Network pharmacology and molecular docking analysis on Shenfu Qiangxin indicate mTOR is a potential target to treat heart failure.

BACKGROUND: Heart failure (HF) is one of the major causes of mortality worldwide with high recurrence rate and poor prognosis. Our study aimed to investigate potential mechanisms and drug targets of Shenfu Qiangxin (SFQX), a cardiotonic-diuretic traditional Chinese medicine, in treating HF. METHODS: An HF-related and SFQX-targeted gene set was established using disease-gene databases and the Traditional Chinese Medicine Systems Pharmacology database. We performed gene function and pathway enrichment analysis and constructed protein-protein interaction (PPI) network to investigate the potential mechanisms. We also performed molecular docking to analyze the interaction patterns between the active compounds and targeted protein. RESULTS: A gene set with 217 genes was identified. The gene function enrichment indicated that SFQX can regulate apoptotic process, inflammatory response, response to oxidative stress and cellular response to hypoxia. The pathway enrichment indicated that most genes were involved in PI3K-Akt pathway. Eighteen hub target genes were identified in PPI network and subnetworks. mTOR was the key gene among hub genes, which are involved in PI3K-Akt pathway. The molecular docking analysis indicated that 6 active compounds of SFQX can bind to the kinase domain of mTOR, which exerted potential therapeutic mechanisms of SFQX in treating HF. CONCLUSIONS: The results of network pharmacology analysis highlight the intervention on PI3K-Akt pathway of SFQX in the treatment of HF. mTOR is a key drug target to help protect myocardium.

Effects of dietary astaxanthin on growth performance, muscle composition, non-specific immunity, gene expression, and ammonia resistance of juvenile ivory shell (Babylonia areolate).

Astaxanthin is one of the important immunopotentators in aquaculture. However, little is known about the physiological changes and stress resistance effects of astaxanthin in marine gastropods. In this study, the effects of different astaxanthin concentrations (0, 25, 50, 75, and 100 mg/kg) on the growth, muscle composition, immune function, and resistance to ammonia stress in Babylonia areolata were investigated after three months of rearing. With the increase in astaxanthin content, the weight gain rate (WGR), specific growth rate (SGR), and survival rate (SR) of B. areolata showed an increasing trend. The 75-100 mg/kg group was significantly higher than the control group (0 mg/kg). There was no significant difference in the flesh shell ratio (FSR), viscerosomatic index (VSI), and soft tissue index (STI) of the experimental groups. Astaxanthin (75 mg/kg) significantly increased muscle crude protein content and increased hepatopancreas alkaline phosphatase (AKP), superoxide dismutase (SOD), and catalase (CAT) activity. Astaxanthin (75-100 mg/kg) significantly increased the total antioxidant capacity (T-AOC) and acid phosphatase (ACP) of the hepatopancreas and decreased the malondialdehyde (MDA) content of B. areolata. Astaxanthin significantly induced the expression levels of functional genes, such as SOD, Cu/ZnSOD, ferritin, ACP, and CYC in hepatopancreas and increased the survival rate of B. areolata under ammonia stress. The addition of 75-100 mg/kg astaxanthin to the feed improved the growth performance, muscle composition, immune function, and resistance to ammonia stress of B. areolata.

Mechanism analysis of Buyang Huanwu decoction in treating atherosclerosis based on network pharmacology and in vitro experiments.

Atherosclerosis (AS) is one of the main risk factors of ischemic cardiovascular and cerebrovascular diseases. Buyang Huanwu decoction (BYHWT) is a classic Chinese medicine prescription that is used for treating AS. However, the underlying pharmacological mechanism remains unclear. This study aims to clarify the molecular mechanism of BYHWT in treatment of AS through network pharmacology and in vitro experiments. Molecular structure information and targets of core components of BYHWT were obtained from PubChem and UniProtKB databases. Genes involved in AS were obtained from DisGeNet, GeneCards and OMIM databases. The core targets of BYHWT in AS treatment were identified by protein-protein interaction (PPI) network analysis with STRING platform, and analyzed by gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway enrichment analysis. Molecular docking was used to verify the binding affinity between the core targets and the bioactive ingredients. HUVEC viability, inflammatory response and mRNA expression levels of core target genes were evaluated by cell counting kit 8 assay, enzyme-linked immunosorbent assay (ELISA) and qRT-PCR. A total of 60 candidate compounds and 325 predicted target genes were screened. PPI network analysis suggested that TP53, SRC, STAT3, and AKT1 may be the core targets. BYHWT in AS treatment was associated with 46 signaling pathways. GA120, baicalein, and 3,9-di-o-methylnissolin had good binding affinity with core target proteins. Baicalein treatment could significantly promoted the viability and repress the inflammatory response of HUVEC cells stimulated by ox-LDL. In addition, Baicalein can regulate the expression of core targets including AKT1, MAPK1, PIK3CA, JUN, TP53, SRC, EGFR, and ESR1. In conclusion, BYHWT and its main bioactive component baicalein, inhibit inflammatory response and modulate multiple downstream genes of endothelial cells, and show good potential to block the progression of AS and cardiovascular/cerebrovascular diseases.

Effects of dietary chitosan oligosaccharide on the growth, intestinal microbiota and immunity of juvenile red claw crayfish (Cherax quadricarinatus).

This study aimed to evaluate the potential benefits of chitosan oligosaccharide (COS) on red claw crayfish (Cherax quadricarinatus) and explore its underlying mechanisms. The crayfish were randomly divided into six groups, and the diets were supplemented with COS at levels of 0 (C0), 0.2 (C1), 0.4 (C2), 0.6 (C3), 0.8 (C4), and 1 (C5) g kg-1. Treatment with COS significantly improved the growth performance of the crayfish with a higher weight gain rate (WGR) and specific growth rate (SGR) in the C2 group compared to the C0 group. Additionally, the content of crude protein in the crayfish muscles in the C1 group was significantly higher than that of the C0 group. Regarding non-specific immunity, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and alkaline phosphatase (AKP), and the levels of expression of the genes related to immunity (SOD; anti-lipopolysaccharide factor [ALF]; thioredoxin1 [Trx1]; C-type lysozyme, [C-LZM]; and GSH-Px) in the hepatopancreas and hemolymph increased significantly (P < 0.05) after supplementation with 0.4 g kg-1 of COS, while the content of malondialdehyde (MDA) decreased (P < 0.05). The survival rate of C. quadricarinatus increased (P < 0.05) in the C2, C3, C4, and C5 groups after the challenge with Aeromonas hydrophila. This study found that COS has the potential to modulate the composition of the intestinal microbiota and significantly reduce the abundance of species of the phylum Proteobacteria and the genera Aeromonas and Vibrio in the gut of C. quadricarinatus, while the abundance of bacteria in the phylum Firmicutes and the genus Candidatus_Hepatoplasma improved significantly. This study suggests that the inclusion of COS in the diet of C. quadricarinatus can enhance growth, boost immunity, and increase resistance to infection with A. hydrophila, especially when supplemented at 0.4-0.8 g kg-1.

Microvascularized tumor assembloids model for drug delivery evaluation in colorectal cancer-derived peritoneal metastasis.

Peritoneal metastasis (PM) is a fatal state of colorectal cancer, and only a few patients may benefit from systemic chemotherapy. Although hyperthermic intraperitoneal chemotherapy (HIPEC) brings hope for affected patients, the drug development and preclinical evaluation of HIPEC are seriously lagging behind, mainly due to the lack of an ideal in vitro PM model that makes drug development over-reliant on expensive and inefficient animal experiments. This study developed an in vitro colorectal cancer PM model [microvascularized tumor assembloids (vTA)] based on an assembly strategy of endothelialized microvessels and tumor spheroids. Our data showed that the in vitro perfusion cultured vTA could maintain a similar gene expression pattern to their parental xenografts. Also, the drug penetration pattern of the in vitro HIPEC in vTA could mimic the drug delivery behavior in tumor nodules during in vivo HIPEC. More importantly, we further confirmed the feasibility of constructing a tumor burden-controlled PM animal model using vTA. In conclusion, we propose a simple and effective strategy to construct physiologically simulated PM models in vitro, thus providing a basis for PM-related drug development and preclinical evaluation of locoregional therapies. STATEMENT OF SIGNIFICANCE: This study developed an in vitro colorectal cancer peritoneal metastasis (PM) model based on microvascularized tumor assembloids (vTA) for drug evaluation. With perfusion culture, vTA could maintain a similar gene expression pattern and tumor heterogeneity to their parental xenografts. And the drug penetration pattern in vTA was similar to the drug delivery behavior in tumor nodules under in vivo treatment. Moreover, vTA was more conducive to construct PM animal models with controllable tumor burden. In conclusion, the construction of vTA could provide a new strategy for the PM-related drug development and preclinical evaluation of locoregional therapies.

Banxia Xiexin decoction alleviates AS co-depression disease by regulating the gut microbiome-lipid metabolic axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin decoction (BXD) is a classic Chinese herbal formulation consisting of 7 herbs including Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix, Glycyrrhizae Radix, Coptidis Rhizoma, and Jujubae Fructus, which can exert effects on lowering lipids and alleviating depressive mood disorders via affecting gastrointestinal tract. AIM OF THE STUDY: The pathogenesis of atherosclerosis (AS) co-depression disease has not been well studied, and the current clinical treatment strategies are not satisfactory. As a result, it is critical to find novel methods of treatment. Based on the hypothesis that the gut microbiome may promote the development of AS co-depression disease by regulating host lipid metabolism, this study sought to evaluate the effectiveness and action mechanism of BXD in regulation of the gut microbiome via an intervention in AS co-depression mice. MATERIALS AND METHODS: To determine the primary constituents of BXD, UPLC-Q/TOF-MS analysis was carried out. Sixteen C56BL/6 mice were fed normal chow as a control group; 64 ApoE-/- mice were randomized into four groups (model group and three treatment groups) and fed high-fat chow combined with daily bind stimulation for sixteen weeks to develop the AS co-depression mouse model and were administered saline or low, medium or high concentrations of BXD during the experimental modeling period. The antidepressant efficacy of BXD was examined by weighing, a sucrose preference test, an open field test, and a tail suspension experiment. The effectiveness of BXD as an anti-AS treatment was evaluated by means of biochemical indices, the HE staining method, and the Oil red O staining method. The impacts of BXD on the gut microbiome structure and brain (hippocampus and prefrontal cortex tissue) lipids in mice with the AS co-depression model were examined by 16S rDNA sequencing combined with lipidomics analysis. RESULTS: The main components of BXD include baicalin, berberine, ginsenoside Rb1, and 18 other substances. BXD could improve depression-like behavioral characteristics and AS-related indices in AS co-depression mice; BXD could regulate the abundance of some flora (phylum level: reduced abundance of Proteobacteria and Deferribacteres; genus level: reduced abundance of Clostridium_IV, Helicobacter, and Pseudoflavonifractor, Acetatifactor, Oscillibacter, which were significantly different). The lipidomics analysis showed that the differential lipids between the model and gavaged high-dose BXD (BXH) groups were enriched in glycerophospholipid metabolism, and lysophosphatidylcholine (LPC(20:3)(rep)(rep)) in the hippocampus and LPC(20:4)(rep) in the prefrontal cortex both showed downregulation in BXH. The correlation analysis illustrated that the screened differential lipids were mainly linked to Deferribacteres and Actinobacteria. CONCLUSION: BXD may exert an anti-AS co-depression therapeutic effect by modulating the abundance of some flora and thus intervening in peripheral lipid and brain lipid metabolism (via downregulation of LPC levels).

Bioimpedance Measurement of Knee Injuries Using Bipolar Electrode Configuration.

Currently, there is no suitable solution for the point-of-care diagnosis of knee injuries. A potential portable and low-cost technique for accessing and monitoring knee injuries is bioimpedance measurement. This study validated the feasibility of the bipolar electrode configuration for knee bioimpedance measurement with two electrodes placed on a fixed pair of knee acupuncture locations called Xiyan. Then, the study collected 76 valid samples to investigate the relationship between bioimpedance and knee injuries, among whom 39 patients have unilateral knee injuries, and 37 individuals have healthy knees. The self-contrast results indicated that knee injuries caused a reduction of bioimpedance of the knee by about 5% on average, which was detectable at around 100 kHz (p ≈ 0.001). Furthermore, the results analyzed by principal component analysis and support vector machines show that the detection sensitivity can reach 87.18% using the leave-one-out cross-validation. We also proposed a low-cost and portable bioimpedance measurement device that meets the needs for measuring knee joint bioimpedance.

Revealing mechanism of Caulis Sargentodoxae for the treatment of ulcerative colitis based on network pharmacology approach.

OBJECTIVE: The traditional Chinese medicine Caulis Sargentodoxae is widely used in the treatment of ulcerative colitis (UC), but the mechanism remains unknown. The present study aims to reveal its effective components, targets and pathways through network pharmacology and bioinformatics approaches. MATERIALS AND METHODS: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to identify effective components. The ligand-based targets prediction was achieved through SwissTargetPrediction and TargetNet. UC-related targets were identified using Gene Expression Omnibus (GEO) data and DisGeNET. The common targets of disease and components were constructed and analyzed by PPI network. Lastly, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses are used to explain the functions of these common targets. Components-Targets-Pathways network was visualized and analyzed to further reveal the connection between the components and targets. RESULTS: Eight active components and 102 key targets were identified to play an important role in UC. These targets were related to regulation of protein serine/threonine kinase activity, positive regulation of cell motility, response to molecule of bacterial origin, response to toxic substance, ERK1 and ERK2 cascade, peptidyl-tyrosine modification, inositol lipid-mediated signaling, cellular response to drug, regulation of inflammatory response and leukocyte migration. Moreover, HIF-1 signaling pathway and PI3K-Akt signaling pathway were the key targets involved in UC-related signaling pathways. CONCLUSION: The eight active components of Caulis Sargentodoxae mainly play a therapeutic role for UC through synergistic regulation of HIF-1 signaling pathway and PI3K-Akt signaling pathway.

Ginsenoside Rg1 alleviates ANIT-induced intrahepatic cholestasis in rats via activating farnesoid X receptor and regulating transporters and metabolic enzymes.

Ginsenoside Rg1 is an active ingredient extracted from the roots of ginsenoside, and an α-naphthylisothiocyanate (ANIT)-induced rat model of intrahepatic cholestasis was used to investigate the protective effect of Rg1 on cholestasis. 48 SD male rats were randomly divided into 6 groups: control group, model group, UDCA group (ursodeoxycholic acid), low-dose Rg1 group (10 mg/kg), medium-dose Rg1 group (20 mg/kg) and high-dose Rg1 group (40 mg/kg). The model group, the UDCA group and all the Rg1 group were then intragastrically administered with 80 mg/kg ANIT, and the control group were given equal volume of olive oil. Then the pathological changes in liver tissue were observed, the secretion of bile in the bile duct was measured, and the biochemical markers in serum were quantified, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyl transfer peptidase (GTP) and the content of total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA). The contents of inflammatory mediators in serum were quantified, including tumor necrosis factor (TNF-α), γ-interferon (IFN-γ) and interleukin-1ß (IL-1ß). The contents of superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) in liver homogenate were quantified. Expression of farnesoid X receptor (FXR), transporters and metabolic enzymes in liver tissue was monitored. Rg1 treatment improved liver tissue pathological damage, promoted bile secretion and significantly reduced serum levels of the intrahepatic cholestasis markers ALT, AST, ALP, GTP, TBIL, DBIL and TBA. Rg1 increased the activity of SOD and GSH-Px in liver homogenate, while, reducing the serum levels of MDA and inflammatory mediators. Rg1 also regulated the expression of FXR, bile acid transporters and metabolic enzymes. Overall, Rg1 alleviated liver injury by improving secretion of bile and normalizing the activity of enzymes in the serum. The protective mechanism appeared to be related to the activation of FXR and regulation of liver transporters and metabolic enzymes.

The targeting of non­coding RNAs by curcumin: Facts and hopes for cancer therapy (Review).

Curcumin [(1E,6E)­1,7­bis(4­hydroxy­3­-methoxyphenyl) hepta­1,6­diene­3,5­dione] is a natural polyphenol that is derived from the turmeric plant (curcuma longa L.). Curcumin is widely used in food coloring, preservatives, and condiments. Curcumin possesses anti­tumor, anti­oxidative and anti­inflammatory efficacy, as well as other pharmacological effects. Emerging evidence indicates that curcumin alters microRNAs (miRNAs) and long non­coding RNAs (lncRNAs) in various types of cancers. Both miRNAs and lncRNAs are non­coding RNAs that can epigenetically modulate the expression of multiple genes via post­transcriptional regulation. In the present review, the interactions between curcumin and non­coding RNAs are summarized in numerous types of cancers, including lung, colorectal, prostate, breast, nasopharyngeal, pancreatic, blood, and ovarian cancer, and the vital non­coding RNAs and their downstream targets are described.

Ginsenoside Rg1 Protects against Non-alcoholic Fatty Liver Disease by Ameliorating Lipid Peroxidation, Endoplasmic Reticulum Stress, and Inflammasome Activation.

Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. The purpose of this study is to investigate the protective effects of ginsenoside Rg1 (Rg1), an active ingredient of a natural medicine, and further clarify its protective mechanisms, in a mouse model of NAFLD induced by a high-fat diet. Rg1 significantly reduced liver weight, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), liver free fatty acids (FFAs) and malondialdehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Rg1 also upregulated the expression of peroxisome proliferator-activated receptor-alpha (PPARα), which stimulated fatty acid beta oxidation and promoted the metabolism of FFAs and TG. It also suppressed the expression of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), cysteine-containing aspartate-specific proteases 12 (Caspase 12), and glucose-regulated protein78 (GRP78), which reduced endoplasmic reticulum (ER) stress. Furthermore, Rg1 alleviated liver inflammation by inhibiting the activation of nucleotide binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) and thus reduced the production of inflammatory cytokines, such as interleukin 1-beta (IL-1ß) and interleukin 18 (IL-18). These results suggested that Rg1 may protect against NAFLD, through regulation of lipid peroxidation, ER stress and inflammasome activation.

Structure Identification and In Vitro Anticancer Activity of Lathyrol-3-phenylacetate-5,15-diacetate.

Natural products from the genus Euphorbia show attention-attracting activities, such as anticancer activity. In this article, classical isolation and structure identification were used in a study on Caper Euphorbia Seed. Subsequently, MTT and wound healing assays, flow cytometry, western blotting, Hoechst 33258 staining and fluorescence microscopy examination were applied to investigate the anticancer activity of the obtained compounds. In a result, lathyrol-3-phenyl- acetate-5,15-diacetate (deoxy Euphorbia factor L1, DEFL1) was isolated from Caper Euphorbia Seed. Moreover, the NMR signals were totally assigned. DEFL1 showed potent inhibition against lung cancer A549 cells, with an IC50 value of 17.51 ± 0.85 µM. Furthermore, DEFL1 suppressed wound healing of A549 cells in a concentration-dependent manner. Mechanically, DEFL1 induced apoptosis, with involvement of an increase of reactive oxygen species (ROS), decrease of mitochondrial membrane potential (ΔΨm), release of cytochrome c, activity raise of caspase-9 and 3. Characteristic features of apoptosis were observed by fluorescence microscopy. In summary, DEFL1 inhibited growth and induced apoptosis in lung cancer A549 cells via a mitochondrial pathway.

Identification of a New Series of Potent Adenosine A2A Receptor Antagonists Based on 4-Amino-5-carbonitrile Pyrimidine Template for the Treatment of Parkinson's Disease.

Adenosine receptor A2A antagonists have emerged as potential treatment for Parkinson's disease in the past decade. We have recently reported a series of adenosine receptor antagonists using heterocycles as bioisosteres for a potentially unstable acetamide. These compounds, while showing excellent potency and ligand efficiency, suffered from moderate cytochrome P450 inhibition and high clearance. Here we report a new series of adenosine receptor A2A antagonists based on a 4-amino-5-carbonitrile pyrimidine template. Compounds from this new template exhibit excellent potency and ligand efficiency with low cytochrome P450 inhibition. Although the clearance remains moderate to high, the leading compound, when dosed orally as low as 3 mg/kg, demonstrated excellent efficacy in the haloperidol induced catalepsy rat model for Parkinson's disease.

Nitrogen-doped graphene network supported copper nanoparticles encapsulated with graphene shells for surface-enhanced Raman scattering.

In this study, we demonstrated nitrogen-doped graphene network supported few-layered graphene shell encapsulated Cu nanoparticles (NPs) (Cu@G-NGNs) as a sensing platform, which were constructed by a simple and scalable in situ chemical vapor deposition (CVD) technique with the assistance of a self-assembled three-dimensional (3D) NaCl template. Compared with pure Cu NPs and graphene decorated Cu NPs, the graphene shells can strengthen the plasmonic coupling between graphene and Cu, thereby contributing to an obvious improvement in the local electromagnetic field that was validated by finite element numerical simulations, while the 3D nitrogen-doped graphene walls with a large surface area facilitated molecule adsorption and the doped nitrogen atoms embedded in the graphene lattice can reduce the surface energy of the system. With these merits, a good surface enhanced Raman spectroscopy (SERS) activity of the 3D Cu@G-NGN painting film on glass was demonstrated using rhodamine 6G and crystal violet as model analytes, exhibiting a satisfactory sensitivity, reproducibility and stability. As far as we know, this is the first report on the in situ synthesis of nitrogen-doped graphene/copper nanocomposites and this facile and low-cost Cu-based strategy tends to be a good supplement to Ag and Au based substrates for SERS applications.

Ginsenosides Rg1 from Panax ginseng: A Potential Therapy for Acute Liver Failure Patients?

Acute liver failure (ALF) is a rapidly progressing critical illness with a high mortality rate. Circulating inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play a significant role in the pathophysiology of ALF through promoting hepatocellular apoptosis. Ginsenoside Rg1, the primary active ingredient in Panax ginseng (also termed Asian or Korean ginseng), has been reported to inhibit TNF-α production and has been shown to significantly attenuate liver fibrosis development. Here, we assessed ginsenoside Rg1's potential as a therapy for ALF by investigating the effect of ginsenoside Rg1 treatment on circulating inflammatory markers, hepatocellular apoptosis, and relevant apoptotic signaling pathways in a well-established murine ALF model. We found that ginsenoside Rg1 significantly reduces liver damage in a murine ALF model through inhibiting TNF-α-induced, caspase-dependent hepatocellular apoptosis. These results support the further investigation of ginsenoside Rg1 as a therapeutic candidate for ALF.