Geniposide ameliorates atherosclerosis by restoring lipophagy via suppressing PARP1/PI3K/AKT signaling pathway.

BACKGROUND: Atherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear. PURPOSE: To evaluate the efficacy and mechanism of Geniposide in treating AS. STUDY DESIGN AND METHODS: Geniposide was administered to high-fat diet-fed ApoE-/- mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression. RESULTS: In vivo, Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro, Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro. Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1. CONCLUSION: Geniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1.

Huanglian Jiedu decoction inhibits vascular smooth muscle cell-derived foam cell formation by activating autophagy via suppressing P2RY12.

ETHNOPHARMACOLOGICAL RELEVANCE: Huanglian Jiedu Decoction (HLJDD) is a Chinese medicine with a long history of therapeutic application. It is widely used in treating atherosclerosis (AS) in Chinese medicine theory and clinical practice. However, the mechanism of HLJDD in treating AS remains unclear. AIM OF THE STUDY: To investigate the efficacy and mechanism of HLJDD in treating AS. MATERIALS AND METHODS: AS was induced on high-fat diet-fed ApoE-/- mice, with the aorta pathological changes evaluated with lipid content and plaque progression. In vitro, foam cells were induced by subjecting primary mouse aortic vascular smooth muscle cells (VSMCs) to oxLDL incubation. After HLJDD intervention, VSMCs were assessed with lipid stack, apoptosis, oxidative stress, and the expression of foam cell markers. The effects of P2RY12 were tested by adopting clopidogrel hydrogen sulfate (CDL) in vivo and transfecting P2RY12 over-expressive plasmid in vitro. Autophagy was inhibited by Chloroquine or transfecting siRNA targeting ATG7 (siATG7). The mechanism of HLJDD treating atherosclerosis was explored using network pharmacology and validated with molecular docking and co-immunoprecipitation. RESULTS: HLJDD exhibited a dose-dependent reduction in lipid deposition, collagen loss, and necrosis within plaques. It also reversed lipid accumulation and down-regulated the expression of foam cell markers. P2RY12 inhibition alleviated AS, while P2RY12 overexpression enhanced foam cell formation and blocked the therapeutic effects of HLJDD. Network pharmacological analysis suggested that HLJDD might mediate PI3K/AKT signaling pathway-induced autophagy. P2RY12 overexpression also impaired autophagy. Similarly, inhibiting autophagy counteracted the effect of CDL, exacerbated AS in vivo, and promoted foam cell formation in vitro. However, HLJDD treatment mitigated these detrimental effects by suppressing the PI3K/AKT signaling pathway. Immunofluorescence and molecular docking revealed a high affinity between P2RY12 and PIK3CB, while co-immunoprecipitation assays illustrated their interaction. CONCLUSIONS: HLJDD inhibited AS in vivo and foam cell formation in vitro by restoring P2RY12/PI3K/AKT signaling pathway-suppressed autophagy. This study is the first to reveal an interaction between P2RY12 and PI3K3CB.

Synergistic effect of photo-thermal oxidation for a low concentration of HCHO over Bi3+-TiO2/MnFeOx catalysts at ambient temperature.

Formaldehyde (HCHO) has been one of the important air pollutants, and the effective removal of HCHO at ambient temperature has been a big challenge. In this work, the synergistic effect of photo-thermal oxidation with Bi3+-TiO2/MnFeOx for a low concentration of HCHO was investigated. MnFeOx was synthesized by the complexation method (CM) and co-precipitation (CP), and TiO2 with Bi3+ doping supported on MnFeOx was prepared by using the hydrothermal method to obtain a higher oxidation performance. The results demonstrated an excellent oxidation activity of MnFeOx (CM) for HCHO at ambient temperature, attributed to the morphology effect (large surface areas and small crystal sizes), the large absorption of oxygen, and the interaction and oxygen vacancy formed between MnO2 and FeOx. Although Bi3+-TiO2/MnFeOx showed a similar result as MnFeOx at 48 h, the oxidation activities for HCHO were improved prominently under photo-thermal oxidation at 12 h. The improvement was ascribed to the synergistic effect of Bi3+-TiO2 and MnFeOx with surface adsorbed oxygen, and more generated reactive oxygen species on the surface. In particular, 2 wt% Bi3+-TiO2/MnFeOx displayed the highest activity (90.2%) and good stability (5 cycles), and the HCHO average conversion was increased from 46.2 to 58.2% at 12 h. The feasible oxidation mechanism and reaction pathway were also interpreted. This work provides a new insight for the development of photocatalysts supported on transition metal oxides to oxidize HCHO at ambient temperature.

Improved activity and stability for chlorobenzene oxidation over ternary Cu-Mn-O-Ce solid solution supported on cordierite.

A series of CuMnOx/CeO2/cordierite and CuMnCeOx/cordierite catalysts prepared by a complex method with citric acid were investigated for the performance of chlorobenzene (CB) oxidation. The effects of the molar ratio of Mn/Cu, transition metal oxide loading, calcination temperature and time were investigated as the main investigation factor for the performance. Meanwhile, XRD, SEM, BET, H2-TPR, O2-TPD and XPS were conducted to characterize the physicochemical properties of these catalysts. The results demonstrated that CuMnOx/CeO2/cordierite catalysts prepared by step-by-step synthesis with the Cu/Mn molar ratio of 5:2 exhibited a high activity (T90 = 350 °C), owing to the incorporation of CuO and MnOx for forming CuMn2O4 spinel oxide supported on CeO2 surface. More importantly, CuMnCeOx/cordierite catalysts prepared by one-step exhibited the highest oxidation activity (T90 < 300 °C) attributed to the low H2 reduction temperature and desorption energy of surface oxygen, and the formed Cu-Mn-O-Ce solid solution and CeO2 promoted the high dispersion of CuMnOx in the supported catalysts. In addition, the possible oxidation mechanism was described to demonstrate the by-products generation and oxygen transfer of CuMnCeOx catalysts.

Lexicon and attention-based named entity recognition for kiwifruit diseases and pests: A Deep learning approach.

Named Entity Recognition (NER) is a crucial step in mining information from massive agricultural texts, which is required in the construction of many knowledge-based agricultural support systems, such as agricultural technology question answering systems. The vital domain characteristics of Chinese agricultural text cause the Chinese NER (CNER) in kiwifruit diseases and pests to suffer from the insensitivity of common word segmentation tools to kiwifruit-related texts and the feature extraction capability of the sequence encoding layer being challenged. In order to alleviate the above problems, effectively mine information from kiwifruit-related texts to provide support for agricultural support systems such as agricultural question answering systems, this study constructed a novel Chinese agricultural NER (CANER) model KIWINER by statistics-based new word detection and two novel modules, AttSoftlexicon (Criss-cross attention-based Softlexicon) and PCAT (Parallel connection criss-cross attention), proposed in this paper. Specifically, new words were detected to improve the adaptability of word segmentation tools to kiwifruit-related texts, thereby constructing a kiwifruit lexicon. The AttSoftlexicon integrates word information into the model and makes full use of the word information with the help of Criss-cross attention network (CCNet). And the PCAT improves the feature extraction ability of sequence encoding layer through CCNet and parallel connection structure. The performance of KIWINER was evaluated on four datasets, namely KIWID (Self-annotated), Boson, ClueNER, and People's Daily, which achieved optimal F1-scores of 88.94%, 85.13%, 80.52%, and 92.82%, respectively. Experimental results in many aspects illustrated that methods proposed in this paper can effectively improve the recognition effect of kiwifruit diseases and pests named entities, especially for diseases and pests with strong domain characteristics.

A New Gold Nanoparticles and Paclitaxel Co-Delivery System for Enhanced Anti-Cancer Effect Through Chemo-Photothermal Combination.

Limited chemotherapeutic efficiency, drug resistance and side effect are primary obstacles for cancer treatment. The development of co-delivery system with synergistic treatment modes should be a promising strategy. Here, we fabricated a multi-functionalized nanocarrier with a combination of chemotherapeutic agent and gold nanoparticles (AuNPs), which could integrate chemo-photothermal therapy and improve entire anti-cancer index. Particularly, Paclitaxel nanocrystals (PTX NC) were first fabricated as a platform, on surface of which AuNPs were decorated and polydopamine (PDA) layer act as capping, stabilizing and hydrophilic agents for PTX NC, providing a bridge connecting AuNPs to PTX. These AuNPs decorated PTX NC exhibited good physico-chemical properties like optimal sizes, stability and photothermal efficiency. Compared to other PTX formulations, they displayed considerably improved biocompatibility, selectivity, intracellular uptake, cytotoxicity, apoptosis induction activity and P-glycoprotein (Pgp) inhibitory capability, owing to a synergistic/ cooperative effect from AuNPs, PTX and NIR treatment, photothermal-triggered drug release and nano-scaled structure. Mitochondria-mediated signaling pathway is underlying mechanism for cytotoxic and apoptotic effect from AuNPs decorated PTX NC, in terms of Mitochondria damage, a loss of Mitochondrial membrane potential, intensified oxidative stress, DNA breakage, Caspase 3 activation, up-regulated expression in pro-apoptotic genes like p53, Caspase 3 and Bax and down-regulated level in anti-apoptotic gene like Bcl-2.

Life-Cycle Cost Analysis of Long-Span CFRP Cable-Stayed Bridges.

With the advantages of high strength, light weight, high corrosion and fatigue resistance, and low relaxation, carbon-fiber-reinforced polymer (CFRP) is an excellent cable material for cable-stayed bridges. However, the relatively high unit price of CFRP compared to that of steel may hinder the large-scale application of CFRP stay cables. This paper presents the economic comparison between long-span cable-stayed bridges using CFRP cables and the corresponding steel cable-stayed bridges through life-cycle cost analysis (LCCA). Three CFRP cable-stayed bridges with a main span of 600 m, 1200 m, and 1800 m, respectively, along with their steel counterparts, were designed, and their life-cycle costs (LCCs) were calculated. The comparison of LCCs was not only between the CFRP and steel cable-stayed bridges with the same span, but also between the cable-stayed bridges with different spans. Furthermore, the different unit prices of CFRP cables and different replacement frequencies of steel cables were also investigated. The results show that the initial design and construction cost of the long-span CFRP cable-stayed bridge is higher than that of the corresponding steel cable-stayed bridge, although using CFRP cables can reduce the materials used, primarily due to the higher unit price of the CFRP cable. Despite the higher initial cost, the long-span CFRP cable-stayed bridge can still achieve lower LCC than the steel cable-stayed bridge, because it has significantly lower rehabilitation cost and user cost, as well as slightly lower vulnerability cost. Furthermore, with the increase in the main span and the decrease in the unit price of CFRP cables, the LCC advantage of the long-span CFRP cable-stayed bridge becomes more obvious.

Gold Nanoparticle-Decorated Drug Nanocrystals for Enhancing Anticancer Efficacy and Reversing Drug Resistance Through Chemo-/Photothermal Therapy.

Limited chemotherapeutic efficiency, drug resistance, and side effects are primary obstacles for cancer treatment. The development of co-delivery systems with synergistic treatment modes should be a promising strategy. Here, we fabricated a multifunctionalized nanocarrier with a combination of chemotherapeutic agents and gold nanoparticles (AuNPs), which could integrate chemo-photothermal therapy, thus enhancing overall anticancer efficacy, sensitizing drug-resistant cancer cells, and diminishing cancer stem cells (CSCs). To be specific, camptothecin nanocrystals (CPT NCs) were prepared as a platform, on the surface of which AuNPs were decorated and a hyaluronic acid layer acted as capping, stabilizing, targeting, and hydrophilic agents for CPT NCs, and reducing agents for AuNPs, providing a bridge connecting AuNPs to CPT. These AuNP-decorated CPT NCs exhibited good physico-chemical properties such as optimal sizes, payload, stability, and photothermal efficiency. Compared to other CPT formulations, they displayed considerably improved biocompatibility, selectivity, intracellular uptake, cytotoxicity, apoptosis induction activity, Pgp inhibitory capability, and anti-CSC activity, owing to a synergistic/cooperative effect from AuNPs, CPT, near-infrared treatment, pH/photothermal-triggered drug release, and nanoscaled structure. A mitochondrial-mediated signaling pathway is the underlying mechanism for cytotoxic and apoptotic effects from AuNP-decorated CPT NCs, in terms of mitochondrial dysfunction, intensified oxidative stress, DNA fragmentation, caspase 3 activation, upregulation of proapoptotic genes such as p53, Bax, and caspase 3, and lower levels of antiapoptotic Bcl-2.

Silver nanoparticles functionalized Paclitaxel nanocrystals enhance overall anti-cancer effect on human cancer cells.

For chemotherapeutic drugs, precise tumor-targeting and high anti-cancer efficiency is equally important in order to enhance chemotherapy and reverse drug resistance. The combination of multifunctional agents to achieve synergy should be a promising strategy. In our study, we have successfully developed novel multifunctionalized drug nanocrystals to realize co-delivery of the organic drug Paclitaxel (PTX), inorganic silver nanoparticles (AgNPs) and a tumor targeting agent. To be specific, PTX nanocrystals were first prepared as a template, then coated with polydopamine (PDA). The PDA layer was utilized as the connection bridge to produce and deposit AgNPs in situ, and provide sites for tumor-targeting peptide NR1 (RGDARF) grafting. As a result, these NR1/AgNP-decorated drug nanocrystals exhibited dramatically improved cellular uptake efficiency, in vitro anti-cancer activity and an anti-migratory effect against a variety of cancer cells, which was attributable to the synergistic, or at least additive, effect of the AgNPs and PTX, enhanced cellular uptake efficiency through NR1-receptor interaction, pH-responsive drug release and the nanoscaled nature. In particular, high anti-cancer activity and low side effects from these NR1/AgNP-decorated PTX nanocrystals were well balanced in terms of good selectivity and biocompatibility. Moreover, these novel drug nanocrystals displayed strong apoptotic-inducing potency, resulting in cell membrane lysis, nuclear damage, mitochondria dysfunction, excessive ROS release and double-stranded DNA breakage. The potential acting mechanism and molecular basis of these novel drug nanocrystals is relevant to the regulation of mitochondria-mediated apoptosis with a greater Bax-to-Bcl-2 ratio and the activation of pro-apoptotic P53 and caspase 3.