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Chronological aging is by far the strongest risk factor for age-related dementia and Alzheimer’s disease. Senescent cells accumulated in the aging and Alzheimer’s disease brains are now recognized as the keys to describing such an association. Cellular senescence is a classic phenomenon characterized by stable cell arrest, which is thought to be applicable only to dividing cells. Emerging evidence indicates that fully differentiated post-mitotic neurons are also capable of becoming senescent, with roles in contributing to both brain aging and disease pathogenesis. The key question that arises is the identity of the upstream triggers and the molecular mechanisms that underly such changes. Here, we highlight the potential role of persistent DNA damage response as the major driver of senescent phenotypes and discuss the current evidence and molecular mechanisms that connect DNA repair infidelity, cell cycle re-entry and terminal fate decision in committing neuronal cell senescence.

Supplementary Figures 1-6, Tables 1-2 from A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

Gold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/β-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/β-catenin signaling. Cancer Res; 70(1); 329–37

Adiponectin is an adipocyte-derived hormone with a wide range of beneficial effects on obesity-related medical complications. Numerous epidemiological investigations in diverse ethnic groups have identified a lower adiponectin level as an independent risk factor for nonalcoholic fatty liver diseases and liver dysfunctions. Animal studies have demonstrated that replenishment of adiponectin protects against various forms of hepatic injuries, suggesting it to be a potential drug candidate for the treatment of liver diseases. This study was designed to investigate the cellular and molecular mechanisms underlying the hepatoprotective effects of adiponectin. Our results demonstrated that in adiponectin knockout (ADN-KO) mice, there was a preexisting condition of hepatic steatosis and mitochondrial dysfunction that might contribute to the increased vulnerabilities of these mice to secondary liver injuries induced by obesity and other conditions. Adenovirus-mediated replenishment of adiponectin depleted lipid accumulation, restored the oxidative activities of mitochondrial respiratory chain (MRC) complexes, and prevented the accumulation of lipid peroxidation products in ADN-KO mice but had no obvious effects on mitochondrial biogenesis. The gene and protein levels of uncoupling protein 2 (UCP2), a mitochondrial membrane transporter, were decreased in ADN-KO mice and could be significantly up-regulated by adiponectin treatment. Moreover, the effects of adiponectin on mitochondrial activities and on protection against endotoxin-induced liver injuries were significantly attenuated in UCP2 knockout mice. Conclusion: These results suggest that the hepatoprotective properties of adiponectin are mediated at least in part by an enhancement of the activities of MRC complexes through a mechanism involving UCP2. Copyright © 2008 by the American Association for the Study of Liver Diseases., link_to_OA_fulltext

Male Sprague-Dawley rats were subcutaneously injected with 2.5mg/kg phenylephrine or 2.5mg/kg isoproterenol or both (2.5mg/kg for each drug) for 4 days, twice a day. Samples of scapular brown adipose tissue (BAT) and epididymal white adipose tissue (WAT) were collected for the measurement of adrenomedullin (AM) levels and the gene expression of preproAM, calcitonin receptor like receptor (CRLR) and its activity modifying proteins (RAMPs) by radioimmunoassay and RT-PCR. These values were compared with those in the rats that received 0.9% saline. The gene expression of AM and AM receptor components in BAT are much less than that in epididymal WAT. In BAT there were an increase in AM peptide level after a combined treatment of alpha(1) and beta adrenoceptor agonists and increases in preproAM mRNA levels for rats treated with alpha(1) and beta receptor agonists alone or in combination. Both CRLR and RAMP2 mRNA levels of alphabeta group were increased significantly. In WAT, AM peptide level, RAMP1 and RAMP2 mRNA expression levels were augmented in the alpha group while CRLR mRNA level was enhanced in the beta group. The levels of AM, its receptor and RAMPs are much less in BAT than in WAT but adrenergic stimulation has a greater effect on the AM and its receptor components in BAT than those in WAT. AM stimulates lipolysis and increases the level of uncoupling protein-1 (UCP-1) in BAT. It may therefore enhance thermogenesis by increasing the availability of free fatty acids substrate as well as the UCP-1 level on the mitochondrial membrane.

Neural crest cells are a transient population of stem cells in vertebrates that give rise to the entire peripheral nervous system (PNS) as well as various non-neural progenies. A peculiar control and coordination of proliferation, migration and differentiation is required for neural crest cells to generate a full diversity of progenies, navigate different organs and establish functional domains in their target organs. Defects in such developmental process may lead to a board spectrum of congenital disorders, and in some cases, also cancer. In this review, we will focus on one specific neurocristopathy in the PNS: the Hirschsprung’s disease (colonic aganglionosis), to emphasize how unraveling the molecular mechanisms underlying the neural crest cell fate determination and progression may facilitate our understanding of the disease etiologies and future development of therapies.

The gold (III) porphyrin complex, gold-2a, elicits anti-tumor activity by targeting the Wnt/β-catenin signaling pathway [Chow KH et al, Cancer Research 2010;70(1):329-37]. Here, the molecular mechanisms underlying the inhibitory effects of this compound on WNT1 gene expression were elucidated further. A response element to gold-2a was identified located within the -1290 to -1112 nt region of the WNT1 promoter, containing a binding site for the transcription regulator Yin Yang 1 (YY1). Gold-2a promoted the association of YY1 and suppressor of zeste 12 (Suz12; a component of the polycomb repressor complex 2) with the WNT1 promoter. Under normal culture conditions, the intracellular translocalization of YY1 was synchronized with cell cycle progression and WNT1 expression. Gold-2a promoted the nuclear accumulation and abolished the nuclear exportation of YY1, resulting in a persistent inhibition of WNT1 expression and a cell cycle arrest at G1/S phase. A dimorphic role of YY1 in regulating cell proliferation and division was revealed. Thus, the present study extends the understanding of the anti-tumor mechanism of gold-2a to the epigenetic level, which involves the modulation of the dynamic interactions between YY1 and a specific region of the WNT1 promoter.

Gold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/β-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/β-catenin signaling. Cancer Res; 70(1); 329–37

Background: Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive. Methodology/Principal Findings: In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT) transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K)/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN) activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1) and thioredoxin reductase (TrxR1) were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1. Conclusion: Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/ Akt signalling pathway through a mechanism involving Trx1/TrxR1 redox regulations. © 2009 Lam et al., published_or_final_version

Adiponectin (ADN) is an adipokine possessing growth inhibitory activities against various types of cancer cells. Our previous results demonstrated that ADN could impede Wnt/beta-catenin-signaling pathways in MDA-MB-231 human breast carcinoma cells [Wang,Y. et al. (2006) Adiponectin modulates the glycogen synthase kinase-3 beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res., 66, 11462-11470]. Here, we extended our studies to elucidate the effects of ADN on regulating the expressions of Wnt inhibitory factor-1 (WIF1), a Wnt antagonist frequently silenced in human breast tumors. Our results showed that ADN time dependently stimulated WIF1 gene and protein expressions in MDA-MB-231 cells. Overexpression of WIF1 exerted similar inhibitory effects to those of ADN on cell proliferations, nuclear beta-catenin activities, cyclin D1 expressions and serum-induced phosphorylations of Akt and glycogen synthase kinase-3 beta. Blockage of WIF1 activities significantly attenuated the suppressive effects of ADN on MDA-MB-231 cell growth. Furthermore, our in vivo studies showed that both supplementation of recombinant ADN and adenovirus-mediated overexpression of this adipokine substantially enhanced WIF1 expressions in MDA-MB-231 tumors implanted in nude mice. More interestingly, we found that ADN could alleviate methylation of CpG islands located within the proximal promoter region of WIF1, possibly involving the specificity protein 1 (Sp1) transcription factor and its downstream target DNA methyltransferase 1 (DNMT1). Upon ADN treatment, the protein levels of both Sp1 and DNMT1 were significantly decreased. Using silencing RNA approaches, we confirmed that downregulation of Sp1 resulted in an increased expression of WIF1 and decreased methylation of WIF1 promoter. Taken together, these data suggest that ADN might elicit its antitumor activities at least partially through promoting WIF1 expressions.