System-level investigation of anti-obesity effects and the potential pathways of Cordyceps militaris in ovariectomized rats.

BACKGROUND: Cordyceps species have been used as tonics to enhance energy, stamina, and libido in traditional Asian medicine for more than 1600 years, indicating their potential for improving reproductive hormone disorders and energy metabolic diseases. Among Cordyceps, Cordyceps militaris has been reported to prevent metabolic syndromes including obesity and benefit the reproductive hormone system, suggesting that Cordyceps militaris can also regulate obesity induced by the menopause. We investigated the effectiveness of Cordyceps militaris extraction (CME) on menopausal obesity and its mechanisms. METHODS: We applied an approach combining in vivo, in vitro, and in silico methods. Ovariectomized rats were administrated CME, and their body weight, area of adipocytes, liver and uterus weight, and lipid levels were measured. Next, after the exposure of MCF-7 human breast cancer cells to CME, cell proliferation and the phosphorylation of estrogen receptor and mitogen-activated protein kinases (MAPK) were measured. Finally, network pharmacological methods were applied to predict the anti-obesity mechanisms of CME. RESULTS: CME prevented overweight, fat accumulation, liver hypertrophy, and lowered triglyceride levels, some of which were improved in a dose-dependent manner. In MCF-7 cell lines, CME showed not only estrogen receptor agonistic activity through an increase in cell proliferation and the phosphorylation of estrogen receptors, but also phosphorylation of extracellular-signal-regulated kinase and p38. In the network pharmacological analysis, bioactive compounds of CME such as cordycepin, adenine, and guanosine were predicted to interact with non-overlapping genes. The targeted genes were related to the insulin signaling pathway, insulin resistance, the MARK signaling pathway, the PI3K-Akt signaling pathway, and the estrogen signaling pathway. CONCLUSIONS: These results suggest that CME has anti-obesity effects in menopause and estrogenic agonistic activity. Compounds in CME have the potential to regulate obesity-related and menopause-related pathways. This study will contribute to developing the understanding of anti-obesity effects and mechanisms of Cordyceps militaris.

Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.

Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL) and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL) delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI). Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.