The stem cell code in oral epithelial tumorigenesis: ‘The cancer stem cell shift hypothesis’

Tumors of the oral cavity provide an ideal model to study various stages of epithelial tumor progression. A group of cancer cells termed cancer stem cells (CSCs) eludes therapy, persists and initiates recurrence augmenting malignant spread of the disease. Hitherto, accurate identification and separation of such minimal residual cells have proven futile due to lack of identifiable traits to single out these cells from the heterogeneous tumor bulk. In this review we have compiled comprehensive evidence from comparative phenotypic and genotypic studies on normal oral mucosa as well as tumors of different grades to elucidate that differential expression patterns of putative stem cells markers may identify ‘minimal residual disease’ in oral squamous cell carcinoma. We propose the “cancer stem cell shift hypothesis” to explain the exact identity and switch-over, tumor-promoting mechanisms adapted by putative CSCs with correlation to tumor staging.     

Reversal effect of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone on multi-drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU

Multi drug resistance (MDR) is a major obstacle in the chemotherapeutic treatment of many human cancers. 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC), a chalcone, isolated from the buds of Cleistocalyx operculatus, has been shown to have antitumor effects on human carcinoma SMMC-7721 cells in vitro and in vivo. In this paper, we studied the reversal effect and the mechanism of DMC on human hepatocellular carcinoma drug-resistant cells BEL-7402/5-FU in vitro. Administration of DMC reversed the multi-drug resistance of human hepatocellular carcinoma BEL-7402/5-FU cells significantly. DMC enhanced the sensitivity of BEL-7402/5-FU cells to 5-fluorouracil (5-FU) and doxorubicin (DOX). Staining with Hoechst 33258 and flow cytometric analysis showed that DMC has apoptosis-inducing effect on BEL-7402/5-FU cells. It could also increase the concentration of 5-FU in the resistant multi-drug-resistant cells. We also observed that over-expression of the multi-drug resistance-associated protein (MRP1) and of the glutathione S-transferase π (GST-π) contributed to MDR in BEL-7402/5-FU cells. The mRNA expressions of MRP1 and GST-π and the protein expression of MRP1 were decreased by DMC. These data demonstrated that DMC could effectively reverse MDR in BEL-7402/5-FU cells.     

The subcommissural organ expresses D<Subscript>2</Subscript>, D<Subscript>3</Subscript>, D<Subscript>4</Subscript>, and D<Subscript>5</Subscript> dopamine receptors

Dopamine receptors have been found in certain populations of non-neuronal cells in the brain, viz., discrete areas of ciliated ependyma and the ependymal cells of the choroid plexus. We have studied the presence of both tyrosine-hydroxylase-immunoreactive nerve fibers and dopamine receptors in the subcommissural organ (SCO), an ependymal brain gland that is located in the roof of the third ventricle and that secretes, into the cerebrospinal fluid, glycoproteins that aggregate to form Reissners fiber (RF). Antibodies against D₂, D₃, D₄, and D₅ dopamine receptors were used in immunoblots of bovine striatum, fresh SCO, and organ-cultured SCO, and in immunocytochemistry of the bovine, rat, and mouse SCO. Only a few tyrosine-hydroxylase fibers appeared to reach the SCO. However, virtually all the secretory ependymal and hypendymal cells of the SCO immunoreacted with antibodies against D₂, D₄, and D₅ receptors, with the last-mentioned rendering the strongest reaction, especially at the ventricular cell pole of the secretory ependymocytes, suggesting that dopamine might reach the SCO via the cerebrospinal fluid. The antibodies against the four subtypes of receptors revealed corresponding bands in immunoblots of striatum and fresh SCO. Although the cultured SCO displayed dopamine receptors, dopamine had no apparent effect on the expression of the SCO-spondin gene/protein or on the release of RF-glycoproteins (SCO-spondin included) by SCO explants, suggesting that dopamine affects the function(s) of the SCO differently from the secretion of RF-glycoproteins.Financial support was provided by grants PI 030756 and Red CIEN, Instituto de Salud Carlos III, Spain (to J.M.P.F.), and 1030265 from Fondecyt, Chile (to E.M.R.)     

PPARα,γ和δ:胰岛素抵抗治疗的靶点

胰岛素抵抗(insulin resistance,IR)是指外周组织对胰岛素的反应敏感性降低,是肝脏疾病和心血管病发生的共同基础,常常是高脂血症和2型糖尿病发病的前奏.过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)属于核受体超家族的成员.PPARs激动剂可通过多种途径改善胰岛素敏感性,例如调节糖脂代谢、抗炎作用以及间接地改善氧化应激状态.这篇综述主要是回顾IR的病理机制及其治疗靶点:PPARα,δ和γ,并阐明针对此类靶点的胰岛素增敏药物的信号转导通路.     

短波紫外线照射对‘金都’火龙果采后保鲜的影响

以‘金都’火龙果(Hylocereus polyrhizus ‘Jindu’)果实为试材,采用波长254 nm紫外杀菌灯为辐射源,给予不同剂量短波紫外线(Ultraviolet-C,UV-C)照射处理,探讨低剂量UV-C对火龙果采后保鲜的影响及作用机理。结果表明,不同剂量UV-C照射处理能有效抑制‘金都’火龙果果实腐烂和电导率上升,降低果实TSS含量,其中1.0 kJ·m–2紫外线辐照效果最好。1.0 kJ·m–2 UV-C处理能极显著提高贮藏期火龙果的SOD和CAT活性,显著提高贮藏早中期的几丁质酶活性和PPO活性,β-1,3葡聚糖酶活性在贮藏后期也显著高于对照,但降低了火龙果贮藏中期(第6天)的POD活性。此外,1.0 kJ·m–2 UV-C处理显著提高火龙果贮藏期H2O2含量(除第6天外),对果实的失水率无影响。采后火龙果应用适当剂量UV-C照射可提高抗病性,延长贮藏保鲜期。     

Expedient synthesis of coumarin-coupled triazoles via ‘click chemistry’ leading to the formation of coumarin-triazole-sugar hybrids

Coumarin-based triazoles were synthesized from 3-azidomethylcoumarin and a terminal acetylenic compound. Uncatalysed thermal conditions result in a mixture of both 1,4- and 1,5-regioisomers or the thermodynamically more stable 1,4-regioisomer, whereas the Cu(I)-catalysed reaction affords only the favourable 1,4-regioisomer. B3LYP/6-31G(d) level of theory has been used to calculate geometry and frequency features of the reactants, transition states (TSs) and products. Computational studies further reveal that 1,4-regioisomeric products are more favourable and also thermodynamically more stable compared to the 1,5-regioisomers.     

Tryptophan-dependent indole-3-acetic acid biosynthesis by ‘IAA-synthase’ proceeds via indole-3-acetamide

Plants are suggested to produce their major growth promoting phytohormone, indole-3-acetic acid (IAA), via multiple redundantly operating pathways. Although great effort has been made and plenty of possible routes have been proposed based on experimental evidence, a complete pathway for IAA production has yet to be demonstrated. In this study, an in-vitro approach was taken to examine the conversion of l-tryptophan (l-trp) to IAA by gas chromatography-mass spectrometry (GC-MS). Especially the influence of putative reaction intermediates on the enzymatic conversion of l-trp to IAA was analyzed. Among the substances tested only indole-3-acetamide (IAM) showed a pronounced effect on the l-trp conversion. We additionally report that IAM is synthesized from l-trp and that it is further converted to IAA by the utilized cell free Arabidopsis extract. Together, our results underscore the functionality of an IAM-dependent auxin biosynthesis pathway in Arabidopsis thaliana.     

Usefulness of resistant gene markers for predicting treatment outcome on second‐line anti‐tuberculosis drugs

Aim: Mutations in rrs [nucleotide (nt) 1401], gyrA gene (codons 90, 91 or 94), tlyA, ethA and thyA genes of Mycobacterium tuberculosis (MTB) were evaluated for their usefulness in predicting treatment outcome of kanamycin (KM), capreomycin (CPM), ofloxacin (OFX), ethionamide (ETH) and para‐aminosalicylic acid (PAS). Methods and Results: DNA sequence analyses of these genes were performed against 188 MTB isolates obtained from patients put on second‐line anti‐TB drugs (SLDs) with well‐documented clinical history and treatment outcome. Mutations in rrs and gyrA have 100% positive predictive value (PPV) in predicting treatment failure for KM and OFX, while 88·9 and 80% were obtained, respectively, when tlyA and rrs mutations were considered in CPM. For ETH and PAS, the PPV of using ethA and thyA mutations to predict treatment failure was 82·5 and 89·3%, respectively. Conclusions: Our study demonstrated high specificities of gene mutations in predicting poor treatment outcome; however, further technical advancement is required to make the molecular detection of resistances to other SLDs feasible in clinical laboratories. Significance and Impact of the Study: This is the first study to correlate different polymorphisms of major SLD resistance gene markers with predicted treatment outcome, using an international set of well‐documented clinical MTB strains.     

Platinum(II) and palladium(II) saccharinato complexes with 2,2′:6′,2″-terpyridine: Synthesis, characterization, crystal structures, photoluminescence and thermal studies

[Pd(sac)(terpy)](sac)·4H₂O (1), [Pt(sac)(terpy)](sac)·5H₂O (2), [PdCl(terpy)](sac)·2H₂O (3) and [PtCl(terpy)](sac)·2H₂O (4) (sac = saccharinate, and terpy = 2,2′:6′,2″-terpyridine) have been synthesized and characterized by elemental analysis, FT-IR, ¹H NMR and ¹³C NMR. In 1 and 2, a tridentate terpy ligand together with an N-coordinated sac ligand form the square-planar geometry around the palladium(II) or platinum(II) ions, while one sac anion remains outside the coordination sphere as a counter-ion. X-ray single crystal studies show that the [M(sac)(terpy)]⁺ ions in 1 and 2 reside in the centers of a hydrogen bonded honeycomb network formed by the uncoordinated sac ions and the lattice water molecules. Complexes 3 and 4 are isostructural and consist of a [M(Cl)(terpy)]⁺ cation, a sac anion and two lattice water molecules. The [M(Cl)(terpy)]⁺ ions interact with each other via M-M and π-π stacking interactions and these π interacted units are assembled to a 2D network by water bridges involving the sac ions and lattice water molecules. Convenient synthetic paths for 1-4 are also presented, and spectral, luminescence and thermal properties were discussed.     

Nobiletin metabolite, 3′,4′-dihydroxy-5,6,7,8-tetramethoxyflavone,inhibits LDL oxidation and down-regulates scavenger receptor expression and activity in THP-1 cells

There is accumulating evidence that LDL oxidation is essential for atherogenesis and antioxidants that prevent oxidation may either decelerate or reduce atherogenesis. Current study focused on the effect and mechanism of 3′,4′-dihydroxy-5,6,7,8-tetramethoxyflavone (DTF), a major metabolite of nobiletin (NOB, a citrus polymethoxylated flavone) on atherogenesis. We found DTF had stronger inhibitory activity than α-tocopherol on inhibiting Cu²⁺-mediated LDL oxidation measured by thiobarbituric acid-reactive substances assay (TBARS), conjugated diene formation and electrophoretic mobility. Monocyte-to-macrophage differentiation plays a vital role in early atherogenesis. DTF (10–20 μM) dose-dependently attenuated differentiation along with the reduced gene expression of scavenger receptors, CD36 and SR-A, in both PMA- and oxidized low-density lipoprotein (oxLDL)-stimulated THP-1 monocytes. Furthermore, DTF treatment of monocytes and macrophages led to reduction of fluorescent DiI-acLDL and DiI-oxLDL uptake. In conclusion, at least three mechanisms are at work in parallel: DTF reduces LDL oxidation, attenuates monocyte differentiation into macrophage and blunts uptake of modified LDL by macrophage. The effect is different from that of NOB, from which DTF is derived. This study thus significantly enhanced our understanding on how DTF may be beneficial against atherogenesis.     

Cyclo‐oxygenase 2 up‐regulates the effect of multidrug resistance

COX‐2 (cyclo‐oxygenase 2), an inducible form of the enzyme that catalyses the first step in the synthesis of prostanoids, is associated with inflammatory diseases and carcinogenesis, which is suspected to promote angiogenesis and tissue invasion of tumours and resistance to apoptosis. COX‐2 is also involved in drug resistance and poor prognosis of many neoplastic diseases or cancers. The activation of the COX‐2/PGE₂ (prostaglandin E₂)/prostaglandin E receptor signal pathway can up‐regulate the expression of all three ABC (ATP‐binding‐cassette) transporters, MDR1/P‐gp (multidrug resistance/P‐glycoprotein), MRP1 (multidrug‐resistance protein 1) and BCRP (breast‐cancer‐resistance protein), which encode efflux pumps, playing important roles in the development of multidrug resistance. In addition, COX inhibitors inhibit the expression of MDR1/P‐gp, MRP1 and BCRP and enhance the cytotoxicity of anticancer drugs. Therefore we can use the COX inhibitors to potentialize the effects of chemotherapeutic agents and reverse multidrug resistance to facilitate the patient who may benefit from addition of COX inhibitors to standard cytotoxic therapy.     

Two-dimensional coordination polymers of Zn(II) and Cd(II) derived from 3,3′,5,5′-azobenzenetetracarboxylic acid exhibiting solvent facilitated structure reversibility

Two Cd(II) and Zn(II) coordination polymers based on 3,3′,5,5′-azobenzenetetracarboxylic acid (H₄abtc): [Cd₂(abtc)(H₂O)₆]·DMF·0.5H₂O (1) and [Zn₂(abtc)(bpy)(H₂O)₂]·DMF·H₂O (2) are synthesized and structurally characterized. Both 1 and 2 are 2D polymers but interconnected by solvent molecules to generate 3D suprastructures. Solvent expulsion leads to rupture of both structures, but upon re-exposure to the solvent mixture they exhibit remarkable ability to regain the original structure reversibly from the almost amorphous solvent-expelled form. Compounds with such structural flexibility and reversibility are expected to have some useful functionality.