Ganoderma triterpenes (GTs) are the major secondary metabolites of Ganoderma lucidum, a traditional Chinese medicine, popularly used for complementary cancer therapy. GTs are lanostane-tetracyclic ...triterpenes. They have been reported to possess anti-tumor, anti-inflammation, antioxidant, antimicrobial and blood fat reducing effects. To date, 316 GTs have been found and their similar chemical structures have proved difficult to elucidate. This paper compiles 316 naturally occurring triterpenes from Ganoderma based on the literature published through January 2013 along with their structures, physiological activities and 13C-NMR spectral data.
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•Lithospermic acid (LA) promoted the length of vessels in zebrafish.•LA promoted the proliferation and migration of HUVECs under VRI-inhibited and normal conditions.•LA promoted ...angiogenesis by regulating the VEGF, PI3K-Akt and MAPK pathways.
LA, one of important phenolic acids of health food Salvia miltiorrhiza Bge. and Crocus sativus L. (Saffron) has defined proangiogenic effect. However, the mechanisms of its proangiogenic effect are unknow. The present study aimed to further evaluate the proangiogenic effect of LA and to explore the potential mechanisms. The results showed that LA restored the length of PTK787-damaged intersegmental vessels (ISVs) and promoted the germination of subintestinal vessels (SIVs) in zebrafish. LA promoted the proliferation and migration of HUVECs under VRI-inhibited and normal conditions. The results of network pharmacology, transcriptomics, and molecular docking showed that ALB, AKT1, EGFR, SRC, and MMP9 were key targets for LA to promote angiogenesis. KEGG enrichment analysis and qPCR analysis showed that LA promoted angiogenesis by regulating the VEGF, PI3K-Akt and MAPK pathways. These results indicated that LA has proangiogenic effects both in vitro and in vivo by regulating the VEGF, PI3K-Akt and MAPK pathways.
A series of novel ligustrazine-oleanolic acid (TOA) derivatives were designed, and synthesized by conjugating amino acids to the 3-hydroxy group of TOA by ester bonds. Their cytotoxicity was ...evaluated on four cancer cell lines (HepG2, HT-29, Hela and BGC-823) by standard MTT assays. The ClogP values were calculated by means of computer simulation, and logP values of both 3β-glycine ester olean-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (6a) and TOA were determined using a shake flask-ultraviolet spectrophotometry method. It was found that 6a and the 3β-L-lysine ester-6g not only displayed good cytotoxicity (IC50<3.5 μM) but also possessed better hydrophilicity than TOA. Moreover, 6a (IC50=4.884 μM) had lower nephrotoxicity than both 6g (IC50=2.310 μM) and cisplatin (CDDP, IC50=3.691 μM) on MDCK cells. Combining Giemsa and DAPI staining, it was further verified that 6a could induce HepG2 apoptosis via nuclei fragmentation and had lower nephrotoxicity. In addition, the structure-activity relationships of these derivatives are briefly discussed.
Hepatic fibrosis is a naturally occurring wound-healing reaction, with an imbalance of extracellular matrix (ECM) during tissue repair response, which can further deteriorate to hepatocellular ...carcinoma without timely treatment. Inhibiting activated hepatic stellate cell (HSC) proliferation and inducing apoptosis are the main methods for the treatment of liver fibrosis. In our previous study, we found that the TOA-glycine derivative (G-TOA) had exhibited more significant inhibitory activity against HepG2 cells and better hydrophilicity than TOA, ligustrazine (TMP), and oleanolic acid (OA). However, inhibiting activated HSC proliferation and inducing apoptosis by G-TOA had not been reported. In this paper, the selective cytotoxicity of G-TOA was evaluated on HSC-T6 cells and L02 cells, and apoptosis mechanisms were explored. It was found that G-TOA could selectively inhibit the proliferation of activated HSC-T6 cells, induce morphological changes, early apoptosis, and mitochondrial membrane potential depolarization, increase intracellular free calcium levels, downregulate the expression of NF-κB/p65 and COX-2 protein, and decrease the ratio of Bcl-2/Bax, thereby inducing HSC-T6 cell apoptosis. Thence, G-TOA might be a potential antifibrosis agent for the therapy of hepatic fibrosis, provided that it exerts anti-fibrosis effects on activated HSC-T6 cells.
Isoliquiritigenin (ISL) is an emerging natural flavonoid found in the roots of licorice, exhibits antioxidant, anti-cancer, anti-inflammatory, anti-allergic, cardioprotective, hepatoprotective and ...neuroprotective properties. However, the effect of ISL in embryonic development is yet to be elucidated, and the mechanisms underlying its target-organ toxicity and harmful side effects are still unclear. In the present study, we employed zebrafish embryos to study the developmental toxicity effect of ISL and its underlying mechanisms. Zebrafish embryos upon treatment with either vehicle control (0.1% DMSO) or ISL solutions for 4–96 h post fertilization (hpf) showed that ISL exposure instigated severe developmental toxicity in heart, liver, and nervous system. Mortality and morphological abnormalities were also observed. High concentrations of ISL exposure resulted in abnormal phenotypes and embryonic malformations including pericardial edema, swim bladder defects, yolk retention, curved body shape and shortening of body length. Moreover, ISL exposure led to significant loss of dopaminergic neurons accompanied by reduced locomotor behaviour. Apoptotic cells were predominantly located in the heart area of 96 hpf embryo. Additionally, ISL significantly increased the levels of reactive oxygen species, lipid peroxidation content and decreased antioxidant enzyme activities. The expressions pattern of apoptosis-related genes Bad, Cyto c, Caspase-9, Caspase-3 and Bax/Bcl-2 indicated that the oxidative stress–induced apoptosis triggered by ISL suggest involvement of Nrf2-HO1/JNK-ERK/mitochondrion pathways. In conclusion, here we provide first evidence that demonstrate ISL-induced dose-dependent developmental toxicity in zebrafish embryos. Furthermore, gene expression patterns in the embryos correlate the above and reveal potential genetic mechanisms of developmental toxicity.
•ISL triggered developmental toxicity in zebrafish, caused death and malformations.•ISL exposure instigated developmental toxicity in heart, liver, and nervous system.•ISL triggered apoptosis in zebrafish via Nrf2-HO1/JNK-ERK/mitochondrion pathway.
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•Soluble hydrophobic support-assisted liquid-phase synthesis technology of Abaloparatide.•Conditions of removing support Tag-OH.•Improving the synthesis conditions of Fragment 4.
...Abaloparatide, a novel parathyroid hormone-related peptide, emerges as a leading drug for treating osteoporosis in postmenopausal women at high risk of fracture. The therapeutic agent has demonstrated efficacy in significantly enhancing bone mineral density, fortifying bone strength, and stimulating bone formation. Developing a synthetic route for Abaloparatide with high-yield and purity products is of paramount importance. This paper reported a newly developed liquid-phase synthetic method based on soluble hydrophobic support assistance for the total synthesis of Abaloparatide, which has proven to be simple, scalable, and highly effective. The optimization of reaction conditions has yielded Abaloparatide with both high yield and purity, producing satisfactory results.
Artemisia vestita Wall. ex Besser is wildly distributed in the western high-altitude area of China and has been used as a Tibetan medicine to treat inflammatory diseases. We previously demonstrated ...the total flavonoids of Artemisia vestita Wall. ex Besser (TFA) showed obvious anti-inflammatory effects and its content was 276.62 mg/g. However, the chemical profile, active ingredients, and anti-inflammatory mechanisms of TFA are not clear.
This study aimed to study the components of TFA, evaluate the anti-inflammatory effects of TFA, and preliminarily predict the anti-inflammatory mechanism of TFA.
TFA was prepared by the semi-biomimetic extraction method and purified by macroporous resin. The components of TFA were analyzed based on LC-MS combined with the targeted metabolomics method. The anti-inflammatory activity of TFA was evaluated using CuSO4-induced and tail cutting-induced zebrafish inflammation models. Based on the network pharmacology method, the anti-inflammatory mechanism of the main components of TFA was preliminarily predicted.
A total of 185 components were identified in TFA. TFA showed significant anti-inflammatory effects on CuSO4-induced and tail cutting-induced zebrafish inflammation models. According to network pharmacology prediction and experimental verification, 10 compounds were identified as the main active ingredients, including 3,7-di-O-methylquercetin, Hesperetin 5-O-glucoside, Myricitrin, et al. Twenty key targets were recognized, such as TNF, AKT1, VEGFA, MMP9, EGFR, PTGS2 et al. Moreover, the TNF signaling pathway and NOD-like receptor signaling pathway were identified to play vital roles in the anti-inflammatory effects of TFA.
This study revealed the chemical profile of TFA and identified the main active ingredients, key targets, and pathways of TFA in anti-inflammatory effects, which is helpful to elucidate the pharmacodynamic substances and action mechanisms of Artemisia vestita Wall. ex Besser, to promote its clinical rational application.
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•A total of 185 components were identified in the total flavonoids of Artemisia vestita Wall. ex Besser (TFA).•TFA showed significant anti-inflammatory effects on CuSO4-induced and tail cutting-induced zebrafish inflammation models.•3,7-di-O-methylquercetin, Biorobin, Isorhamnetin-3-O-neohesperidoside, and Isoquercitrin are active ingredients of TFA.•TNF signaling pathway and NOD-like receptor signaling pathway play vital roles in the anti-inflammatory effects of TFA.
Angiogenesis is particularly important in ischemic cardiovascular diseases such as coronary heart disease (CHD). Xinkeshu tablets (XKS) are a commonly used Chinese patent medicine for CHD with a ...defined clinical effect. However, the proangiogenic effect of XKS remains unknown.
Aim of the study: We attempted to investigate the chemical composition and proangiogenic effect of XKS, as well as its underlying mechanisms.
The chemical composition of a XKS methanol extract was analyzed using a UPLC-Q-Orbitrap-MS system. The compound's proangiogenic effects were evaluated in zebrafish embryos and human umbilical vein endothelial cells (HUVECs). Furthermore, the underlying mechanisms were investigated using transcriptome assays and real-time quantitative PCR validation.
We identified 116 chemical constituents of XKS. XKS significantly stimulated subintestinal vessel plexus (SIVs) growth and rescued tyrosine kinase inhibitor (PTK787)-induced intersegmental vessels (ISVs) injury in zebrafish in a concentration-dependent manner. XKS significantly rescued the proliferation, migration capacity and tube formation of Recombinant VEGFR tyrosine kinase inhibitor II (VRI)-injured HUVECs. XKS promoted angiogenesis through multiple signaling pathways, including metabolic pathways, the PPAR signaling pathway, the AGE-RAGE signaling pathway, the NOD-like receptor signaling pathway, the VEGF signaling pathway, and the PI3K/Akt signaling pathway.
Herein, we identified 116 chemical constituents of XKS for the first time and demonstrated that XKS may regulate angiogenesis through multiple signaling pathways to treat CHD.
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The selfish On-Board-Unit (OBU) attacks Vehicular Ad-Hoc Network (VANET) by various attacks for profit. However, many existing methods are based on the principle of direct reciprocity for ...communication, which makes it easy for large-scale networks to crash when an attack occurs. In order to reduce the number of attackers in the vehicle ad hoc network and restrain the attack motivation of the OBUs, we propose an indirect reciprocal incentive mechanism based on reputation to encourage the OBUs in the VANET to help each other. Since most OBUs are in great need of network services, including potential attackers, when the loss of network services is far greater than the illegal benefits of their attacks, selfish and rational OBUs will give up attacks and take desirable behavior. In addition, to prevent some attacks from tampering with information, we also apply blockchain technology to record the behavior of OBU. The indirect reciprocity process of each OBU in VANET can be regarded as Markov Decision Process (MDP). In order to restrain the attack motivation of selfish nodes and communicate normally without knowing the attack model, an algorithm based on Deep Reinforcement Learning (DRL) is proposed to suppress attack motivation, so as to activate OBU learning in a dynamic environment and make wise decisions. Finally, through a large number of simulation experiments, the performance of our proposed algorithm is obviously better than that of the baseline strategy, and is verified by the simulation results.
•Indirect reciprocity security framework to compute and get the reputation of OBU.•Propose DSAM to learn the process of behavior selection and propagation of OBU.•Discussed the attack rate of the network with and without attack classification.•Blockchain technology to prevent malicious modification of the reputation mechanism.
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