Molecular Implications of MUC5AC-CD44 Axis in Colorectal Cancer Progression and Chemoresistance

BACKGROUND: Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure. METHODS: MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays and in vivo (sub-cutaneous and colon orthotopic) mouse models. Finally, CRC cell lines and xenograft models were used to identify the mechanism of action of MUC5AC. RESULTS: Overexpression of MUC5AC is observed in CRC patient tissues and cell lines. MUC5AC expression resulted in enhanced cell invasion and migration, and decreased apoptosis of CRC cells. MUC5AC interacted with CD44 physically, which was accompanied by the activation of Src signaling. Further, the presence of MUC5AC resulted in enhanced tumorigenesis and appearance of metastatic lesions in orthotopic mouse model. Additionally, up-regulation of MUC5AC resulted in resistance to 5-fluorouracil (5-FU) and oxaliplatin, and its knockout increased sensitivity to these drugs. Finally, we observed that up-regulation of MUC5AC conferred resistance to 5-FU through down-regulation of p53 and its target gene p21 and up-regulation of β-catenin and its target genes CD44 and Lgr5. CONCLUSION: Our findings suggest that differential expression of secretory mucin MUC5AC results in enhanced tumorigenesis and also confers chemoresistance via CD44/β-catenin/p53/p21 signaling

Phylogenetic analyses of Chilomastix and Retortamonas species using in vitro excysted flagellates

Abstract In vitro excystation of cysts of microscopically identified Chilomastix mesnili and Retortamonas sp. isolated from Japanese macaques and Retortamonas sp. isolated from small Indian mongooses could be induced using an established protocol for Giardia intestinalis and subsequently by culturing with H2S-rich Robinson’s medium supplemented with Desulfovibrio desulfuricans. Excystation usually began 2 h after incubation in Robinson’s medium. DNA was isolated from excysted flagellates after 4 h of incubation or from cultured excysted flagellates. Phylogenetic analysis based on their 18S rRNA genes revealed that two isolates of C. mesnili from Japanese macaques belonged to the same cluster as a C. mesnili isolate from humans, whereas a mammalian Retortamonas sp. isolate from a small Indian mongoose belonged to the same cluster as that of an amphibian Retortamonas spp. isolate from a ‘poison arrow frog’ [sequence identity to AF439347 (94.9%)]. These results suggest that the sequence homology of the 18S rRNA gene of the two C. mesnili isolates from Japanese macaques was similar to that of humans, in addition to the morphological similarity, and Retortamonas sp. infection of the amphibian type in the small Indian mongoose highlighted the possibility of the effect of host feeding habitats

Synthesis and structural studies of cobalt complexes of tridentate ligands incorporating azo, oxime and carboxylate functions

335-338The tridentate ligands H2ArL ( where Ar = Ph, p-tolyl, -naphthyl) react with cobalt(II) acetate tetrahydrate, affording the dark green Et4N[CoIII(ArL)2] complex. The two quasireversible couples (in the range -0.65 to -1.20 V) in the cyclic voltammogram represent azo reduction. The X-ray structure of Et4N[Co(PhL)2] has been determined, revealing the meridional binding of the two ligands affording cis-CoN4O2 <span style="font-size:14.0pt;font-family:&quot;Times New Roman&quot;; mso-fareast-font-family:&quot;Times New Roman&quot;;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">geometry.</span

First examples of carboxyl-bonded low-spin manganese(III) complexes

This article does not have an abstract

Synthesis and structure of bis(azooximates) of dichlororhodium(III): the oxime–oximate O–H · · · O bridge and the effect of its deprotonation

The reaction of azooximes RC(NOH)NNPh (R = Me HL1, Ph HL2, or C6H4Me-p HL3) with RhCl3·3H2O afforded red trans-cis-cis(tcc)-[RhCl2L(HL)] 1 which was converted into green [NEt3H][tcc-RhCl2L2] 2 upon treatment with Et3N; 2 isomerises to pink [NEt3H][cct-RhCl2L2] 3 spontaneously in boiling benzene–toluene. The distorted octahedral co-ordination spheres are of type RhCl2No2Na2 (No= oximato N, Na = azo N) with the relative arrangement of donor atom pairs as stated (e.g.tcc = trans-Cl2-cis-No2-cis-Na2). The crystal structures of tcc-[RhCl2L2(HL2)] 1b, [NEt3H][tcc-RhCl2L22] 2b and [NEt3H][cct-RhCl2L32] 3c were determined. In 1b unsymmetrical hydrogen bonding is present, the O · · · O distance being 2.515(5) Å. Upon deprotonation to 2b the distance increases to 2.833(8) Å. In 3c the distance is 4.207(10) Å. The NEt3H+ cations in 2b and 3c are associated with oximato oxygen and cis-RhCl2 chloride respectively. The isomerisation of 2b to 3b in hot toluene is characterised by a high enthalpy and entropy of activation

Synthesis, structure and reactivity of palladated azo-oxime-carboxylates

90-94The bidentate ligands H2L(1) react with sodium tetrachloropalladate to form a presumably dimeric species [PdL]2 which on further treatment with triphenyl phosphine or n-butyl amine furnishes adducts of types [PdL(PPh3)] or [PdL(nBuNH2)] respectively. The X-ray structure of [PdL2(PPh3)] has been determined, revealing the square planar PdN2OP geo metry

Oximato bridged Rh<SUP>III</SUP>2M<SUP>II</SUP> and Rh<SUP>III</SUP>M<SUP>I</SUP> species (M<SUP>II</SUP>= Mn, Co, Ni; M<SUP>I</SUP> = Cu, Ag)

The reaction of [RhCl2(HPhL)(PhL)] with MII(ClO4)2&#183;6H2O in presence of alkali has furnished trinuclear [RhCl2(PhL)2]2M(H2O)2&#183;H2O (HPhL is phenylazobenzaldoxime; M = Mn, Co, Ni). A similar reaction with MI(PPh3)2NO3 yielded binuclear [RhCl2(PhL)2]M(PPh3)2 (M = Cu, Ag). In these molecules the oximato group acts as a bridge between RhIII (bonded at N) and MII or MI (bonded at O). In structurally characterized [RhIIICl2(PhL)2]2Mn(H2O)2&#183;H2O the centrosymmetric distorted octahedral MnO6 coordination sphere is spanned by four oximato oxygen atoms and two water molecules lying in trans position. In the lattice the neighbouring molecules are held together by H2O-H2O-H2O hydrogen bonds generating infinite zigzag chains. The manganese atoms lie parallel to the C-axis, the shortest Mn...Mn distance being 7.992 &#197;. Magnetic exchange interactions if any are small as seen in room temperature magnetic moments. The manganese system displays a strong EPR signal near g = 2.00. In the complex [RhCl2(PhL)2]Cu(PPh3)2 the copper atom is coordinated to two oximato oxygen atoms and the two phosphorus atoms in a distorted tetrahedral geometry. The softness of the phosphine ligand is believed to sustain the stable coordination of hard oximato oxygen to soft CuI. The coordination sphere of the RhIII atom in both the complexes is uniformly trans-RhN4Cl2