Insulin-like growth factor binding proteins (IGFBPs) are major regulators of insulin-like growth factor bioavailability and activity in metabolic signaling. Seven IGFBP family isoforms have been identified. Recent studies have shown that IGFBPs play a pivotal role in metabolic signaling and disease, including the pathogenesis of obesity, diabetes, and cancer. Although many studies have documented the various roles played by IGFBPs, transcriptional regulation of IGFBPs is not well understood. In this review, we focus on the regulatory mechanisms of IGFBP gene expression, and we summarize the findings of transcription factor activity in the IGFBP promoter region.
Biological Availability ; Gene Expression ; Humans ; Insulin-Like Growth Factor Binding Protein 2* ; Insulin-Like Growth Factor Binding Proteins ; Liver ; Metabolic Diseases ; Obesity ; Promoter Regions, Genetic ; Protein Isoforms ; Transcription Factors

The activation of neurotrophic signaling pathways following the upregulation of glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-β family, has a potential neuroprotective effect in the adult brain. Herein, we report that hippocampal transduction of adeno-associated virus serotype 1 (AAV1) with a constitutively active form of ras homolog enriched in brain [Rheb(S16H)], which can stimulate the production of brain-derived neurotrophic factor (BDNF) in hippocampal neurons, induces the increases in expression of GDNF and GDNF family receptor α-1 (GFRα-1), in neurons and astrocytes in the hippocampus of rat brain in vivo . Moreover, upregulation of GDNF and GFRα-1 contributes to neuroprotection against thrombin-induced neurotoxicity in the hippocampus. These results suggest that AAV1-Rheb(S16H) transduction of hippocampal neurons, resulting in neurotrophic interactions between neurons and astrocytes, may be useful for neuroprotection in the adult hippocampus.

Gram-negative bacterial pathogens produce outer membrane vesicles (OMVs) and this secreted cargo plays a role in host-pathogen interactions. OMVs isolated from Burkholderia cepacia induce the cytotoxicity and pro-inflammatory responses both in vitro and in vivo, but OMV components associated with host pathology have not been characterized. This study analyzed the proteomes of OMVs produced by B. cepacia ATCC 25416 and investigated whether proteins in B. cepacia OMVs were responsible for host pathology in vitro. Proteomic analysis revealed that a total of 265 proteins were identified in B. cepacia OMVs. Of the 265 OMV proteins, 179 (67.5%), 32 (12.1%), 27 (10.2%), 17 (6.4%), and 10 (3.8%) were predicted to be located in the cytoplasm, inner membrane, periplasmic space, outer membrane, and extracellular compartment, respectively. Several putative virulence factors were also identified in B. cepacia OMVs. B. cepacia OMVs slightly induced the cytotoxicity in lung epithelial A549 cells, but there was no difference in cytotoxic activity between intact OMVs and proteinase K-treated OMVs. B. cepacia OMVs stimulated the expression of pro-inflammatory cytokine and chemokine genes in A549 cells, but the expression of these cytokine genes was significantly inhibited in A549 cells incubated with proteinase K-treated OMVs. In conclusion, our results suggest that proteins in B. cepaciaOMVs are directly responsible for pro-inflammatory responses in lung epithelial cells.

The encystation of Acanthamoeba leads to the development of metabolically inactive and dormant cysts from vegetative trophozoites under unfavorable conditions. These cysts are highly resistant to anti-Acanthamoeba drugs and biocides. Therefore, the inhibition of encystation would be more effective in treating Acanthamoeba infection. In our previous study, a sirtuin family protein—Acanthamoeba silent-information regulator 2-like protein (AcSir2)—was identified, and its expression was discovered to be critical for Acanthamoeba castellanii proliferation and encystation. In this study, to develop Acanthamoeba sirtuin inhibitors, we examine the effects of sirtinol, a sirtuin inhibitor, on trophozoite growth and encystation. Sirtinol inhibited A. castellanii trophozoites proliferation (IC50=61.24 μM). The encystation rate of cells treated with sirtinol significantly decreased to 39.8% (200 μM sirtinol) after 24 hr of incubation compared to controls. In AcSir2-overexpressing cells, the transcriptional level of cyst-specific cysteine protease (CSCP), an Acanthamoeba cysteine protease involved in the encysting process, was 11.6- and 88.6-fold higher at 48 and 72 hr after induction of encystation compared to control. However, sirtinol suppresses CSCP transcription, resulting that the undegraded organelles and large molecules remained in sirtinol-treated cells during encystation. These results indicated that sirtinol sufficiently inhibited trophozoite proliferation and encystation, and can be used to treat Acanthamoeba infections.