Flavonoids are polyphenolic compounds found throughout the plant kingdom. They occur in every organ but are usually concentrated in leaves and flowers. During the last two decades, in vitro and in vivo studies demonstrated that flavonoids have inhibitory effects on human diseases through targeting of multiple cellular signaling components. Wnt/β-catenin signaling regulates proliferation, differentiation and fate specification in developmental stages and controls tissue homeostasis in adult life. For these reasons, this pathway has received great attention in the last years as potential pathway involved in distinct Human pathologies. In this review we discuss the emerging potential mechanisms for flavonoids on Wnt/β-catenin signaling in cancer and possible investigation strategies to understand flavonoids mode of action on this signaling pathway.

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Isoquercitrin isolated from the aerial parts of Hyptis fasciculata was evaluated according to its capacity to interfere with glioblastoma (Gbm) cell growth. Gbm cells were incubated with isoquercitrin, quercetin, or rutin at concentrations of 25, 50, and 100 mumol/l for 24, 48, and 72 h. Quercetin and rutin affected Gbm cell proliferation after treatment times of longer than 24 h. However, increasing concentrations of isoquercitrin inhibited 50% of Gbm cell proliferation at 24 h and further reached nearly 90% inhibition at 72 h. This effect did not affect cell morphology, cell viability, or cleaved capase-3 levels, indicating that isoquercitrin did not induce Gbm cell death. A marked reduction in cyclin D1 levels and an increase in p27 levels were observed when 100 micromol/l of isoquercitrin was added to Gbm cells. Interestingly, nuclear beta-catenin staining observed in a subpopulation of untreated Gbm cells was found in the cytoplasm after 100-micromol/l isoquercitrin treatment. Collectively, these data show that isoquercitrin reduces Gbm cell growth without inducing apoptosis, possibly by modulating the control of the cell cycle. Our data also suggest that beta-catenin-mediated signaling may be involved on the antiproliferative activity of isoquercitrin.

Background: Recent studies point at functions of bradykinin in the CNS including neuromodulation and neuroprotection. Results: Bradykinin augments neurogenesis of neural stem cells from embryonic telencephalon, whereas bradykinin receptor inhibition promotes gliogenesis. Conclusion: Bradykinin acts as switch for phenotype determination using an in vitro system of migrating cells, closely reflecting conditions of cortex development. Significance: Novel functions are described for bradykinin with therapeutic relevance.

SUMMARYPodocytes are highly specialized cells in the vertebrate kidney. They participate in the formation of the size-exclusion barrier of the glomerulus/glomus and recruit mesangial and endothelial cells to form a mature glomerulus. At least six transcription factors (wt1, foxc2, hey1, tcf21, lmx1b and mafb) are known to be involved in podocyte specification, but how they interact to drive the differentiation program is unknown. The Xenopus pronephros was used as a paradigm to address this question. All six podocyte transcription factors were systematically eliminated by antisense morpholino oligomers. Changes in the expression of the podocyte transcription factors and of four selected markers of terminal differentiation (nphs1, kirrel, ptpru and nphs2) were analyzed by in situ hybridization. The data were assembled into a transcriptional regulatory network for podocyte development. Although eliminating the six transcription factors individually interfered with aspects of podocyte development, no single gene regulated the entire differentiation program. Only the combined knockdown of wt1 and foxc2 resulted in a loss of all podocyte marker gene expression. Gain-of-function studies showed that wt1 and foxc2 were sufficient to increase podocyte gene expression within the glomus proper. However, the combination of wt1, foxc2 and Notch signaling was required for ectopic expression in ventral marginal zone explants. Together, this approach demonstrates how complex interactions are required for the correct spatiotemporal execution of the podocyte gene expression program.

While highly active during development, Wnt/β-catenin signaling becomes quiescent in adult kidneys and reactivates during kidney injury (7-10). Activation of this signaling leads to a fibrotic response and promotes the progression of CKD via the upregulation of profibrotic mediators, such as fibronectin, the renin-angiotensin system, plasminogen activator inhibitor-1, and [11][12][13]. Induction of MMP-7 by Wnt/β-catenin is particularly interesting, because it is the most robust β-catenin downstream target, and its expression primarily occurs in renal tubules (14-16). As a secreted protein that can be detected in the urine, MMP-7 is an effective noninvasive urinary biomarker for activation of Wnt/β-catenin after kidney injury (16,17).In the current study, we evaluated kidney injury after chronic infusion of angiotensin II (Ang II) using conditional knockout mice with tubule-specific ablation of β-catenin (18). Interestingly, although the genetic mutation was restricted to renal tubules, we found that these mice had significant protection against glomerular injury and proteinuria, accompanied by a reduced MMP-7 expression. These results were replicated in an Adriamycin-induced proteinuria model. We further demonstrate that MMP-7 could degrade the slit diaphragm protein nephrin and impaired integrity of the glomerular filtration barrier. In vivo exposure of mice to elevated MMP-7 levels was sufficient to cause proteinuria, and global ablation of MMP-7 protected mice from Ang II-induced glomerular injury. Our findings illustrate that tubular injury promotes glomerular damage by β-catenin-driven release of MMP-7.

Overactivation of the Wnt/β-catenin pathway in adult tissues has been implicated in many diseases, such as colorectal cancer. Finding chemical substances that can prevent this phenomenon is an emerging problem. Recently, several natural compounds have been described as Wnt/β-catenin inhibitors and might be promising agents for the control of carcinogenesis. Here, we describe two natural substances, derricin and derricidin, belonging to the chalcone subclass, that show potent transcriptional inhibition of the Wnt/β-catenin pathway. Both chalcones are able to affect the cell distribution of β-catenin, and inhibit Wnt-specific reporter activity in HCT116 cells and in Xenopus embryos. Derricin and derricidin also strongly inhibited canonical Wnt activity in vitro, and rescued the Wnt-induced double axis phenotype in Xenopus embryos. As a consequence of Wnt/β-catenin inhibition, derricin and derricidin treatments reduce cell viability and lead to cell cycle arrest in colorectal cancer cell lines. Taken together, our results strongly support these chalcones as novel negative modulators of the Wnt/β-catenin pathway and colon cancer cell growth in vitro.