Insulin-like growth factor 1 modulates bioengineered tooth morphogenesis

Regenerative therapy to replace missing teeth is a critical area of research. Functional bioengineered teeth have been produced by the organ germ method using mouse tooth germ cells. However, these bioengineered teeth are significantly smaller in size and exhibit an abnormal crown shape when compared with natural teeth. The proper sizes and shapes of teeth contribute to their normal function. Therefore, a method is needed to control the morphology of bioengineered teeth. Here, we investigated whether insulin-like growth factor 1 (IGF1) can regulate the sizes and shapes of bioengineered teeth, and assessed underlying mechanisms of such regulation. IGF1 treatment significantly increased the size of bioengineered tooth germs, while preserving normal tooth histology. IGF1-treated bioengineered teeth, which were developed from bioengineered tooth germs in subrenal capsules and jawbones, showed increased sizes and cusp numbers. IGF1 increased the number of fibroblast growth factor (Fgf4)-expressing enamel knots in bioengineered tooth germs and enhanced the proliferation and differentiation of dental epithelial and mesenchymal cells. This study is the first to reveal that IGF1 increases the sizes and cusp numbers of bioengineered teeth via the induction of enamel knot formation, as well as the proliferation and differentiation of dental epithelial and mesenchymal cells

レゾルシル酸ラクトンLL-Z1640-2の成人T細胞白血病/リンパ腫に対する治療効果

Adult T-cell leukaemia/lymphoma (ATL) remains incurable. The NF-κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF-β-activated kinase 1 (TAK1), an IκB kinase-activating kinase, triggers the activation of NF-κB. The resorcylic acid lactone LL-Z1640-2 is a potent irreversible inhibitor of TAK1/extracellular signal-regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL-Z1640-2 against ATL. LL-Z1640-2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of IRF4 strongly induced ATL cell death while downregulating MYC. LL-Z1640-2 as well as the NF-κB inhibitor BAY11-7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF-κB-IRF4-MYC axis. The treatment with LL-Z1640-2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL-Z1640-2 against IL-2-responsive ATL cells in the presence of IL-2. Therefore, LL-Z1640-2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL-Z1640-2

Social behavior modulates songbird interpeduncular nucleus function

International audienceMale zebra finches produce the same song while alone and during courtship of a female. However, singing-related activity in the anterior forebrain nuclei lateral magnocellular anterior nidopallium and Area X markedly depends on the social context. Thus, the anterior forebrain should receive a signal of social context from outside the song system. Here we investigated a possible source of such modulation, the midbrain interpeduncular nucleus, by monitoring immediate early genes and synaptic activity. The level of immunoreactivity for egr1 was high and calretinin was low following courtship directed singing, but the opposite pattern was seen after solo undirected singing. Further, pairs of stimulation caused depression of synaptic responses after directed singing, but facilitation after undirected singing

Investigation of behavioral and anatomical lateralization in courtship singing

International audience[No abstract

Modulation of singing-related gene expression by social context in diencephalon and midbrain cholinergic nuclei

International audienceBirdsong may have several functions as a communicative signal. Zebra finches?produce acoustically similar songs while alone (undirected) and to female birds (directed). Recent studies have shown that the level of neural activity and of expression of the immediate early gene egr-1 in the anterior forebrain (AF) nuclei LMAN and Area X are much higher during undirected than directed singing. To investigate possible sources of this modulation, we examined singing-related gene expression in the medial Habenula (Hb) and interpeduncular (IPN) nuclei. Consistently there is an opposite pattern of expression in these nuclei, compared to AF nuclei; a high level of egr-1 expression is seen only after directed singing. Furthermore, expression is stronger in limited subregions of IPN, in a pattern suggesting that the synaptic inputs from MHb to IPN may be lateralized. We are combining anterograde tracer injection into left and right MHb with egr-1 expression after courtship singing to test this possiblility. As a possible behavioral source of such lateralization, in initial behavioral results 4 of 5 birds tested viewed the female during initial courtship preferentially with the right eye

Therapeutic efficacy of the resorcylic acid lactone LL‐Z1640‐2 for adult T‐cell leukaemia/lymphoma

Abstract Adult T‐cell leukaemia/lymphoma (ATL) remains incurable. The NF‐κB and interferon regulatory factor 4 (IRF4) signalling pathways are among the critical survival pathways for the progression of ATL. TGF‐β‐activated kinase 1 (TAK1), an IκB kinase‐activating kinase, triggers the activation of NF‐κB. The resorcylic acid lactone LL‐Z1640‐2 is a potent irreversible inhibitor of TAK1/extracellular signal‐regulated kinase 2 (ERK2). We herein examined the therapeutic efficacy of LL‐Z1640‐2 against ATL. LL‐Z1640‐2 effectively suppressed the in vivo growth of ATL cells. It induced in vitro apoptosis and inhibited the nuclear translocation of p65/RelA in ATL cells. The knockdown of IRF4 strongly induced ATL cell death while downregulating MYC. LL‐Z1640‐2 as well as the NF‐κB inhibitor BAY11‐7082 decreased the expression of IRF4 and MYC at the protein and mRNA levels, indicating the suppression of the NF‐κB‐IRF4‐MYC axis. The treatment with LL‐Z1640‐2 also mitigated the phosphorylation of p38 MAPK along with the expression of CC chemokine receptor 4. Furthermore, the inhibition of STAT3/5 potentiated the cytotoxic activity of LL‐Z1640‐2 against IL‐2‐responsive ATL cells in the presence of IL‐2. Therefore, LL‐Z1640‐2 appears to be an effective treatment for ATL. Further studies are needed to develop more potent compounds that retain the active motifs of LL‐Z1640‐2