Cytotoxic ent-Kaurane Diterpenoids from Rabdosia Rubescens.

One new (1) and 11 reported ent-kaurane diterpenoids (2-12) were received from the ethanol extract of the air-dried aerial parts of Rabdosia rubescens collected in Jiyuan. Their structures were determined in accordance with high resolution electrospray ionization mass spectroscopy, one dimensional (1D) and two-dimensional (2D) NMR spectroscopy and the data published in the literature. The cytotoxic activity of these isolated compounds was assessed against SMMC-7721, A-549, H-1299 and SW-480 cancer cell lines. Compounds 2-6 revealed significant cytotoxic activity on lung cancer cell lines A549 with IC50 values from 6.2 to 28.1 µM. Analysis of structure-activity relationship of these tested compounds indicated the carbonyl at C-15 and hydroxy at C-1 together could be crucial groups for inhibiting lung cancer cell lines A549 proliferation.

Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and also an important metabolic disorder associated with insulin resistance (IR). Hyperandrogenism is a key feature of PCOS. However, whether hyperandrogenism can cause IR in PCOS remains largely unknown. The mammalian target of rapamycin complex 1 (mTORC1) and its regulated autophagy are closely associated with IR. In the present study, we investigated the role of mTORC1-autophagy pathway in skeletal muscle IR in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. DHEA-treated mice exhibited whole-body and skeletal muscle IR, along with the activated mTORC1, repressed autophagy, impaired mitochondria, and reduced plasma membrane glucose transporter 4 (GLUT4) expression in skeletal muscle of the mice. In cultured C2C12 myotubes, treatment with high dose testosterone activated mTORC1, reduced autophagy, impaired mitochondria, decreased insulin-stimulated glucose uptake, and induced IR. Inhibition of mTORC1 or induction of autophagy restored mitochondrial function, up-regulated insulin-stimulated glucose uptake, and increased insulin sensitivity. On the contrary, inhibition of autophagy exacerbated testosterone-induced impairment. Our findings suggest that the mTORC1-autophagy pathway might contribute to androgen excess-induced skeletal muscle IR in prepubertal female mice by impairing mitochondrial function and reducing insulin-stimulated glucose uptake. These data would help understanding the role of hyperandrogenism and the underlying mechanism in the pathogenesis of skeletal muscle IR in PCOS.

Black Cohosh Ameliorates Metabolic Disorders in Female Ovariectomized Rats.

Estrogen deficiency is associated with metabolic derangements in menopausal women. Black cohosh has been widely used as an alternative therapy in the treatment of menopausal syndrome. However, its role in metabolism needs to be defined. The aim of the present study was to investigate the long-term effect of black cohosh on glucose and lipid metabolism in a rat model of post-menopause. Adult female Sprague-Dawley rats were sham operated (SHAM), ovariectomized (OVX), OVX with the treatment of estradiol valerate (OVX + E), or OVX with the treatment of isopropanolic black cohosh extract (OVX + iCR). Body weight, body composition, and blood glucose levels of the animals were monitored. The rats were then sacrificed after 3 months of the treatments. At the end of the experiment, OVX + iCR and OVX + E rats exhibited a significant decrease in body weight gain, body and abdominal fat mass, serum triglycerides levels, hepatic fat accumulation, and adipocyte hypertrophy compared with OVX rats. In addition, insulin resistance and glucose intolerance were improved in OVX + iCR but not in OVX + E rats. No hepatotoxicity was detected in OVX + iCR animals. Furthermore, western blot analysis suggested the increased lipolysis in adipose tissue of OVX + iCR and OVX + E rats. Data from in vitro experiments using cultured primary rat adipocytes also showed that black cohosh could affect lipolysis of adipocytes. In conclusion, the long-term treatment of black cohosh at a proper dosage ameliorated metabolic derangements in OVX rats. Thus, this drug is promising for the treatment of metabolic disorders in menopausal and post-menopausal women.

Effects of an isopropanolic-aqueous black cohosh extract on central body temperature of ovariectomized rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Black cohosh (Cimicifuga racemosa) is widely used in menopause symptoms strategy. AIM OF THE STUDY: The aim of this study was to examine the effect of isopropanolic black cohosh extract (iCR) on the central body temperature (CBT) of ovariectomized rats (OVX) and elaborate its possible effects in alleviating menopause related hot flushes. MATERIALS AND METHODS: 64 female Sprague-Dawley rats, weighing 230 ± 10g and aged 6-8 weeks, were divided into four groups: ovariectomy (OVX), sham, ovariectomy plus estradiol valerate (OVX+E), and ovariectomy plus iCR (OVX+ICR). The sham group underwent a sham surgery without ovariectomies, while the other three groups underwent bilateral ovariectomies under sterile conditions and a temperature implant was embedded in the abdominal cavity of all four groups. After 2-week recovery period, the temperature of all animals was monitored for 6 weeks. RESULTS: CBT of four groups maintained a normal circadian rhythm, with a low day CBT and a high night CBT. CBTs of the sham group were lower than that of the other three groups. The day CBTs of the (OVX+E) group and (OVX+ICR) group were lower than that of the OVX group from day 2 and day 22 respectively. For the difference between day and night CBT, the sham group was smallest, while (OVX+E) and (OVX+ICR) groups were higher than that of OVX group. The amplitude of day and night CBT, CBT fluctuation frequency at 5 min intervals, were higher for the OVX group than the sham group; the amplitude of day and night CBT of (OVX+E) group and the amplitude of night CBT of (OVX+ICR) group were higher than those of OVX group; while the amplitude of day CBT of (OVX+ICR) group was lower than that of OVX group; CBT fluctuation frequency at 5 min intervals was higher for the (OVX+E) and (OVX+ICR) groups than the OVX group. CONCLUSIONS: Ovariectomized rats had abnormal thermoregulation, demonstrating an increase in day and night CBT, greater difference between day and night CBT, higher amplitude of day and night CBT, and more CBT fluctuation frequency. For the herbal extract iCR, the onset of affecting abnormal thermoregulation took longer than that of estradiol valerate. ICR had a significant effect on day CBT but was only little effective on night CBT of ovariectomized rats.