Effective targeting of mitochondria has emerged as an alternative strategy in cancer chemotherapy. However, considering mitochondria's crucial role in cellular energetics, metabolism and signaling, targeting mitochondria with small molecules would lead to severe side effects in cancer patients. Moreover, mitochondrial functions are highly dependent on other cellular organelles like nucleus. Hence, simultaneous targeting of mitochondria and nucleus could lead to more effective anticancer strategy. To achieve this goal, we have developed sub 200 nm particles from dual drug conjugates derived from direct tethering of mitochondria damaging drug (α- tocopheryl succinate) and nucleus damaging drugs (cisplatin, doxorubicin and paclitaxel). These dual drug conjugated nanoparticles were internalized into the acidic lysosomal compartments of the HeLa cervical cancer cells through endocytosis and induced apoptosis through cell cycle arrest. These nanoparticles damaged mitochondrial morphology and triggered the release of cytochrome c. Furthermore, these nanoparticles target nucleus to induce DNA damage, fragment the nuclear morphology and damage the cytoskeletal protein tubulin. Therefore, these dual drug conjugated nanoparticles can be successfully used as a platform technology for simultaneous targeting of multiple subcellular organelles in cancer cells to improve the therapeutic efficacy of the free drugs.

Mitochondrial morphology regulatory proteins interact with signaling pathways involved in differentiation. In Drosophila oogenesis, EGFR signaling regulates mitochondrial fragmentation in posterior follicle cells (PFCs). EGFR driven oocyte patterning and Notch signaling mediated differentiation are abrogated when PFCs are deficient for the mitochondrial fission protein Drp1. It is not known whether fused mitochondrial morphology in drp1 mutant PFCs exerts its effects on these signaling pathways through a change in mitochondrial electron transport chain (ETC) activity. In this study we show that aggregated mitochondria in drp1 mutant PFCs have increased mitochondrial membrane potential. We perform experiments to assess the signaling pathway regulating mitochondrial membrane potential and how this impacts follicle cell differentiation. We find that drp1 mutant PFCs show increase in phosphorylated ERK (dpERK) formed downstream of EGFR signaling. ERK regulates high mitochondrial membrane potential in drp1 mutant PFCs. PFCs depleted of ERK and drp1 are able to undergo Notch mediated differentiation. Notably mitochondrial membrane potential decrease via ETC inhibition activates Notch signaling at an earlier stage in wild type and suppresses the Notch signaling defect in drp1 mutant PFCs. Thus, this study shows that the EGFR pathway maintains mitochondrial morphology and mitochondrial membrane potential in follicle cells for its functioning and decrease in mitochondrial membrane potential is needed for Notch mediated differentiation.

Medicinal plants serve as rich sources of diverse bioactive phytochemicals that might even take part in bioreduction and stabilization of phytogenic nanoparticles with immense therapeutic properties. Herein, we report for the first time the rapid efficient synthesis of novel platinum–palladium bimetallic nanoparticles (Pt–PdNPs) along with individual platinum (PtNPs) and palladium (PdNPs) nanoparticles using a medicinal plant, Dioscorea bulbifera tuber extract (DBTE). High-resolution transmission electron microscopy revealed monodispersed PtNPs of size 2–5 nm, while PdNPs and Pt–PdNPs between 10 and 25 nm. Energy dispersive spectroscopy analysis confirmed 30.88%±1.73% elemental Pt and 68.96%±1.48% elemental Pd in the bimetallic nanoparticles. Fourier transform infrared spectra indicated strong peaks at 3,373 cm −1 , attributed to hydroxyl group of polyphenolic compounds in DBTE that might play a key role in bioreduction in addition to the sharp peaks at 2,937, 1,647, 1,518, and 1,024 cm −1 , associated with C–H stretching, N–H bending in primary amines, N–O stretching in nitro group, and C–C stretch, respectively. Anticancer activity against HeLa cells showed that Pt–PdNPs exhibited more pronounced cell death of 74.25% compared to individual PtNPs (12.6%) or PdNPs (33.15%). Further, Pt–PdNPs showed an enhanced scavenging activity against 2,2-diphenyl-1-picrylhydrazyl, superoxide, nitric oxide, and hydroxyl radicals.

Background: Biological route for synthesis of copper nanoparticles (CuNPs) with therapeutic potential is a major challenge. In this study, CuNPs were synthesized by D. bulbifera tuber extract (DBTE) which were further evaluated for antidiabetic and free radical scavenging activity. Methods: CuNPs synthesized by DBTE were characterized by UV-visible spectroscopy, transmission electron microscopy, energy dispersive spectroscopy and dynamic light scattering. CuNPs were checked for α-amylase and α-glucosidase inhibition along with interaction studies employing fluroscence spectroscopy, circular dichroism spectroscopy and computational docking. DPPH, nitric oxide and superoxide radical scavenging activities of CuNPs were also checked. Results: Spherical monodispersed CuNPs were synthesized within 5 h that was indicated by a colour change from pale blue to brown. Majority of the nanoparticles synthesized were found to be between 12 to 16 nm as showed in DLS which grew till a final size of 86 to 126 nm as indicated in TEM. Bioreduced CuNPs showed 38.70 ± 1.45% and 34.72 ± 1.22% inhibition against porcine and murine pancreatic amylase, respectively with an uncompetitive mode that was further confirmed by docking studies. Fluorescence spectroscopy confirmed the interaction of CuNPs to the enzyme via Trp residues while CD spectra indicated the structural and conformational changes on binding of CuNPs to the enzyme. CuNPs exhibited 99.09 ± 0.15% inhibition against α-glucosidase while 90.67 ± 0.33% inhibition against murine intestinal glucosidase, respectively. CuNPs showed 40.81 ± 1.44%, 79.06 ± 1.02% and 48.39 ± 1.46% scavenging activity against DPPH, nitric oxide and superoxide radicals respectively. Conclusion: D.bulbifera tuber extract mediated bioreduction is most rapid route to synthesize novel CuNPs with promising antidiabetic and antioxidant properties. This is the first detailed report which provides intense scientific rationale for the use of CuNPs as nanomedicine for efficient control of T2DM and oxidative stress.

Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.

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40 41 42 Mitotic divisions depend on the timely assembly and proper orientation of the mitotic spindle. 43

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