Quercetin is a well-known plant flavonol and antioxidant; however, there has been some debate regarding the efficacy and safety of native quercetin as a skin-whitening agent via tyrosinase ...inhibition. Several researchers have synthesized quercetin derivatives as low-toxicity antioxidants and whitening agents. However, no suitable quercetin derivatives have been reported to date. In this study, a novel quercetin derivative was synthesized by the S
2 reaction using quercetin and oleyl bromide. The relationship between the structures and activities of quercetin derivatives as anti-melanogenic agents was assessed using in vitro enzyme kinetics, molecular docking, and quenching studies; cell line experiments; and in vivo zebrafish model studies. Novel 3,7-dioleylquercetin (OQ) exhibited a low cytotoxic concentration level at >100 µg/mL (125 µM), which is five times less toxic than native quercetin. The inhibition mechanism showed that OQ is a competitive inhibitor, similar to native quercetin. Expression of tyrosinase, tyrosinase-related protein 1 (TRP-1) and tyrosinase-related protein 2 (TRP-2), and microphthalmia-associated transcription factor was inhibited in B16F10 melanoma cell lines. mRNA transcription levels of tyrosinase, TRP-1, and TRP-2 decreased in a dose-dependent manner. Melanin formation was confirmed in the zebrafish model using quercetin derivatives. Therefore, OQ might be a valuable asset for the development of novel skin-whitening agents.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Panax quinquefolius, a popular medicinal herb, has been cultivated in China for many years. In this work, the region-specific profiles of metabolites in P. quinquefolius from Wendeng was investigated ...using liquid-chromatography–quadrupole–time-of-flight-(LC–Q–TOF)-based metabolomics analysis. The three most abundant biomarkers, identified as ginsenoside Rb3, notoginsenoside R1, and ginsenoside Rc, were the representative chemical components employed in the network pharmacology analysis. In addition, molecular docking and western blotting analyses revealed that the three compounds were effective binding ligands with Hsp90α, resulting in the inactivation of SRC and PI3K kinase, which eventually led to the inactivation of the Akt and ERK pathways and lung cancer suppression. The outcomes obtained herein demonstrated the intriguing chemical characteristics and potential functional activities of P. quinquefolius from Wendeng.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Clozapine is one of the antipsychotic drugs for treating schizophrenia, but its cardiotoxicity was the primary obstacle for its clinical use, due to the unknown mechanism of clozapine-induced ...cardiotoxicity. In this study, we studied the cardiotoxicity of clozapine by employing zebrafish embryos. Acute clozapine exposure showed dose-dependent mortality with the LC
50
at 59.36 μmol L
−1
and 49.60 μmol L
−1
when determined at 48 and 72 h post exposure, respectively. Morphological abnormalities like pericardial edema, incompletely heart looping, and bradycardia were detected after clozapine exposure in a time- and dose-dependent manner. Clozapine treatment also resulted in a slower heart rate and disturbed rhythm in zebrafish embryos. Also, oxidative stress was observed after clozapine exposure by measurement of ROS (reactive oxygen species), MDA (a lipid peroxidation marker), antioxidant enzyme activities, and oxidative stress-related gene expression. The elevation of inflammation coincided with oxidative stress by the assay of inflammation-related genes expression accompanied by clozapine incubation. Collectively, the data indicate that clozapine might achieve cardiotoxic effect in zebrafish larva through increasing oxidative stress, attenuation in antioxidant defense, and up-regulation of inflammatory cytokines. The data could provide experimental explanations for myocarditis and pericarditis induced by clozapine in clinics, and help find an effective solution to reduce its cardiotoxicity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Bacillus amyloliquefaciens
has been widely used as a probiotic in the field of biological control,and its antibacterial compounds plays an important role in the prevention and control of plant, ...livestock and poultry diseases. It has the advantages of green, safe and efficiency. This study aims to separate and purify active ingredient from
Bacillus amyloliquefaciens
GN59 and study its antibacterial activity. A novel compound was isolated from GN59 by column chromatography on silica gel and HPLC purification. The chemical structure was identified as α-
d
-glucopyranosyl-(1 → 1′)-3′-amino-3′-deoxy-β-
d
-glucopyranoside (a,β-3-trehalosamine) on the basis of spectroscopic analysis. This is the first report about a,β-3-trehalosamine isolated from biological resources on an antibiotic activity against pathogenic bacterium. The 3′-neotrehalosamine displayed antibacterial activity across a broad spectrum of microorganisms, including different gram-positive and gram-negative bacteria, with minimal inhibitory concentration (MIC) values ranging from 0.5 to 0.7 mg/mL. The results indicated that the 3′-neotrehalosamine from GN59 might be a potential candidate for bactericide.
Aim of the study: Ischemic diseases have a huge impact on people’s health, which can cause blood supply blockage or restriction in specific tissues. Researchers must develop novel drugs with great ...efficacy and low toxicity for the prevention and treatment of such diseases. Isopropyl caffeic acid (KYZ) was one of the metabolites of caffeic acid
in vivo
. This study is to explore the protective effect and mechanism of KYZ on ischemic disease from the perspective of angiogenesis
in vivo
and
in vitro
, providing support for the treatment of ischemic diseases and the discovery of a new candidate drug. Methods: The network pharmacology and molecular docking were used to predict the targets of KYZ. In addition, the effects of KYZ on damaged and normal blood vessels were evaluated using the
Tg (fli1: EGFP)
transgenic zebrafish. The HUVECs model was used to study the effects of KYZ on proliferation, migration, and tube formation. The same dosage of caffeic acid (CA) was also administered
in vitro
and
in vivo
at the same time to assess the pharmacodynamic difference between the two compounds. Western Blot and ELISA methods were used to detect the expression of related target proteins. Results: The result from the network pharmacology indicated that the targets of KYZ were related to angiogenesis. It was also found that KYZ could repair the vascular damage induced by the PTK787 and promote the growth of subintestinal vessels in normal zebrafish. The result also indicated that KYZ’s angiogenic ability is better than the precursor compound CA. In HUVECs, KYZ could promote cell proliferation, migration, and tube formation. Further mechanistic study suggested that the KYZ could induce the release of VEGF factor in HUVECs, up-regulate the expression of VEGFR2, and activate the PI3K/AKT and MEK/ERK signaling pathways. Conclusions: These data show that KYZ may promote angiogenesis through VEGF, PI3K/AKT, and MEK/ERK signaling pathways, suggesting that KYZ exhibited great potential in the treatment of ischemic cardio-cerebrovascular diseases.
Aconitine (AC), one of the bioactive diterpenoid alkaloids extracted from
plants, is widely used in traditional herbal medicine to treat various diseases. Emerging evidence indicates that AC has ...attracted great interest for its wide cardiotoxicity and neurotoxicity. However, the toxic effects of AC on embryonic development and its underlying mechanisms remain unclear. Here, a developmental toxicity assay of AC was performed on zebrafish embryos from 4 to 96 h post fertilization (hpf), and its underlying mechanisms were discussed. AC exposure impaired the cardiac, liver, and neurodevelopment. Especially, a high dose of AC (7.27 and 8.23 μM) exposure resulted in malformations at 72 and 96 hpf, including reduced body length, curved body shape, pericardial edema, yolk retention, swim bladder and brain developmental deficiency, and degeneration of dopaminergic neurons. High-concentration AC exposure caused a deficient cardiovascular system with cardiac dysfunctions, increased heart rates at 72 and 96 hpf, and reduced locomotor behavior at 120 hpf. AC treatment significantly increased the ROS level and triggered cell apoptosis in the heart and brain regions of embryos at 96 hpf in 7.27 and 8.23 μM AC treatment zebrafish. Oxidative stress was confirmed by reduced levels of T-SOD activity associated with accumulation of lipid peroxidation in larvae. The expression levels of oxidative stress-related genes (
,
,
, and
)
and
were significantly downregulated at 96 hpf. The expression pattern of JNK and mitochondrial apoptosis-related genes (
,
,
,
, and
) was significantly upregulated. Taken together, all these parameters collectively provide the first evidence of AC-induced developmental toxicity in zebrafish embryo/larvae through ROS-medicated mitochondrial apoptosis involving Nrf2/HO-1 and JNK/Erk pathways.
Alzheimer’s disease (AD) is the most prevalent neural disorder. However, the therapeutic agents for AD are limited.
Eucommia ulmoides
Olive (EUO) is widely used as a traditional Chinese herb to treat ...various neurodegenerative disorders. Therefore, we investigated whether the extracts of EUO male flower (EUMF) have therapeutic effects against AD. We focused on the flavonoids of EUMF and identified the composition using a targeted HPLC-MS analysis. As a result, 125 flavonoids and flavanols, 32 flavanones, 22 isoflavonoids, 11 chalcones and dihydrochalcones, and 17 anthocyanins were identified. Then, the anti-AD effects of the EUMF were tested by using zebrafish AD model. The behavioral changes were detected by automated video-tracking system. Aβ deposition was assayed by thioflavin S staining. Ache activity and cell apoptosis in zebrafish were tested by, Acetylcholine Assay Kit and TUNEL assay, respectively. The results showed that EUMF significantly rescued the dyskinesia of zebrafish and inhibited Aβ deposition, Ache activity, and occurrence of cell apoptosis in the head of zebrafish induced by AlCl
3
. We also investigated the mechanism underlying anti-AD effects of EUMF by RT-qPCR and found that EUMF ameliorated AD-like symptoms possibly through inhibiting excessive autophagy and the abnormal expressions of
ache
and
slc6a3
genes. In summary, our findings suggested EUMF can be a therapeutic candidate for AD treatment.
Lipids are key factors in nutrition, structural function, metabolic features, and other biological functions. In this study, the lipids from the heads of four species of shrimp (
(FC),
(PJ),
(PV), ...and
(PCC)) were compared and characterized based on UPLC-Q-Exactive Orbitrap/MS. We compared the differences in lipid composition of four kinds of shrimp head using multivariate analysis. In addition, a zebrafish model was used to evaluate pro-angiogenic, anti-inflammatory, anti-thrombotic, and cardioprotective activities of the shrimp head lipids. The lipids from the four kinds of shrimp head had different degrees of pro-angiogenic activities, and the activities of PCC and PJ shrimp lipids were more significant than those of the other two species. Four lipid groups displayed strong anti-inflammatory activities. For antithrombotic activity, only PCC (25 μg/mL) and PV (100 μg/mL) groups showed obvious activity. In terms of cardioprotective activity, the four kinds of lipid groups significantly increased the zebrafish heart rhythms. The heart distances were shortened, except for those of the FC (100 μg/mL) and PJ (25 μg/mL) groups. Our comprehensive lipidomics analysis and bioactivity study of lipids from different sources could provide a basis for the better utilization of shrimp.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Berberine is a naturally occurring isoquinoline alkaloid with moderate antitumor effect. It has been proved that berberine can affect the microenvironment of cancer cells, which is critical for ...cancer therapy and improving human immunity. Therefore, structural modification of berberine to obtain derivatives with high antitumor effect attracts the great attention of scientists. This paper describes the synthesis and in vitro antitumor investigation of some 9-
O
-alkylated and carbohydrate-modified berberine derivatives using high efficient strategy. The cytotoxicity investigation was accomplished on different cancer cell lines by the well-optimized MTT assay, and the results indicated that 9-
O
-hydrophobic modified berberine derivative
9
with long lipid chain showed promising in vitro antitumor activity with the IC
50
value as low as 4.87 ± 0.24 μM. Percentage of apoptosis was measured by a Hoechst 33342/PI staining strategy on HeLa cells, which revealed that compound
9
could induce 84% of cell apoptosis at very low concentration (5 μM). Flow cytometry analysis indicated that compound
9
might inhibit HeLa cell proliferation by G2 phase arrest. The expression of various cell apoptosis proteins was measured by western blot analysis, and the results indicated that compound
9
could induce over-expression of Caspase-3, Parp, and Bax and down-regulate the expression of P53 and PCNA. All these data indicated the high potential of compound
9
for developing novel anticancer drugs.
Graphic Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background Polyphyllin VII (PP7), a steroidal saponin from P. polyphylla has been found to exert strong anticancer activity. Little is known about the anti-angiogenesis and anti-metastasis properties ...of PP7. In this study, the anti-angiogenic and anti-metastatic effects of PP7 on HCC and the molecular mechanisms were evaluated. Methods Effect of PP7 on angiogenesis was assessed by tube formation assay and applied a transgenic Tg(fli1:EGFP) zebrafish model. Effects of PP7 on tumor metastasis and invasion were examined in cell migration and invasion assay, zebrafish tumor xenograft models and lung metastasis mouse models. The protein levels were examined by Western blotting. Results PP7 significantly decreased the tube formation of human umbilical vein endothelial cells, the number and length of ISVs and SIVs of transgenic zebrafish, and the metastasis and invasion of cancer cells in vitro and in vivo. The anti-angiogenic and anti-metastatic effects of PP7 in HepG2 cells were attributable, at least partially, to downregulated NF-κB/MMP-9/VEGF signaling pathway. Conclusion This study demonstrates that PP7 possesses strong anti-angiogenesis and anti-metastasis activities, suggesting that PP7 could be a potential candidate agent for HCC treatment. Keywords: Polyphyllin VII, Hepatocellular carcinoma cells, Anti-angiogenesis, Anti-metastasis, NF-κB/MMP-9/VEGF pathway
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