F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear beta-catenin function

Aberrant activation of beta-catenin has been implicated in a variety of human diseases, including cancer. In spite of significant progress, the regulation of active Wnt/beta-catenin-signaling pathways is still poorly understood. In this study, we show that F-box protein 16 (FBXO16) is a putative tumor suppressor. It is a component of the SCF (SKP1-Cullin1-F-box protein) complex, which targets the nuclear beta-catenin protein to facilitate proteasomal degradation through the 26S proteasome. FBXO16 interacts physically with the C-terminal domain of beta-catenin and promotes its lysine 48-linked polyubiquitination. In addition, it inhibits epithelial-to-mesenchymal transition (EMT) by attenuating the level of beta-catenin. Therefore, depletion of FBXO16 leads to increased levels of beta-catenin, which then promotes cell invasion, tumor growth, and EMT of cancer cells. Furthermore, FBXO16 and beta-catenin share an inverse correlation of cellular expression in clinical breast cancer patient samples. In summary, we propose that FBXO16 functions as a putative tumor suppressor by forming an SCF(FBXO16) complex that targets nuclear beta-catenin in a unique manner for ubiquitination and subsequent proteasomal degradation to prevent malignancy. This work suggests a novel therapeutic strategy against human cancers related to aberrant beta-catenin activation

Healing Potential of Picrorhiza kurroa (Scrofulariaceae) rhizomes against indomethacin-induced gastric ulceration: a mechanistic exploration.

<p>Abstract</p> <p>Background</p> <p>The present study was undertaken to evaluate the potential of the rhizomes of the Indian medicinal plant, <it>Picrorhiza kurroa </it>in healing indomethacin-induced acute stomach ulceration in mice and examine its capacity to modulate oxidative stress and the levels of prostaglandin (PGE₂) and EGF during the process.</p> <p>Methods</p> <p>Male swiss albino mice, ulcerated with indomethacin (18 mg/kg, p. o., single dose) were treated up to 7 days with different doses of the methanol extract of <it>P. kurroa </it>rhizomes (designated as PK). The healing capacity of the most effective dose of PK (20 mg/kg, p. o. × 3 d) was compared with that of omeprazole (Omez) (3 mg/kg, p. o. × 3 d). The effects of the drug-treatment for one and three days on the biochemical parameters were assessed by comparing the results with that of untreated mice of the 1^stand 3^rdday of ulceration. The stomach tissues of the mice were used for the biochemical analysis.</p> <p>Results</p> <p>The macroscopic indices revealed maximum ulceration on the 3^rdday after indomethacin administration, which was effectively healed by PK. Under the optimized treatment regime, PK and Omez reduced the ulcer indices by 45.1% (<it>P </it>< 0.01), and 76.3% respectively (<it>P </it>< 0.001), compared to the untreated ulcerated mice.</p> <p>Compared to the ulcerated untreated mice, those treated with PK for 3 days showed decreased the levels of thiobarbituric acid reactive substances (TBARS) (32.7%, <it>P </it>< 0.05) and protein carbonyl (37.7%, <it>P </it>< 0.001), and increased mucin (42.2%, <it>P </it>< 0.01), mucosal PGE₂(21.4%, <it>P </it>< 0.05), and expressions of COX-1 and 2 (26.9% and 18.5%, <it>P </it>< 0.05), EGF (149.0%, <it>P </it>< 0.001) and VEGF (56.9%, <it>P </it>< 0.01). Omez reduced the TBARS (29.4%, <it>P </it>< 0.05), and protein carbonyl (38.9%, <it>P </it>< 0.001), and increased mucin (38.3%, <it>P </it>< 0.01), without altering the other parameters significantly.</p> <p>Conclusion</p> <p>PK (20 mg/kg, p. o. × 3 days) could effectively heal indomethacin-induced stomach ulceration in mice by reducing oxidative stress, and promoting mucin secretion, prostaglandin synthesis and augmenting expressions of cyclooxygenase enzymes and growth factors.</p

Organophotoredox-Catalyzed Direct C-H Functionalization of “Drug Prejudice” at Room Temperature

Organophotocatalytic C─H bond functionalization has attracted lot of attention in the past several years due to the possibility of catalysing reactions in a metal-free environment. Continuing on these lines, we repot herein an organophotoredox catalyzed C─H functionalization of imidazo[1,2-a]pyridines and related heterocycles with malonates under mild conditions providing excellent yields of the products at room temperature. Although, C─3 functionalization of imidazo[1,2-a]pyridines are known, this is the first report involving malonates as coupling partners leading to the synthesis of a range of functionalized products including Zolpidem, a sedative-hypnotic medicine. </p

Morphometric analysis of oral submucous fibrosis and its correlation with histological staging and clinical severity of trismus

AbstractAimTo quantify the histopathological changes in oral submucous fibrosis morphometrically and to correlate those findings with the histological grading and clinical severity of trismus.MethodsA total of hundred histological sections of oral submucous fibrosis were analysed morphometrically by using interactive image analysis system (Image Pro-Plus,V 6.0). Histological staging and the severity of trismus were then compared with the morphometry results. ANOVA and Pearson’s chi square tests were applied using the software SPSS V. 13.0 for statistical analysis.ResultsThe thickness of the epithelium and subepithelial collagen showed no statistically significant differences between the different stages (p value>0.05). However, blood vessel density, mean blood vessel area and mean diameter of the vessels were indirectly proportional to the histological stages (p value<0.001). Histological stages directly correlate the frequency of trismus, but the severity of trismus showed relation neither with the staging nor with the degree of collagenization, measured morphometrically (p value>0.05).ConclusionsThe thickness of the epithelium and subepithelial collagen should not be included in the histological staging criteria of oral submucous fibrosis. Probably the degree of hyalinization of collagen fibres and involvement of muscle fibres are more important in causing trismus, rather than a simple increase in the subepithelial collagen thickness

Synthesis of 1-deoxy-1-hydroxymethyl-and 1-deoxy-1-epi-hydroxymethyl castanospermine as new potential immunomodulating agents

Two new C-1 epimeric hydroxymethyl castanospermine congeners 2a and 2b, synthesized by stereocontrolled intramolecular double reductive amination of d-glucose derived β-keto ester as a key step, showed impressive immuno-potentiating property. The bioactivity was mediated through up-regulation of T<SUB>H1</SUB>/T<SUB>H2</SUB> cytokine ratio. The finding suggested that immunmodulatory activity of polyhydroxylated indolizidine alkaloids can be tuned by minor structural/stereochemical alterations

Comparative time dependent activity of PK and Omez in regulating the expression of tissue EGF in acute gastric ulcerated mice

The EGF expression was quantified using Biovis MV500 software. Data are expressed as means ± SEM for fifteen mice. < 0.001 compared to the normal mice; < 0.001 compared to the respective ulcerated mice, < 0.01 compared to the Omez-treated mice. N – normal mice, UU – ulcerated untreated mice, PK – ulcerated PK-treated mice, Omez – ulcerated Omez-treated mice.<p><b>Copyright information:</b></p><p>Taken from "Healing Potential of (Scrofulariaceae) rhizomes against indomethacin-induced gastric ulceration: a mechanistic exploration."</p><p>http://www.biomedcentral.com/1472-6882/8/3</p><p>BMC Complementary and Alternative Medicine 2008;8():3-3.</p><p>Published online 31 Jan 2008</p><p>PMCID:PMC2266895.</p><p></p