Radioprotective effect of self-assembled low molecular weight Fucoidan-Chitosan nanoparticles.

Fucoidan, a sulphated polysaccharide, plays a vital role in reducing cellular oxidative damage by exerting potential antioxidant activity. However, because of the negative surface charges of oligofucoidan, it shows poor oral intestinal absorption. To overcome this drawback, the oligofucoidan polysaccharides self-assembled with opposite charge based polysaccharides (chitosan) to form the chitosan-fucoidan polysaccharides (C1-F3P) nanoparticles (NPs) of 190-230 nm in size. The oligofucoidan and C1-F3P NPs were studied for their radioprotective property using mice exposed to 5 Gy radiation. The C1-F3P NPs prevents radiation induced lipid peroxidation and restores intestinal enzymatic and non-enzymatic antioxidants (p < 0.05) status. In addition, hematoxylin-eosin staining revealed the radioprotective effect of oligofucoidan and C1-F3P NPs by mitigating the loss of crypt and villi in the small intestine. Thus, the present study demonstrated that C1-F3P NPs can be considered as a radioprotective agent that can be used for the prevention and treatment of Gy-radiation-induced intestine injury.

Folate-Gold-Bilirubin Nanoconjugate Induces Apoptotic Death in Multidrug-Resistant Oral Carcinoma Cells.

BACKGROUND: Gold nanoparticles (GNPs) are receiving increasing attention as drug delivery carriers due to their high surface-to-volume ratio, hydrophilicity, and functionality. Drug delivery by nanocarriers has the potential to bypass P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) by altering the drug internalization mechanism and/or intracellular release pattern, inhibiting the activity of ABC-transporter efflux pumps, or downregulating the expression of genes responsible for the activity of efflux pumps. OBJECTIVE: We developed a folate-gold-bilirubin (FGB) nanoconjugate to reverse MDR in P-expressing KB-ChR-8-5 cells. METHODS: The P-gp overexpressing KB-ChR-8-5 cells were incubated with the FGB nanoconjugate, bilirubin, or GNPs. Various cellular endpoints, such as cytotoxicity, ROS generation, DNA damage, and apoptosis, were analyzed using analytical methods. Further, a KB-ChR-8-5 cell-bearing tumor xenograft was developed and the anticancer potential of the prepared FGB nanoparticles was compared to that of bilirubin or GNPs in this preclinical model. RESULTS: The FGB nanoconjugate was found to be a stronger inhibitor of the viability of multidrug-resistant KB-ChR-8-5 cells than bilirubin and GNPs treatment alone. The nanoconjugate induced reactive oxygen species (ROS) formation, DNA strand breaks, and apoptotic morphological changes in the P-gp-overexpressing drug-resistant cells to a greater degree than bilirubin treatment alone. Also, the FGB nanoparticles led to stronger suppression of tumor development in the KB-ChR-8-5 xenograft mouse model than achieved with bilirubin treatment alone. Thus, the present results suggest that the FGB nanoconjugate suppresses tumor growth in drug-resistant tumor cells by inducing apoptotic cell death. CONCLUSION: FGB nanoparticles significantly inhibit tumor growth, probably through the folate receptor, which is highly expressed in KB cells. Hence, folate-gold-bilirubin nanoparticles could be a promising agent for inducing apoptosis in P-gp-overexpressing drug-resistant cancer cells.

Correction: The preventive effect of linalool on acute and chronic UVB-mediated skin carcinogenesis in Swiss albino mice.

Correction for 'The preventive effect of linalool on acute and chronic UVB-mediated skin carcinogenesis in Swiss albino mice' by Srithar Gunaseelan, et al., Photochem. Photobiol. Sci., 2016, 15, 851-860.

Ferulic acid reverses P-glycoprotein-mediated multidrug resistance via inhibition of PI3K/Akt/NF-κB signaling pathway.

In this study, the modulatory effect of ferulic acid on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) was examined in KB ChR8-5 resistant cells and drug-resistant tumor xenografts. We observed that ferulic acid enhanced the cytotoxicity of doxorubicin and vincristine in the P-gp overexpressing KB ChR8-5 cells. Further, ferulic acid enhances the doxorubicin induced γH2AX foci formation and synergistically augmented doxorubicin-induced apoptotic signaling in the drug-resistant cells. It has also been noticed that NF-κB nuclear translocation was suppressed by ferulic acid and that this response might be associated with the modulation of phosphatidyinositol 3-kinase (PI3K)/Akt/signaling pathway. We also found that ferulic acid and doxorubicin combination reduced the size of KB ChR8-5 tumor xenograft by threefold as compared to doxorubicin-alone treated group. Thus, ferulic acid contributes to the reversal of the MDR through suppression of P-gp expression via the inhibition of PI3K/Akt/NF-κB signaling pathway.

Linalool prevents oxidative stress activated protein kinases in single UVB-exposed human skin cells.

Ultraviolet-B radiation (285-320 nm) elicits a number of cellular signaling elements. We investigated the preventive effect of linalool, a natural monoterpene, against UVB-induced oxidative imbalance, activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling in HDFa cells. We observed that linalool treatment (30 µM) prevented acute UVB-irradiation (20 mJ/cm2) mediated loss of activities of antioxidant enzymes in HDFa cells. The comet assay results illustrate that linalool significantly prevents UVB-mediated 8-deoxy guanosine formation (oxidative DNA damage) rather than UVB-induced cyclobutane pyrimidine (CPD) formation. This might be due to its ability to prevent UVB-induced ROS formation and to restore the oxidative imbalance of cells. This has been reflected in UVB-induced overexpression of MAPK and NF-κB signaling. We observed that linalool inhibited UVB-induced phosphorylation of ERK1, JNK and p38 proteins of MAPK family. Linalool inhibited UVB-induced activation of NF-κB/p65 by activating IκBa. We further observed that UVB-induced expression of TNF-α, IL6, IL-10, MMP-2 and MMP-9 was modulated by linalool treatment in HDFa cells. Thus, linalool protects the human skin cells from the oxidative damages of UVB radiation and modulates MAPK and NF-κB signaling in HDFa cells. The present findings substantiate that linalool may act as a photoprotective agent against UVB-induced skin damages.

The preventive effect of linalool on acute and chronic UVB-mediated skin carcinogenesis in Swiss albino mice.

In this study, we evaluated the role of linalool in acute ultraviolet-B (UVB; 280-320 nm) radiation-induced inflammation and chronic UVB-mediated photocarcinogenesis in mouse skin. Acute UVB-irradiation (180 mJ cm(-2)) causes hyperplasia, edema formation, lipid peroxidation, antioxidant depletion, and overexpression of cyclooxygenase-2 (COX-2) and ornithine decarboxylase (ODC) in mouse skin. Topical or intraperitoneal (i.p.) treatment of linalool prevented acute UVB-induced hyperplasia, edema formation, lipid peroxidation, and antioxidant depletion in mouse skin. Further, linalool treatment prevented UVB-induced overexpression of COX-2 and ODC in mouse skin. In the chronic study, mice were subjected to UVB-exposure thrice weekly for 30 weeks. Chronic UVB-exposure induced tumor incidence and expression of proliferative markers such as NF-κB, TNF-α, IL-6, COX-2, VEGF, TGF-ß1, Bcl-2 and mutated p53 in mouse skin. Treatment with linalool before each UVB-exposure significantly prevented the expression of these proliferative markers and subsequently decreased the tumor incidence in mice skin. Histopathological studies confirmed the development of dysplasia and squamous cell carcinoma (SCC) in the chronic UVB-exposed mouse skin; and this was prevented by both topical and i.p. linalool treatment. Therefore, linalool may be considered as a photochemopreventive agent against UVB radiation induced skin carcinogenesis.

Ferulic acid reverses ABCB1-mediated paclitaxel resistance in MDR cell lines.

Multidrug resistance (MDR) remains a major obstacle in cancer chemotherapy. The use of the dietary phytochemicals as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention as a plausible approach for overcoming the drug resistance. The aim of this study was to investigate whether a naturally occurring diet-based phenolic acid, ferulic acid, could sensitize paclitaxel efficacy in ABCB1 overexpressing (P-glycoprotein) colchicine selected KB Ch(R)8-5 cell line. In vitro drug efflux assays demonstrated that ferulic acid inhibits P-glycoprotein transport function in drug resistant KB Ch(R)8-5 cell lines. However, ferulic acid significantly downregulates ABCB1 expression in a concentration dependent manner. Cytotoxicity assay reveals that ferulic acid decreased paclitaxel resistance in KBCh(R)8-5 and HEK293/ABCB1 cells, which indicates its chemosensitizing potential. Clonogenic cell survival assay and apoptotic morphological staining further confirm the chemosensitizing potential of ferulic acid in drug resistant KB Ch(R)8-5 cell lines. Ferulic acid treatment enhances paclitaxel mediated cell cycle arrest and upregulates paclitaxel-induced apoptotic signaling in KB resistant cells. Hence, it has been concluded that downregulation of ABCB1 and subsequent induction of paclitaxel-mediated cell cycle arrest and apoptotic signaling may be the cause for the chemosensitizing potential of ferulic acid in P-gp overexpressing cell lines.

Caffeic Acid Inhibits UVB-induced Inflammation and Photocarcinogenesis Through Activation of Peroxisome Proliferator-activated Receptor-γ in Mouse Skin.

In this study, the effect of caffeic acid (CA) on both acute and chronic UVB-irradiation-induced inflammation and photocarcinogenesis was investigated in Swiss albino mice. Animals were exposed to 180 mJ cm(-2) of UVB once daily for 10 consecutive days and thrice weekly for 30 weeks for acute and chronic study respectively. UVB exposure for 10 consecutive days showed edema formation, increased lipid peroxidation and decreased antioxidant status with activation of inflammatory molecules such as TNF-α, IL-6, COX-2 and NF-κB. However, CA (15 mg per kg.b.wt.) administration before each UVB exposure decreased lipid peroxidation, inflammatory markers expression and enhanced antioxidant status probably through the activation of peroxisome proliferator-activated receptors (PPARγ) in the mice skin. PPARγ is considered a potential target for photochemoprevention because it inhibits UVB-mediated inflammatory responses. In this study, UVB exposure for 30 weeks caused squamous cell carcinoma and upregulation of iNOS, VEGF and TGF-ß and downregulation of p53 and tumor incidence in the mice skin. Both topical (CAT) and intraperitoneal (CAIP) treatment before each UVB exposure downregulates iNOS, VEGF, TGF-ß, upregulates p53 and reduces tumors multiplicity in the mice skin. Thus, CA offers protection against UVB-induced photocarcinogenesis probably through activation of anti-inflammatory transcription factor PPARγ in the mice.