Autophagy induced by HIF1α overexpression supports trophoblast invasion by supplying cellular energy.

Extravillous trophoblasts (EVTs) characterize the invasion of the maternal decidua under low oxygen and poor nutrition at the early feto-maternal interface to establish a successful pregnancy. We previously reported that autophagy in EVTs was activated under 2% O2 in vitro, and autophagy activation was also observed in EVTs at the early feto-maternal interface in vivo. Here, we show that autophagy is an energy source for the invasion of EVTs. Cobalt chloride (CoCl2), which induces hypoxia inducible factor 1α (HIF1α) overexpression, activated autophagy in HTR8/SVneo cells, an EVT cell line. The number of invading HTR8-ATG4B(C74A) cells, an autophagy-deficient EVT cell line, was markedly reduced by 81 percent with the CoCl2 treatment through the suppression of MMP9 level, although CoCl2 did not affect the cellular invasion of HTR8-mStrawberry cells, a control cell line. HTR8-ATG4B(C74A) cells treated with CoCl2 showed a decrease in cellular adenosine triphosphate (ATP) levels and a compensatory increase in the expression of purinergic receptor P2X ligand-gated ion channel 7 (P2RX7), which is stimulated with ATP, whereas HTR8-mStrawberry cells maintained cellular ATP levels and did not affect P2RX7 expression. Furthermore, the decreased invasiveness of HTR8-ATG4B(C74A) cells treated with CoCl2 was neutralized by ATP supplementation to the level of HTR8-ATG4B(C74A) cells treated without CoCl2. These results suggest that autophagy plays a role in maintaining homeostasis by countervailing HIF1α-mediated cellular energy consumption in EVTs.

Herbal medicine Shakuyaku-kanzo-to reduces paclitaxel-induced painful peripheral neuropathy in mice.

OBJECTIVES: Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors such as breast, ovarian and lung cancer. However, it sometimes induces moderate to severe muscle pain, and impairs the patients' quality of life. An appropriate method for relieving this pain is not well established. Shakuyaku-kanzo-to, a herbal medicine, is known to relieve menstrual pain, muscle spasm, and muscle pain, and its effectiveness is expected. To ascertain the effectiveness of Shakuyaku-kanzo-to on paclitaxel-induced pain, we investigated the effects of Shakuyaku-kanzo-to and its constituent herbal medicines in a mouse model. METHODS: Seven-week-old male ddY mice were used. To make a mouse model of paclitaxel-induced pain, different single, intraperitoneally injected doses of this drug were tested in various groups of mice, and the optimal dose was determined. To estimate the effects of Shakuyaku-kanzo-to, the constituent herbal medicines Shakuyaku and Kanzo, and loxoprofen sodium as a non-steroidal anti-inflammatory drug on paclitaxel-induced pain, mechanical allodynia and hyperalgesia of the hind paw were assessed. RESULTS: Paclitaxel administered at a dose of 10mg/kg or more produced allodynia and hyperalgesia; the time courses were similar to those of pain after paclitaxel administration in cancer patients. Shakuyaku-kanzo-to significantly relieved the allodynia and hyperalgesia induced by paclitaxel (10mg/kg). Shakuyaku and Kanzo inhibited the allodynia and hyperalgesia to some extent, but not significantly, while loxoprofen sodium was without effects. CONCLUSIONS: A single administration of paclitaxel (10mg/kg) produced allodynia and hyperalgesia in mice, suggesting that it could be used as an animal model resembling the painful conditions observed in humans medicated with this drug. Using this model, Shakuyaku-kanzo-to was shown to relieve paclitaxel-induced painful peripheral neuropathy.