Graphical abstractPromising antileishmanial properties were observed with Sargentodoxa cuneata mediated Ag and AuNPs. This study opens a platform for the synthesis new leishmanicidal agents AbstractLeishmaniasis remains one of the fatal diseases worldwide and the conventional antileishmanial therapies are associated with several drawbacks. Therefore, there is a need to develop new antileishmanial strategies. Biogenic silver and gold nanoparticles possess broad-spectrum antimicrobial activities and could be future alternative to current antimicrobial agents. In this report, we present a simple and green approach to synthesize silver and gold nanoparticles with efficient biological activities. Phytochemicals from Sargentodoxa cuneata were used to reduce and stabilize the silver and gold ions into metallic nanoparticles. The synthesized nanoparticles were characterized by UV-visible spectroscopy (surface plasmon resonance), X-ray diffraction analysis (crystallinity), High-resolution transmission electron microscopy (size and morphology), energy dispersive X-ray (elemental composition) and FTIR (surface functionalities). Under the optimized conditions, the synthesized silver nanoparticles were spherical in shape, small size (3-8 nm) and well dispersed. However, the gold nanoparticles were mostly hexagonal in shapes with approximate size from 15 to 30 nm. Promising antileishmanial activity was shown by silver and gold nanoparticles with an IC 50 value of 4.37 and 5.29 µg/mL respectively. Silver nanoparticles also exhibited significant antibacterial activity against Staphylococcus aureus (32 ± 3 mm), Pseudomonas araginosis (16 ± 2 mm), and Bacillus subtilis (18 ± 2 mm). The depicted biological activities of nanoparticles are not simply due to the capped silver and gold atoms but also to their surface macromolecules. Thus, the use of Sargentodoxa cuneata as reducing and capping agent will retain its biological activities even after the depletion of maintained silver and gold. The findings of this study indicate that, these nanoparticles could be an alternative, safe, and effective source of antileishmanial agents. 4 assay, and capillary electrophoresis 9-12 . These nanostructures upon cellular uptake behave as thermal scalpels to kill the infected cell 13,14 .Silver is a promising agent possessing broad spectrum antibacterial activity with minimum chance of bacterial resistance to it 15 . It has been published that silver ions interfere with bacterial DNA replication, disrupt cell membrane, inhibit critically important enzymes and damage bacteria by a process called respiratory burst mechanism 16-18 . Furthermore, silver and gold nanoparticles have the ability to produce reactive oxygen species (ROS), which play an important role in killing pathogenic microbes. It has been reported that leishmania parasites are highly sensitive to ROS 19 . In order to kill leishmania parasite by a treatment that involve reactive species, a continuous supply of these oxygen species can be ensured with the use of noble metal nanoparticles...
The canonical Wnt pathway plays a crucial role in embryonic development, and its deregulation is involved in human diseases. The LRP6 single-span transmembrane coreceptor is essential for transmission of canonical Wnt signaling. However, due to the lack of immunological reagents, our understanding of LRP6 structure and function has relied on studies involving its overexpression, and regulation of the endogenous receptor by the Wnt ligand has remained unexplored. Using a highly sensitive and specific antibody to LRP6, we demonstrate that the endogenous receptor is modified by N-glycosylation and is phosphorylated in response to Wnt stimulation in a sustained yet ligand-dependent manner. Moreover, following triggering by Wnt, endogenous LRP6 is internalized and recycled back to the cellular membrane within hours of the initial stimulus. Finally, we have identified a novel feedback mechanism by which Wnt, acting through -catenin, negatively regulates LRP6 at the mRNA level. Together, these findings contribute significantly to our understanding of LRP6 function and uncover a new level of regulation of Wnt signaling. In light of the direct role that the Wnt pathway plays in human bone diseases and malignancies, our findings may support the development of novel therapeutic approaches that target Wnt signaling through LRP6.The highly conserved canonical Wnt pathway plays a critical role in cell fate determination and tissue development (7, 23). Moreover, aberrant activation of Wnt signaling is causally involved in human cancers (9, 28). Members of this family of secreted glycoproteins interact with two coreceptors, the Frizzled seven-pass transmembrane receptor and the low-density lipoprotein (LDL) receptor-related protein LRP5/6. Wnt-receptor interactions lead to inhibition of -catenin phosphorylation by casein kinase 1-␣ (CK1-␣) and glycogen synthase kinase-, which occurs within a protein complex containing axin and the tumor suppressor adenomatous polyposis coli. Inhibition of -catenin phosphorylation impairs its degradation and results in accumulation of the uncomplexed cytosolic molecule, which translocates to the nucleus and interacts with TCF/LEF factors to activate transcription (9,13,24).Frizzled receptors are known to mediate signaling through both the Wnt--catenin "canonical" pathway and other, "noncanonical" ones, such as the planar cell polarity and Wnt/Ca 2ϩ pathways. In contrast, the LRP6 receptor and the family member LRP5 specifically function in the Wnt--catenin pathway (5, 13, 17). In fact, inactivation of the LRP5/6 homologue arrow in Drosophila melanogaster results in a phenotype similar to that of the wingless mutant, and injection of LRP6 mRNA into Xenopus laevis embryos enhances Wnt-induced developmental defects (33, 35). Moreover, mice deficient for LRP6 exhibit defects resembling those caused by the loss of various Wnt proteins (27). There is evidence supporting a dual-receptor model in which independent binding of Wnt to Frizzled and LRP6 recruits these two proteins into a receptor comp...
Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni's correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.
BackgroundColorectal cancer (CRC) is the 3rd most common type of cancer worldwide. New anti-cancer agents are needed for treating late stage colorectal cancer as most of the deaths occur due to cancer metastasis. A recently developed compound, 3c has shown to have potent antitumor effect; however the mechanism underlying the antitumor effect remains unknown.Methods3c-induced inhibition of proliferation was measured in the absence and presence NAC using MTT in HT-29 and SW620 cells and xCELLigence RTCA DP instrument. 3c-induced apoptotic studies were performed using flow cytometry. 3c-induced redox alterations were measured by ROS production using fluorescence plate reader and flow cytometry and mitochondrial membrane potential by flow cytometry; NADPH and GSH levels were determined by colorimetric assays. Bcl2 family protein expression and cytochrome c release and PARP activation was done by western blotting. Caspase activation was measured by ELISA. Cell migration assay was done using the real time xCELLigence RTCA DP system in SW620 cells and wound healing assay in HT-29.ResultsMany anticancer therapeutics exert their effects by inducing reactive oxygen species (ROS). In this study, we demonstrate that 3c-induced inhibition of cell proliferation is reversed by the antioxidant, N-acetylcysteine, suggesting that 3c acts via increased production of ROS in HT-29 cells. This was confirmed by the direct measurement of ROS in 3c-treated colorectal cancer cells. Additionally, treatment with 3c resulted in decreased NADPH and glutathione levels in HT-29 cells. Further, investigation of the apoptotic pathway showed increased release of cytochrome c resulting in the activation of caspase-9, which in turn activated caspase-3 and −6. 3c also (i) increased p53 and Bax expression, (ii) decreased Bcl2 and BclxL expression and (iii) induced PARP cleavage in human colorectal cancer cells. Confirming our observations, NAC significantly inhibited induction of apoptosis, ROS production, cytochrome c release and PARP cleavage. The results further demonstrate that 3c inhibits cell migration by modulating EMT markers and inhibiting TGFβ-induced phosphorylation of Smad2 and Samd3.ConclusionsOur findings thus demonstrate that 3c disrupts redox balance in colorectal cancer cells and support the notion that this agent may be effective for the treatment of colorectal cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3005-7) contains supplementary material, which is available to authorized users.
Epidermal growth factor receptors (EGFRs/HERs) and downstream signaling pathways have been implicated in the pathogenesis of several malignancies including breast cancer and its resistance to treatment with chemotherapeutic drugs. Consequently, several monoclonal antibodies as well as small molecule inhibitors targeting these pathways have emerged as therapeutic tools in the recent past. However, studies have shown that utilizing these molecules in combination with chemotherapy has yielded only limited success. This review describes the current understanding of EGFRs/HERs and associated signaling pathways in relation to development of breast cancer and responses to various cancer treatments in the hope of pointing to improved prevention, diagnosis and treatment. Also, we review the role of breast cancer stem cells (BCSCs) in disease and the potential to target these cells.
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