-2.

Global Natural Products Social (GNPS) molecular networking platform was applied to discovery the undescribed compounds from the common marine fungi Aspergillus versicolor CGF9-1-2, ultimately resulting in isolation of four new polyketides, decumbenone E (1), decumbenone F (2), 2'-epi-8-O-methylnidurufin (6), (-)-phomoindene A (7), one new nucleoside, 3-methyl-9-(2-methylbutene)-xanthine (8), and five known analogues. Their structures were elucidated based on 1D/2D NMR spectroscopic and HRESIMS data analyses, meanwhile, the absolute configurations of new compounds were established based on the X-ray crystallographic experiments, as well as the electronic circular dichroism (ECD) analysis. All compounds were predicted pharmaceutical chemistry with ten commonly disease-related proteins by molecular docking. In addition, all compounds against TDP1 were performed in vitro, which was consistent with the docking result, and compound 6 shown a weak inhibitory activity.

PFOS impairs cardiac function and energy metabolism under high-fat diet: Insights into role of circulating macrophage emphasized by exposure distribution.

Per- and polyfluoroalkyl substances (PFAS), widely utilized in consumer products, have been linked to an increased risk of cardiovascular disease (CVD). With the increasing prevalence of high-fat diet, a common risk factor for CVD, the PFAS exposed populations who consume a high-fat diet will inevitably grow and may have a higher CVD risk. However, the potential toxic effect and mode of action remain elusive. We constructed a mouse model orally exposed to perfluorooctane sulfonate (PFOS), a prototypical PFAS, and fed a high-fat diet. PFOS exposure induced cardiomyopathy and structural abnormalities in the mice heart. Moreover, a characteristic of energy metabolism remodeling from aerobic to anaerobic process was observed. Interestingly, PFOS was rarely detected in heart but showed high level in serum, suggesting an indirect route of action for PFOS-caused cardiac toxicity. We further demonstrated that PFOS-caused circulating inflammation promoted metabolic remodeling and contractile dysfunction in cardiomyocytes. Wherein, PFOS stimulated the release of IL-1ß from circulating proinflammatory macrophages mediated by NF-κB and caspase-1. This study provides valuable data on PFAS-induced cardiac risks associated with exposed populations with increasing high-fat diet consumption, highlighting the significance of indirect pathways in PFOS's impact on the heart, based on the distribution of internal exposure.