Mapping of cytosol-facing organelle outer membrane proximity proteome by proximity-dependent biotinylation in living Arabidopsis cells.

The cytosol-facing outer membrane (OM) of organelles communicates with other cellular compartments to exchange proteins, metabolites, and signaling molecules. Cellular surveillance systems also target OM-resident proteins to control organellar homeostasis and ensure cell survival under stress. However, the OM proximity proteomes have never been mapped in plant cells since using traditional approaches to discover OM proteins and identify their dynamically interacting partners remains challenging. In this study, we developed an OM proximity labeling (OMPL) system using biotin ligase-mediated proximity biotinylation to identify the proximity proteins of the OMs of mitochondria, chloroplasts, and peroxisomes in living Arabidopsis (Arabidopsis thaliana) cells. Using this approach, we mapped the OM proximity proteome of these three organelles under normal conditions and examined the effects of the ultraviolet-B (UV-B) or high light (HL) stress on the abundances of OM proximity proteins. We demonstrate the power of this system with the discovery of cytosolic factors and OM receptor candidates potentially involved in local protein translation and translocation. The candidate proteins that are involved in mitochondrion-peroxisome, mitochondrion-chloroplast, or peroxisome-chloroplast contacts, and in the organellar quality control system are also proposed based on OMPL analysis. OMPL-generated OM proximity proteomes are valuable sources of candidates for functional validation and suggest directions for further investigation of important questions in cell biology.

Electrocatalytic Coupling of Nitrate and Formaldehyde for Hexamethylenetetramine Synthesis via C-N Bond Construction and Ring Formation.

Hexamethylenetetramine (HMTA) is extensively used in the defense industry, medicines, food, plastics, rubber, and other applications. Traditional organic synthesis of HMTA relies on ammonia derived from the Haber process at high temperatures and pressures. In contrast, electrochemical methods enable a safe and green one-pot synthesis of HMTA from waste NO3-. However, HMTA synthesis through the electrochemical method is challenging owing to the complex reaction pathways involving C-N bond construction and ring formation. In this study, HMTA was efficiently synthesized over electrochemical oxidation-derived copper (e-OD-Cu), with a yield of 76.8% and a Faradaic efficiency of 74.9% at -0.30 VRHE. The catalytic mechanism and reaction pathway of HMTA synthesis on e-OD-Cu were investigated through a series of in situ characterization methods and density-functional theory calculations. The results demonstrated that the electrocatalytic synthesis of HMTA involved a tandem electrochemical-chemical reaction. Additionally, the results indicated that the presence of Cu vacancies enhanced substrate adsorption and inhibited the further hydrogenation of C═N. Overall, this study provides an electrocatalytic method for HMTA synthesis and an electrochemical strategy for constructing multiple C-N bonds.

Enhancing the Electrocatalytic Hydrogenation of Furfural via Anion-Induced Molecular Activation and Adsorption.

The electrocatalytic hydrogenation (ECH) of furfural (FF) to furfuryl alcohol, which does not require additional hydrogen or high pressure, is a green and promising production route. In this study, we explore the effects of anions on FF ECH in two buffer electrolytes (KHCO3 and phosphate-buffered saline [PBS]). Anions influence the yield of furfuryl alcohol through molecular activation and adsorption. Molecular dynamics simulations show that bicarbonate is present in the first shell layer of the FF molecule and induces strong hydrogen bonding interactions. In contrast, hydrogen phosphate is present only in the second shell layer, resulting in weak hydrogen bonding interactions. Owing to the interfacial anions and hydrogen bonding, FF molecules exhibit strong flat adsorption on the electrode surface in the KHCO3 solution, while weak adsorption is observed in the PBS solution, as confirmed by operando synchrotron-radiation Fourier-transform infrared spectroscopy and in situ Raman spectroscopy. Density-functional theory calculations reveal that the overall anionic hydrogen bonding network promotes the activation of the carbonyl group in the FF molecule in KHCO3, whereas electrophilic activity is inhibited in PBS. Consequently, FF ECH demonstrates much faster kinetics in KHCO3, while it exhibits sluggish ECH kinetics and a severe hydrogen evolution reaction in PBS. This work introduces a new strategy to optimize the catalytic process through the modulation of the microenvironment.

Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling.

A metabolic illness known as non-alcoholic fatty liver disease (NAFLD), affects more than one-quarter of the world's population. Bile acids (BAs), as detergents involved in lipid digestion, show an abnormal metabolism in patients with NAFLD. However, BAs can affect other organs as well, such as the brain, where it has a neuroprotective effect. According to a series of studies, brain disorders may be extrahepatic manifestations of NAFLD, such as depression, changes to the cerebrovascular system, and worsening cognitive ability. Consequently, we propose that NAFLD affects the development of brain disease, through the bile acid signaling pathway. Through direct or indirect channels, BAs can send messages to the brain. Some BAs may operate directly on the central Farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) by overcoming the blood-brain barrier (BBB). Furthermore, glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor (FGF) 19 are released from the intestine FXR and GPBAR1 receptors, upon activation, both of which send signals to the brain. Inflammatory, systemic metabolic disorders in the liver and brain are regulated by the bile acid-activated receptors FXR and GPBAR1, which are potential therapeutic targets. From a bile acid viewpoint, we examine the bile acid signaling changes in NAFLD and brain disease. We also recommend the development of dual GPBAR1/FXR ligands to reduce side effects and manage NAFLD and brain disease efficiently.

Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 Inflammasome Signalling pathway.

BACKGROUND: Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Qingkailing (QKL) injection, a patented Chinese medicine approved by the China Food and Drug Administration, has been widely used in clinical practice to treat cerebral ischemia in China. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is activated in cerebral ischemia and thus, is an effective therapeutic target. AMP-activated protein kinase (AMPK) is an important regulator inhibiting NLRP3 inflammasome activation. METHODS: We investigated the potential of QKL injection to provide neuroprotection after cerebral ischemia in a rat model of middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats (210-230 g) were randomly divided into three groups which consist of sham, MCAO and 3 ml/kg QKL. Rats in the QKL group received intraperitoneal injections of 3 ml/kg QKL, while rats in other groups were given saline in the same volumes. After 90 min ischemia and 24 h reperfusion, neurological function, laser speckle imaging, brain infarction, brain water content and brain blood barrier permeability were examined and cell apoptosis at prefrontal cortex were evaluated 24 h after MCAO, and western blot and real-time quantitative polymerase chain reaction was also researched, respectively. RESULTS: Intraperitoneal administration of QKL alleviated neurological deficiencies, cerebral infarction, blood-brain barrier permeability, brain oedema and brain cell apoptosis after MCAO induction. QKL decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1ß, and increased anti-inflammatory cytokines, IL-4 and IL-10. Furthermore, QKL activated phosphorylated AMPK, decreased oxidative stress and decreased NLRP3 inflammasome activation. CONCLUSIONS: QKL relieved cerebral ischemia reperfusion injury and suppressed the inflammatory response by inhibiting AMPK-mediated activation of the NLRP3 inflammasome. These results suggest that QKL might have potential in treating brain inflammatory response and attenuating the cerebral ischemia-reperfusion injury.

Effect of traditional Chinese medicine formula Sinisan on chronic restraint stress-induced nonalcoholic fatty liver disease: a rat study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) represents one of the most common forms of liver disease worldwide, and it is always regarded as a consequence of a sedentary, food-abundant lifestyle, sitting for an extended time, and a low physical activity level, which often coincide with chronic and long-lasting psychological stress. A Chinese medicine Sinisan (SNS) may be a potential formula for treating this kind of disease. METHODS: In this study, a long-term chronic restraint stress protocol was used to investigate the mechanism underlying stress-induced NALFD. To investigate the effect of SNS treatment on stress-induced NAFLD, we measured the liver and serum values of total cholesterol (TC), triglyceride (TG), liver free fatty acids (FFA), low-density lipoprotein, superoxide dismutase, tumor necrosis factor-α, malondialdehyde, interleukin (IL)-6, and serum values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Results are shown as a mean ± standard deviation. Significant differences between the groups were evaluated using the Student t-test. For multiple comparisons, one-way analysis of variance (ANOVA) was used. If the results of ANOVA indicated significant differences, post hoc analysis was performed with the Tukey test or Dunnett test, and p < 0.05 was considered statistically significant. RESULTS: Long-term chronic stress led to steatosis and non-alcoholic steatohepatitis. Additionally, SNS treatment significantly increased body weight gain (p < 0.01) and sucrose preference (p < 0.001), and it reduced the liver values of TC, TG, and FFA (p < 0.05). SNS also reduced the serum values of AST and ALT (p < 0.001), and the liver value of IL-6 (p < 0.01). CONCLUSIONS: This study's results demonstrate that psychological stress may be a significant risk factor of NAFLD. Furthermore, the traditional Chinese medicine formula SNS may have some beneficial effect in antagonizing psychological stress and stress-related NAFLD.

Erythropoietin Pathway: A Potential Target for the Treatment of Depression.

During the past decade, accumulating evidence from both clinical and experimental studies has indicated that erythropoietin may have antidepressant effects. In addition to the kidney and liver, many organs have been identified as secretory tissues for erythropoietin, including the brain. Its receptor is expressed in cerebral and spinal cord neurons, the hypothalamus, hippocampus, neocortex, dorsal root ganglia, nerve axons, and Schwann cells. These findings may highlight new functions for erythropoietin, which was originally considered to play a crucial role in the progress of erythroid differentiation. Erythropoietin and its receptor signaling through JAK2 activate multiple downstream signaling pathways including STAT5, PI3K/Akt, NF-κB, and MAPK. These factors may play an important role in inflammation and neuroprogression in the nervous system. This is particularly true for the hippocampus, which is possibly related to learning, memory, neurocognitive deficits and mood alterations. Thus, the influence of erythropoietin on the downstream pathways known to be involved in the treatment of depression makes the erythropoietin-related pathway an attractive target for the development of new therapeutic approaches. Focusing on erythropoietin may help us understand the pathogenic mechanisms of depression and the molecular basis of its treatment.

PANoptosis-like death in acute-on-chronic liver failure injury.

The pathogenesis of Acute-on-chronic liver failure (ACLF) involves several forms of cell death, such as pyroptosis, apoptosis, and necroptosis, which consist of PANoptosis. To explore PANoptosis as a regulated cell death pathway in ACLF. Firstly, a bioinformatic strategy was used to observe the role of the PANoptosis pathway in ACLF and identify differentially expressed genes related to PANoptosis. Enrichment analysis showed that PANoptosis-related pathways were up-regulated in ACLF. We screened out BAX from the intersection of pyroptosis, apoptosis, necroptosis, and DEGs. Secondly, we screened articles from literature databases related to PANoptosis and liver failure, and specific forms of PANoptosis were reported in different experimental models in vitro and in vivo. Secondly, we established a model of ACLF using carbon tetrachloride-induced liver fibrosis, followed by D-galactosamine and lipopolysaccharide joint acute attacks. A substantial release of inflammatory factors(IL-6, IL-18, TNFα, and IFNγ) and the key proteins of PANoptosis (NLRP3, CASP1, GSDMD, BAX, CASP8, CASP3, CASP7, and MLKL) were detected independently in the ACLF rats. Finally, we found that combining TNF-α/INF-γ inflammatory cytokines could induce L02 cells PANoptosis. Our study highlighted the potential role of ACLF and helps drug discovery targeting PANoptosis in the future.

DiffStyler: Controllable Dual Diffusion for Text-Driven Image Stylization.

Despite the impressive results of arbitrary image-guided style transfer methods, text-driven image stylization has recently been proposed for transferring a natural image into a stylized one according to textual descriptions of the target style provided by the user. Unlike the previous image-to-image transfer approaches, text-guided stylization progress provides users with a more precise and intuitive way to express the desired style. However, the huge discrepancy between cross-modal inputs/outputs makes it challenging to conduct text-driven image stylization in a typical feed-forward CNN pipeline. In this article, we present DiffStyler, a dual diffusion processing architecture to control the balance between the content and style of the diffused results. The cross-modal style information can be easily integrated as guidance during the diffusion process step-by-step. Furthermore, we propose a content image-based learnable noise on which the reverse denoising process is based, enabling the stylization results to better preserve the structure information of the content image. We validate the proposed DiffStyler beyond the baseline methods through extensive qualitative and quantitative experiments. The code is available at https://github.com/haha-lisa/Diffstyler.

The Coptidis Rhizoma and Bovis Calculus herb pair attenuates NASH and inhibits the NLRP3 inflammasome activation.

The Coptidis Rhizoma and Bovis Calculus herb pair possesses clearing heat and detoxifying effects. The aim of this study was to reveal the effects and mechanisms of the herb pair in the treatment of NASH by network pharmacology and experimental verification. A network pharmacology-based approach was employed to predict the putative mechanism of the herb pair against NASH. The high-fat diet (HFD) and methionine/choline deficient (MCD) diet induced NASH models were used to evaluate efficacy and mechanism of the herb pair. Network pharmacological analysis showed that the herb pair modulated NOD-like receptor pathway. In the HFD mice, herb pair reduced body weight, blood sugar, serum ALT, AST, TBA, TC, TG and LDL-C contents, also improved the general morphology and pathological manifestations. Hepatic transcriptomics study showed that herb pair attenuated NASH by regulating NOD-like receptor signaling pathway. Western blotting showed that herb pair reduced the protein expression levels of NLRP3, cleaved Caspase-1 and cleaved IL-1ß. In the MCD mice, herb pair also reduced serum ALT, ALT and TBA levels, improved liver pathological manifestations, inhibited the protein expression levels of NLRP3, cleaved Caspase-1 and cleaved IL-1ß. Our findings proved that the Coptidis Rhizoma and Bovis Calculus herb pair attenuates NASH through suppression of NLRP3 inflammasome activation. This will demonstrate effective pharmacological evidence for the clinical application of herb pair.

Unilamellar MnO2 nanosheets confined Ru-clusters combined with pulse electrocatalysis for biomass electrooxidation in neutral electrolytes.

The electrochemical oxidation of 5-hydroxymethylfurfural (HMFOR) in alkaline electrolyte is a promising strategy for producing high-value chemicals from biomass derivatives. However, the disproportionation of aldehyde groups under strong alkaline conditions and the polymerization of HMF to form humic substances can impact the purity of 2,5-furandicarboxylic acid (FDCA) products. The use of neutral electrolytes offers an alternative environment for electrolysis, but the lack of OH- ions in the electrolyte often leads to low current density and low yields of FDCA. In this study, a sandwich-structured catalyst, consisting of Ru clusters confined between unilamellar MnO2 nanosheets (S-Ru/MnO2), was used in conjunction with an electrochemical pulse method to realize the electrochemical conversion of 5-hydroxymethylfurfural into FDCA in neutral electrolytes. Pulse electrolysis and the strong electron transfer between Ru clusters and MnO2 nanosheets help maintain Ru in a low oxidation state, ensuring high activity. The increased *OH generation led to a groundbreaking current density of 47 mA/cm2 at 1.55 V vs. reversible hydrogen electrode (RHE) and an outstanding yield rate of 98.7 % for FDCA in a neutral electrolyte. This work provides a strategy that combines electrocatalyst design with an electrolysis technique to achieve remarkable performance in neutral HMFOR.

Potential Biomedical Limitations of Graphene Nanomaterials.

Graphene-family nanomaterials (GFNs) possess mechanical stiffness, optical properties, and biocompatibility making them promising materials for biomedical applications. However, to realize the potential of graphene in biomedicine, it must overcome several challenges that arise when it enters the body's circulatory system. Current research focuses on the development of tumor-targeting devices using graphene, but GFNs accumulated in different tissues and cells through different pathways, which can cause toxic reactions leading to cell apoptosis and body dysfunction when the accumulated amount exceeds a certain limit. In addition, as a foreign substance, graphene can induce complex inflammatory reactions with immune cells and inflammatory factors, potentially enhancing or impairing the body's immune function. This review discusses the biomedical applications of graphene, the effects of graphene materials on human immune function, and the biotoxicity of graphene materials.

Tongxinluo attenuates atherosclerosis by inhibiting ROS/NLRP3/caspase-1-mediated endothelial cell pyroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL) is one of the most common traditional Chinese medicines and plays a vital role in treating atherosclerosis (AS). Endothelial cell (EC) pyroptosis plays a crucial role in the development of AS. Previous research revealed the inhibitory function of TXL in EC apoptosis and autophagy. However, whether TXL can inhibit the pyroptosis of ECs has not been determined. AIM OF THE STUDY: To explore the influence of TXL on EC pyroptosis and determine its underlying mechanism of action in AS. MATERIALS AND METHODS: The TXL components were determined by ultra-performance liquid chromatography coupled with a photodiode array detector. We used ApoE-/- mice to establish a disease model of AS. After treatment with TXL, we recorded pathological changes in the mice and performed immunofluorescence staining of mice aortas. We also measured protein and gene levels to explore the influence of TXL on pyroptosis in vivo. The model was established by stimulating mouse aortic endothelial cells (MAECs) with oxidized low-density lipoprotein (ox-LDL) and analyzing the effect of TXL on pyroptosis by Western blotting (WB), real-time PCR (RT-PCR), and flow cytometry (FCM). We also investigated the impact of TXL on reactive oxygen species (ROS) by FCM and WB. RESULTS: Ten major components of TXL were detected. The vivo results showed that TXL inhibited the development of AS and decreased EC pyroptosis, the activation of caspase-1, and the release of inflammatory cytokines. The vitro experiments showed that TXL significantly reduced the extent of injury to MAECs by oxidized LDL (ox-LDL). TXL reversed the high expression of gasdermin D and other proteins induced by ox-LDL and had a significant synergistic effect with the caspase-1 inhibitor VX-765. We also confirmed that TXL decreased the accumulation of ROS and the expression levels of its essential regulatory proteins Cox2 and iNOS. When ROS accumulation was reduced, EC pyroptotic damage was reduced accordingly. CONCLUSION: Our results indicated that TXL inhibited EC pyroptosis in AS. Reducing the accumulation of ROS may be the essential mechanism of AS inhibition by TXL.

Exploring the Temporal Consistency of Arbitrary Style Transfer: A Channelwise Perspective.

Arbitrary image stylization by neural networks has become a popular topic, and video stylization is attracting more attention as an extension of image stylization. However, when image stylization methods are applied to videos, unsatisfactory results that suffer from severe flickering effects appear. In this article, we conducted a detailed and comprehensive analysis of the cause of such flickering effects. Systematic comparisons among typical neural style transfer approaches show that the feature migration modules for state-of-the-art (SOTA) learning systems are ill-conditioned and could lead to a channelwise misalignment between the input content representations and the generated frames. Unlike traditional methods that relieve the misalignment via additional optical flow constraints or regularization modules, we focus on keeping the temporal consistency by aligning each output frame with the input frame. To this end, we propose a simple yet efficient multichannel correlation network (MCCNet), to ensure that output frames are directly aligned with inputs in the hidden feature space while maintaining the desired style patterns. An inner channel similarity loss is adopted to eliminate side effects caused by the absence of nonlinear operations such as softmax for strict alignment. Furthermore, to improve the performance of MCCNet under complex light conditions, we introduce an illumination loss during training. Qualitative and quantitative evaluations demonstrate that MCCNet performs well in arbitrary video and image style transfer tasks. Code is available at https://github.com/kongxiuxiu/MCCNetV2.

Agrimonia pilosa: A Phytochemical and Pharmacological Review.

Agrimonia pilosa Ledeb., which belongs to Agrimonia and Rosaceae, is used in traditional Chinese medicine. It exhibits excellent medicinal properties and has been used to treat various diseases, such as tumors, trichomoniasis, vaginitis, diarrhea, and dysentery. Phytochemical studies have revealed that Agrimonia has over 100 secondary metabolites that can be categorized into six classes, i.e., flavonoids, isocoumarins, triterpenes, phloroglucinol derivatives, tannins, and organic acids. This review summarizes recently published literature on the chemical structures of 90 bioactive compounds that have been identified in A. pilosa and examines their pharmacological properties, including their antitumor, anti-inflammatory, antioxidant, antibacterial, and antidiabetic properties, as well as the potential development of parasitic resistance to these chemicals. This review highlights existing knowledge gap and serves as a basis for developing novel preparations of A. pilosa with medicinal value.

Entrepreneurship education of college students and entrepreneurial psychology of new entrepreneurs under causal attribution theory.

With the rapid development of information technology, the society's demand for innovative talents has become increasingly prominent. The purpose of this study is to optimize the teaching strategies of entrepreneurship education for college students, further cultivate college students' entrepreneurial ideas, and promote the formation of entrepreneurial values. The problems existing in entrepreneurship education in colleges and universities are studied based on entrepreneurial psychology and attribution theory. A questionnaire survey is conducted on the problems with a high probability of entrepreneurial failure of college students. The heads of new ventures in Xi'an are selected. Then, 300 questionnaires are distributed, and 209 are returned. The survey results are analyzed using failure attribution and failure learning. Suggestions are provided for management strategies of new ventures. The results show that the Corrected Item-Total Correlation (CITC) value of R-1 is 0.65, and the CITC value of R-2 is 0.35. In addition, the Kaiser-Meyer-Olkin (KMO) values of entrepreneurial failure attribution and entrepreneurial failure mode are both greater than 0.7, which indicates that the scale of entrepreneurial failure attribution has good validity and can be used for factor analysis. However, the KMO values of entrepreneurial failure attribution and entrepreneurial failure learning model are both greater than 0.7, and the significance of Bartlett sphericity test is 0.00, which indicates that the survey has good validity. The research has practical application and reference value for the cultivation of college students' innovative and entrepreneurial ability.

Task-Aware Sampling Layer for Point-Wise Analysis.

Sampling, grouping, and aggregation are three important components in the multi-scale analysis of point clouds. In this paper, we present a novel data-driven sampler learning strategy for point-wise analysis tasks. Unlike the widely used sampling technique, Farthest Point Sampling (FPS), we propose to learn sampling and downstream applications jointly. Our key insight is that uniform sampling methods like FPS are not always optimal for different tasks: sampling more points around boundary areas can make the point-wise classification easier for segmentation. Towards this end, we propose a novel sampler learning strategy that learns sampling point displacement supervised by task-related ground truth information and can be trained jointly with the underlying tasks. We further demonstrate our methods in various point-wise analysis tasks, including semantic part segmentation, point cloud completion, and keypoint detection. Our experiments show that jointly learning of the sampler and task brings better performance than using FPS in various point-based networks.

Jieduan-Niwan Formula Ameliorates Oxidative Stress and Apoptosis in Acute-on-Chronic Liver Failure by Suppressing HMGB1/TLR-4/NF-κB Signaling Pathway: A Study In Vivo and In Vitro.

Jieduan-Niwan (JDNW) formula is a traditional Chinese medicine compound created by the famous Chinese medicine expert Professor Qian Ying, and has been used clinically for decades to treat acute-on-chronic liver failure (ACLF) and exhibits remarkable efficacy. However, the exact mechanism remains to be discovered. As an important hepatocyte damage-associated molecular patterns (DAMP) factor, high mobility group box 1 (HMGB1) is a potential therapeutic target as an accelerator of ACLF in the pathogenesis. Therefore, the present study investigated whether JDNW inhibits the overexpression and cytoplasmic translocation of HMGB1 in ACLF liver tissue and alleviates its mediated oxidative stress and apoptosis. In vivo, an immune-induced ACLF rat model was established, and then treated with JDNW for 5, 10, and 15 d. The results showed that a large number of cytoplasmic translocations of HMGB1 occurred in the ACLF group. And there was an increase in the expression of HMGB1 in the M-5 d group. After the intervention of JDNW, the overexpression and translocation of HMGB1 were inhibited. In vitro, D-GaLN caused an increase in the expression and translocation of HMGB1 in L02 cells. Similar to the inhibitor of HMGB1, JDNW serum alleviated this kind of increase. Further tests showed that JDNW attenuated ACLF-related oxidative stress and apoptosis, and the inhibition was associated with the regulation of TLR-4/NF-κB signaling pathway. In conclusion, our present findings suggest that the therapeutic effect of JDNW on ACLF was associated with the inhibition of high expression and cytoplasmic translocation of HMGB1 during the acute injury phase, thus, attenuating oxidative stress injury and apoptosis induced by HMGB1/TLR-4/NF-κB pathway.

Pharmacological Mechanisms of Tinglizi against Chronic Heart Failure Determined by Network Pharmacology and Molecular Docking.

OBJECTIVE: Tinglizi has been extensively used to treat chronic heart failure (CHF) in modern times, but the material basis and pharmacological mechanisms are still unclear. To explore the material basis and corresponding potential targets and to elucidate the mechanism of Tinglizi, network pharmacology and molecular docking methods were utilized. METHODS: The main chemical compounds and potential targets of Tinglizi were collected from the pharmacological database analysis platform (TCMSP). The corresponding genes of related action targets were queried through gene cards and UniProt database. The corresponding genes of CHF-related targets were searched through Disgenet database, and the intersection targets were obtained by drawing Venn map with the target genes related to pharmacodynamic components. Then, drug targets and disease targets were intersected and put into STRING database to establish a protein interaction network. The "active ingredient-CHF target" network was constructed with Cytoscape 3.8.2. Finally, Gene Ontology (GO) Enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of intersection targets were analyzed using metascape. With the aid of SYBYL software, the key active ingredients and core targets were docked at molecular level, and the results were visualized by PyMOL software. Molecular docking was carried out to investigate interactions between active compounds and potential targets. RESULTS: A total of 12 active components in Tinglizi were chosen from the TCMSP database, and 193 corresponding targets were predicted. Twenty-nine potential targets of Tinglizi on CHF were obtained, of which nine were the core targets of this study. Twenty GO items were obtained by GO function enrichment analysis (P < 0.05), and 10 signal pathways were screened by KEGG pathway enrichment analysis (P < 0.05), which is closely related to the treatment of CHF by Tinglizi. The constructed drug compound composition action target disease network shows that quercetin, kaempferol, and other active compounds play a key role in the whole network. The results of molecular docking showed that all the key active ingredients, such as quercetin and isorhamnetin, were able to successfully dock with ADRB2 and HMOX1 with a total score above 5.0, suggesting that these key components have a strong binding force with the targets. CONCLUSION: Through network pharmacology and molecular docking technology, we found that the main components of Tinglizi in the treatment of CHF are quercetin, kaempferol, ß-sitosterol, isorhamnetin, and so on. The action targets are beta 2-adrenergic receptor (ADRB2), heme oxygenase 1 (HMOX1), and so on. The main pathways are advanced glycation end products/receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor (HIF-1) signaling pathway, estrogen signaling pathway, and so on. They play an integrated role in the treatment of CHF.

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer's disease.

There is yet no effective drug for Alzheimer's disease (AD) which is one of the world's most common neurodegenerative diseases. The Qin-Zhi-Zhu-Dan Formula (QZZD) is derived from a widely used Chinese patent drug-Qing-Kai-Ling Injection. It consists of Radix Scutellariae, Fructus Gardeniae, and Pulvis Fellis Suis. Recent study showed that QZZD and its effective components played important roles in anti-inflammation, antioxidative stress and preventing brain injury. It was noted that QZZD had protective effects on the brain, but the mechanism remained unclear. This study aims to investigate the mechanism of QZZD in the treatment of AD combining network pharmacology approach with experimental validation. In the network pharmacology analysis, a total of 15 active compounds of QZZD and 135 putative targets against AD were first obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then applied to clarify the biological mechanism. The anti-inflammatory mechanism of QZZD was proved, and a synthetic pathway-TNFR1-ERK1/2-NF-κBp65 signaling pathway was obtained. On the basis of the above discoveries, we further validated the protective effects QZZD on neurons with an APP/PS1 double transgenic mouse model. Weight change of the mice was monitored to assess QZZD's influence on the digestive system; water maze experiment was used for evaluating the effects on spatial learning and memory; Western blotting and immunohistochemistry analysis were used to detect the predicted key proteins in network pharmacology analysis, including Aß, IL-6, NF-κBp65, TNFR1, p-ERK1/2, and ERK1/2. We proved that QZZD could improve neuroinflammation and attenuate neuronal death without influencing the digestive system in APP/PS1 double transgenic mice with dementia. Combining animal pharmacodynamic experiments with network pharmacology analysis, we confirmed the importance of inflammation in pathogenesis of AD, clarified the pharmacodynamic characteristics of QZZD in treating AD, and proved its neuroprotective effects through the regulation of TNFR1-ERK1/2-NF-κBp65 signaling pathway, which might provide reference for studies on treatment of AD in the future.