Studies on Labisia pumila var. alata extract with phytoestrogenic effects: impact on biological activities and gene expression

摘要

In Malaysia, Labisia pumila var. alata (LPva) has been used by women for generations.Traditionally, the plant is boiled, either alone or in decoction with other herbs. It is claimed tohave health benefits such as to contract the uterus after childbirth, allay painful menstruation andirregular periods and to generally alleviate fatigue. Therefore, we aimed to investigate thescientific basis of LPva phytoestrogenic activities in different animal models and cell lines.In Paper I, we investigated the effects of a standardized water extract of LPva (10, 20 and 50mg/kg body weight/day) and compared to estrogen replacement (ERT), on body weight gain,uterus weight, adipose tissue mRNA and protein levels of adipokines in ovariectomized (OVX)female Sprague-Dawley rats. After a month of oral treatment, ERT- and LPva-treated OVX ratsshowed significantly less weight gain compared to untreated OVX rats. Ovariectomy causedplasma leptin levels to decrease significantly but when treated with LPva or ERT, plasma leptinand mRNA levels increased to levels higher or comparable to that seen in the sham operatedcontrol rats (SHAM). In contrast, the elevated plasma resistin concentrations in OVX rats weresignificantly reduced in rats given ERT and LPva extracts. The uterus to body weight ratio ofuntreated OVX rats was significantly low compared to SHAM, but showed dose-dependentincrease upon treatment with LPva. The study provides evidence that LPva exerts uterotrophiceffect and regulates body weight gain.In Paper II, we evaluated the effects of LPva on 11-beta hydroxysteroid dehydrogenase type-1(Hsd11b1) and corticosterone (CORT) expressions in OVX rats. Hsd11b1 was chosen because itwas highly expressed in a microarray analysis of OVX rat liver compared to SHAM. Usingsamples from Paper I, Hsd11b1 expressions were measured and found that mRNA levels inliver of OVX rats were significantly increased when compared to SHAM and restored to normallevel after treatment with LPva or ERT. In adipose tissues, the Hsd11b1 mRNA level of OVXgroup was increased by 55 % in comparison to SHAM, normalized in LPva. Protein levels of11β-HSD1 were down-regulated in both liver and adipose tissue of LPva- and ERT-treated rats,in comparison to OVX rats. CORT levels in OVX group increased significantly compared toSHAM. The results showed that the treatment with LPva normalized Hsd11b1 mRNAexpression and 11β-HSD1 levels in OVX rats, in parallel with decreased CORT levels. Thus,LPva is useful for postmenopausal treatment based upon its regulation at body weight partiallyvia inhibition of Hsd11b1 expression in adipose tissue and liver.In Paper III, we investigated the effect of LPva on body composition and metabolic features ina rat model of polycystic ovary syndrome (PCOS). LPva (50 mg/kg body weight daily)increased uterine weight (27%) and insulin sensitivity (36%) measured by euglycemichyperinsulinemic clamp compared to control PCOS rats. Lipid profile was improved in LPvarats and plasma resistin levels were increased. In adipose tissue, LPva decreased leptin mRNAexpression but did not affect expression of resistin and adiponectin. No effects on bodycomposition, adipocyte size or plasma leptin levels were observed. Therefore, in this study,LPva increases uterine weight, indicating estrogenic effects, and improves insulin sensitivity andlipid profile in PCOS rats without affecting body composition.In Paper IV, the effects of LPva treatment on urinary tract infection (UTI) were investigated inan infection model using uropathogenic Escherichia coli (UPEC) strain CFT073 and thebladder epithelial cell line, T24. Our results demonstrate that LPva treatment induced apoptosisand significantly reduced the number of intracellular E.coli in bladder epithelial cells. LPvainducedapoptosis was coupled with up-regulated expression of pro-apoptotic caveolin-1. LPvatreatment down-regulated the expression of β1 integrin as indicated by reduced levels of genespecific mRNA. However, LPva did not exhibit direct antimicrobial properties and did notinfluence antimicrobial peptide levels in cells. These findings suggest that LPva facilitates theexfoliation of infected bladder cells and may thereby mediate beneficial effects during UTI.