Mei-Na Jin

Alkaloids from Pachysandra terminalis inhibit breast cancer invasion and have potential for development as antimetastasis therapeutic agents.

The aim of the present study was to identify potentially useful natural compounds for the development of novel therapeutic agents to inhibit metastasis. A phytochemical investigation of Pachysandra terminalis resulted in the isolation of seven new pregnane alkaloids, terminamines A-G (1-7), and seven known alkaloids (8-14). The structures of 1-7 were elucidated by 1D- and 2D-NMR spectroscopic and mass spectrometric methods. Compounds 1-5 and 8-14 inhibited the migration of MB-MDA-231 breast cancer cells induced by the chemokine epithelial growth factor. In addition, compound 1 inhibited phosphorylation of integrin β(1), which plays an important role in MB-MDA-231 cell adhesion and metastasis.

Synthesis and antimetastatic effects of E-salignone amide derivatives.

Preclinical Research

Synthesis and Antidiabetic Activity of 5,7-Dihydroxyflavonoids and Analogs

In a study to evaluate the structural elements essential for the antidiabetic activity of flavonoids, we synthesized two series of flavonoids, 5,7‐dihydroxyflavanones and 5,7‐dihydroxyflavones. In a screening for potential antidiabetic activity, most of the flavonoids showed a remarkable in vitro activity, and compounds 1f, 2d, and 3c were significantly more effective than the positive control, metformin. The biological activity was mainly affected by structural modification at the ring B moiety of the flavonoid skeleton. The results suggest that 5,7‐dihydroxyflavonoids can be considered as promising candidates in the development of new antidiabetic lead compounds.

Antidepressant-like effect of the saponins part of ethanol extract from SHF.

ETHNOPHARMACOLOGICAL RELEVANCE Suanzaorenhehuan Formula (SHF) has been used for treating depression-like disorders for many years in China. The saponins part of the SHF (SSHF) extract was the antidepressant effective component. AIM OF STUDY To investigate the antidepressant-like effect of SSHF and its possible mechanisms. MATERIALS AND METHODS Experimental approaches including the forced swim test (FST), the tail suspension test (TST) and unpredictable chronic mild stress (UCMS) were used to evaluate the effects of SSHF. The possible mechanisms were explored by measuring monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme (MAO) activities, antioxidant enzyme activities and free radicals levels in the brains of UCMS-exposed mice. RESULTS The results showed that SSHF (10, 20, 40mg/kg) significantly decreased the immobility period in FST and TST in mice after two-week treatment. Whereas, SSHF had no significant effect on locomotor activity in mice. It was also found that the serotonin (5-HT) and noradrenaline (NE) levels in the hippocampus and frontal cortex were significantly increased only in 40mg/kg SSHF treated mice. In addition, SSHF (10, 20, 40mg/kg) significantly inhibited monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) after 21-day UCMS exposure. SSHF (10, 20, 40mg/kg) significantly decreased the nitrous oxide (NO) levels, and increased the activities of total antioxidant capability (T-AOC), glutathione peroxidase (GSH-PX), and catalase (CAT) in different degrees in the brains of UCMS-exposed mice. CONCLUSIONS Our results suggested that SSHF may effectively produce an antidepressant-like effect, which appeared to involve the serotonergic, noradrenergic, monoamine oxidase enzyme and antioxidant systems.

Anti-obesity and anti-diabetic effects of flavonoid derivative (Fla-CN) via microRNA in high fat diet induced obesity mice

3-O-[(E)-4-(4-cyanophenyl)-2-oxobut-3-en-1-yl]kaempferol (Fla-CN), a semi-synthesized flavonoid derivative of tiliroside, reduces whole-body adiposity, ameliorates metabolic lipid disorder, improves insulin sensitivity and benefits other disorders characterized by insulin resistance in high fat diet induced obesity mice. The improvement of insulin sensitivity and the reduction of weight gain are correlated with the changes of leptin and adiponectin levels. As a result, Fla-CN treatment could increase the expressions of pAMPK and miR-27 in the liver and adipose tissues. Meanwhile, we discovered that the expressions of various adipogenesis genes were downregulated, which were target genes of miR-27. This is the first report for the action of miR-27 by flavonoid derivative in rodents. The action of Fla-CN might be through multiple approaches including AMPK activation and enhancement in miR-27 expression.

Flavonoid derivative (Fla-CN) inhibited adipocyte differentiation via activating AMPK and up-regulating microRNA-27 in 3T3-L1 cells.

Abstract Fla‐CN (3‐O‐[(E)‐4‐(4‐cyanophenyl)‐2‐oxobut‐3‐en‐1‐yl] kaempferol) is a semi‐synthesized flavonoid derivative of tiliroside which exhibited anti‐diabetic effect in vivo. Our previous study revealed the role of Fla‐CN in anti‐obesity and anti‐diabetes in vivo, but the underlying mechanism remained to be addressed. The present study aimed to investigate the mechanism of anti‐adipogenesis in vitro. Fla‐CN markedly inhibited intracellular lipid accumulation in a dose‐dependent manner, and the inhibitory effect was mainly limited to the early stage of adipocyte differentiation in vitro. Further investigations revealed that Fla‐CN up‐regulated the expression level of miR‐27a/b and suppressed its target genes expression including peroxisome proliferator‐activated receptor gamma (PPAR&ggr;) and CCAAT/enhancer binding protein &agr; (C/EBP&agr;). Furthermore, the phosphorylation of AMP‐activated protein kinase (AMPK) was also enhanced by Fla‐CN in pre‐adipocyte differentiation. These effects were abolished when cells were treated with miR‐27a/b inhibitor and AMPK inhibitor Compound C. Additionally, Fla‐CN reduced the expressions of adipocyte‐specific genes such as sterol regulatory element‐binding transcription factor 1c (SREBP‐1c), fatty acid synthase (FAS) and adipocyte fatty acid binding protein (aP2). In conclusion, these results suggested a mechanism of Fla‐CN for adipocyte differentiation inhibition of 3T3‐L1 cells through miR‐27a/b induction and AMPK activation.

A New Megastigmane Alkaloid from Pachysandra terminalis with Antitumor Metastasis Effect

9-(N,N-Dimethyl)-4,7-megastigmedien-3-one (1) was isolated from Pachysandra terminalis and identified by 1D and 2D NMR spectroscopic and mass spectrometric methods. Compound 1 revealed significant anti-metastasis effect on cancer cell migration and invasion through suppressing the expressions of p-PKCζ and p-integrin β1 in human breast cancer cells, and also showed anti-angiogenic activity on human umbilical vein endothelial cells.

Antitumor metastasis pregnane alkaloids from Pachysandra terminalis

Three new pregnane alkaloids, named terminamines H–J (1–3), together with two known alkaloids (4 and 5), were isolated from the ethanol extract of Pachysandra terminalis. The structures of isolated compounds were elucidated by spectroscopic methods, including 1H and 13C NMR, 2D NMR, and HR-ESI-MS. Compounds 1, 4, and 5 revealed significant anti-metastasis activities. In addition, compound 1 inhibited the expression of p-PKCζ in MDA-MB-231 cells, and compound 4 inhibited the expressions of p-PKCζ in MDA-MB-231 and A549 cells.

Flavonoid derivative exerts an antidiabetic effect via AMPK activation in diet-induced obesity mice

Abstract In our previous study, a derivative of tiliroside, 3-O-[(E)-4-(4-ethoxyphenyl)-2-oxobut-3-en-1-yl]kaempferol (Fla-OEt) significantly enhanced glucose consumption in insulin resistant HepG2 cells. This article deals with the antihyperglycemic and antihyperlipidemic effects of Fla-OEt in diet-induced obesity (DIO) mice. Daily administration of Fla-OEt significantly decreased oral glucose tolerance test, intraperitoneal insulin tolerance test and serum lipids. Hyperinsulinemic–euglycemic clamp and the ratio of high-density-lipoprotein/low-density-lipoprotein with Fla-OEt treatment were increased comparing with high-fat diet (HFD) group, so lipid metabolism was improved. Histopathology examination showed that the Fla-OEt restored the damage of adipose tissues and liver in DIO mice. Moreover, compared with HFD group, Fla-OEt treatment significantly increased the phosphorylation of AMPK and ACC in adiposity tissues, liver, and muscles. The mechanism of its action might be the activation of AMPK pathway. It appears that Fla-OEt is worth further study for development as a lead compound for a potential antidiabetic agent. Graphical abstract

Synthesis and Antimetastatic Effect of E-salignone

Our research group showed that E-salignone inhibited the invasion of human breast cancer MDA-MB-231 cells induced by the chemokine epidermal growth factor (EGF). Due to the limited natural resources, we had to prepare sizable quantities of E-salignone for the antimetastasis investigation. E-Salignone was synthesized by methylation of the corresponding amine by reductive amination with paraformaldehyde in the presence of sodium triacetoxyhydroborate. The synthesized E-salignone exhibited significant inhibitory effects on the invasion of human MDA-MB-231 breast cancer cells and non-small cell lung cancer cells (A549) induced by the chemokine EGF with IC50 values of 0.36 μM and 5.77 μM, respectively. Since angiogenesis is required for tumor metastasis, anti-angiogenesis is consider a promising approach for tumor therapy. In our investigation of antimetastatic activity, E-salignone potently inhibited the migration of HUVEC and MDA-MB-231 in the wound healing assay.