Adiponectin is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties. Here, we investigated whether adiponectin regulates angiogenic processes in vitro and in vivo.

The molecular mechanisms underlying cell fate determination from common progenitors in the vertebrate CNS remain elusive. We previously reported that the OTX2 homeoprotein regulates retinal photoreceptor cell fate determination. While Otx2 transactivation is a pivotal process for photoreceptor cell fate determination, its transactivation mechanism in the retina is unknown. Here, we identified an evolutionarily conserved Otx2 enhancer of ϳ500 bp, named embryonic enhancer locus for photoreceptor Otx2 transcription (EELPOT), which can recapitulate initial Otx2 expression in the embryonic mouse retina. We found that the RAX homeoprotein interacts with EELPOT to transactivate Otx2, mainly in the final cell cycle of retinal progenitors. Conditional inactivation of Rax results in downregulation of Otx2 expression in vivo. We also showed that NOTCH-HES signaling negatively regulates EELPOT to suppress Otx2 expression. These results suggest that the integrated activity of cell-intrinsic and -extrinsic factors on EELPOT underlies the molecular basis of photoreceptor cell fate determination in the embryonic retina.

Radical hysterectomy and bilateral pelvic lymphadenectomy were done on 875 patients diagnosed with cervical carcinoma Stages IB (484 patients), IIA (96 patients), and IIB (295 patients). The number of positive nodes was 0 in 620 patients (N0), one in 98 patients (N1), two to three in 80 patients (N2), four to 18 in 45 patients (N4), and unresectable in 32 patients. Cumulative 5-year survival rates were 89%, 81%, 63%, 41%, and 23%, respectively. Significant survival reduction rates (P less than 0.05) from N0 to N1 were insignificant in Stage IB patients (92% versus 91%), in those patients without parametrial invasion (92% versus 90%), and in those with parametrial invasion (76% versus 72%). Survival reduction rates (P less than 0.01) from N1 to N2 resulted from a reduction in IB patients without parametrial invasion (100%-71%, P less than 0.01). Survival reduction rates (P less than 0.05) from N2 to N4 resulted from a reduction in Stage IIB patients with parametrial invasion (60%-29%, P less than 0.05). These figures suggest that the number of positive nodes is a more indicative prognostic factor than the existence of nodal metastasis, and that the 5-year survival rates of those patients with one positive node can be improved up to the level of those without nodal metastasis.

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To establish the genetic tools for conditional gene deletion in mouse retinal progenitors, we generated a Dkk3-Cre transgenic mouse line using bacterial artificial chromosome (BAC) transgenesis. Cre recombination efficiency in vivo was assayed by crossing this transgenic line, termed BAC-Dkk3-Cre, with the CAG-CAT-Z reporter line. This BAC-Dkk3-Cre line showed Cre recombinase activity in most retinal progenitors. Cre activity was detectable from embryonic day 10.5 (E10.5) and generally restricted to the retina during embryogenesis. To verify that BAC-Dkk3-Cre mice successfully circumvented lethality, we generated Otx2flox/flox/BAC-Dkk3-Cre+ mice as Otx2 conditional knockout mice. The Otx2flox/flox/BAC-Dkk3-Cre+ mice were viable, and their retina showed loss of mature cell-type markers of photoreceptor cells, bipolar cells, and horizontal cells, in contrast, amacrine-like cells noticeably increased. Thus, the BAC-Dkk3-Cre transgenic mouse line provides a powerful tool for generating conditional knockout mouse lines for studying loss of gene functions in the developing retina.

Mirogabalin ([(1,5,6)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid), a novel ligand for the subunit of voltage-gated calcium channels, is being developed to treat pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. In the present study, we investigated the in vitro binding characteristics and in vivo analgesic effects of mirogabalin compared with those of pregabalin, a standard ligand. Mirogabalin showed potent and selective binding affinities for the subunits, while having no effects on 186 off-target proteins. Similar to pregabalin, mirogabalin did not show clear subtype selectivity (-1 vs. -2) or species differences (human vs. rat). However, in contrast to pregabalin, mirogabalin showed greater binding affinities for human-1, human -2, rat-1, and rat -2 subunits; further, it had a slower dissociation rate for the-1 subunit than the -2 subunit. Additionally, in experimental neuropathic pain models, partial sciatic nerve ligation rats and streptozotocin-induced diabetic rats, mirogabalin showed more potent and longer lasting analgesic effects. In safety pharmacological evaluations, mirogabalin and pregabalin inhibited rota-rod performance and locomotor activity in rats; however, the safety indices of mirogabalin were superior to those of pregabalin. In conclusion, mirogabalin shows potent and selective binding affinities for the human and rat subunits, and slower dissociation rates for the -1 subunit than the-2 subunit. It shows potent and long-lasting analgesic effects in rat models of neuropathic pain, and wider safety margins for side effects of the central nervous system. These properties of mirogabalin can be associated with its unique binding characteristics.

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