Aberrant activation of Wnt/ß-catenin signaling pathway contributes to the sequential progression of DMBA-induced HBP carcinomas.

Wnt signaling pathway mediated via interactions between ß-catenin and members of the TCF/LEF-1 family of transcription factors plays a central role in the regulation of epithelial cell proliferation, apoptosis, differentiation, adhesion, epithelial-mesenchymal transition, and invasion. Aberrant activation of the Wnt/ß-catenin signaling pathway with overexpression of Wnt and Fz, mutations of APC, ß-catenin, and axin 1, and cytoplasmic accumulation of ß-catenin have been frequently reported in a broad spectrum of human malignancies including oral squamous cell carcinomas (OSCCs). However, changes in the components of the Wnt signaling pathway have not been documented during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis, a paradigm for oral oncogenesis and chemointervention. In this study, we evaluated the role of ß-catenin accumulation and Wnt ligands, Wnt signaling members (Fz, Dvl, APC, GSK-3ß, axin, and WIF) and the downstream targets of Wnt (cyclin D1, MMP-2, and MMP-9) during the sequential progression of DMBA-induced HBP carcinomas by semi-quantitative RT-PCR and western blot analyses. Our data reveal a correlation between ß-catenin accumulation and activation of Wnt signaling, and its downstream effector molecules during the sequential development of HBP carcinomas from hyperplasia to invasive carcinoma through dysplasia. Our data also support a pivotal role for ß-catenin in the malignant transition of the HBP. Aberrant Wnt signaling may be a hallmark of progression to malignancy during DMBA-induced HBP carcinogenesis and could be a potential preventive and therapeutic target for suppression of OSCC.

The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors.

Epidemiological studies have consistently demonstrated the protective effects of dietary phytochemicals against cancer risk. Quercetin, a ubiquitous dietary flavonoid, has attracted considerable attention owing to its potent antioxidant and antiproliferative activities. The present study was designed to investigate the chemopreventive as well as the therapeutic ability of quercetin to modulate the key hallmark capabilities of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinomas. We analyzed the expression of markers associated with cell proliferation and survival (PCNA, p21, p53, cyclin D1, GST-P), apoptosis (Fas, Fas-L, Bcl-2 family proteins, cytochrome-C, Apaf-1, caspases, PARP, survivin, cFLIP, API1), invasion (MMPs, TIMP-2, RECK), angiogenesis (PlGF, VEGF, VEGF receptors, HIF-1α), as well as the epigenetic markers (HDAC-1, DNMT1) by immunohistochemical, Western blot, and RT-PCR analyses. Simultaneous administration of quercetin to DMBA-painted hamsters reduced tumor incidence and tumor burden, while posttreatment of quercetin resulted in a significant tumor growth delay. In addition, quercetin administration induced cell cycle arrest and apoptosis and blocked invasion and angiogenesis. We found a positive correlation between the inhibition of HDAC-1 and DNMT1 by quercetin and its anticancer properties. A dietary phytochemical such as quercetin that modulates a plethora of molecules offers promise as an ideal candidate for multitargeted cancer prevention and therapy.

Mitochondria-mediated apoptosis in patients with adenocarcinoma of the breast: Correlation with histological grade and menopausal status.

The present study was designed to investigate the abnormalities in the expression of apoptosis-associated proteins that lead to the progression of breast cancer. Sixty breast cancer patients histologically categorized as grade I, II and III, and as pre- and post-menopausal were chosen for the study. We analyzed the expression of the anti-apoptotic and pro-apoptotic Bcl-2 family proteins as well as cytochrome C, Apaf-1 and caspases in tumour and adjacent tissues by immunohistochemical and Western blot analyses. The breast tumours analyzed in the present study were characterized by increased expression of Bcl-2, Bcl-xL and Mcl-1, associated with downregulation in the expression of Bax, cytosolic cytochrome C, Apaf-1 and caspases. The magnitude of the changes was however more pronounced in premenopausal patients and in grade III tumours. The results of the present study confirm that differential expression patterns of Bcl-2 family proteins and caspases are involved in evasion of apoptosis and in the progression of breast cancer.

Eugenol induces apoptosis and inhibits invasion and angiogenesis in a rat model of gastric carcinogenesis induced by MNNG.

AIMS: Combining apoptosis induction with anti-invasive and anti-angiogenic treatment is gaining increasing attention as a promising strategy for cancer chemoprevention. In the present study, eugenol (4-allyl-2-methoxyphenol) was evaluated for its chemopreventive effects on N-methyl-N(')-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in Wistar rats by analyzing markers of apoptosis, invasion and angiogenesis. MAIN METHODS: The expressions of markers of apoptosis (Bcl-2, Bcl-xL, Bax, Apaf-1, cytochrome C, caspase-9, caspase-3 and poly(ADP-ribose)polymerase; PARP), invasion (matrix metalloproteinase-2; MMP-2, matrix metalloproteinase-9; MMP-9, reversion-inducing cysteine rich protein with Kazal motifs; RECK and tissue inhibitors of metalloproteinase-2; TIMP-2) and angiogenesis (vascular endothelial growth factor; VEGF and VEGF receptor1; VEGFR1) in stomach tissue of experimental and control animals were measured by gelatin zymogram, immunohistochemical, Western blot and RT-PCR analysis. KEY FINDINGS: Rats administered MNNG developed gastric carcinomas that displayed apoptosis avoidance coupled to upregulation of pro-invasive and angiogenic factors. Administration of eugenol induced apoptosis via the mitochondrial pathway by modulating the Bcl-2 family proteins, Apaf-1, cytochrome C, and caspases and inhibiting invasion, and angiogenesis as evidenced by changes in the activities of MMPs and the expression of MMP-2 and -9, VEGF, VEGFR1, TIMP-2 and RECK. SIGNIFICANCE: Phytochemicals such as eugenol that are capable of manipulating the equilibrium between pro- and anti-apoptotic proteins as well as the delicate balance between stimulators and inhibitors of invasion and angiogenesis are attractive candidates for preventing tumour progression.

Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives.

The synthesis of a series of novel dispiropyrrolidines has been accomplished by 1,3-dipolar cycloaddition reaction with 5-arylidene-1,3-thiazolidine-2,4-dione and 5-arylidene-4-thioxo-1,3-thiazolidine-2-one derivatives as dipolarophiles. The structure and stereochemistry of the cycloadduct have been established by single crystal X-ray structure and spectroscopic techniques. Molecular docking studies were performed on 1FM9 protein. The synthesized compounds were screened for their antidiabetic activity on male Wistar rats.

Biomaterial Surface patterning of self assembled monolayers for controlling neuronal cell behavior.

Control of the position, growth and subsequent function of living cells is a fundamental problem in tissue and cellular engineering. The development of a generation of 'smart' biomaterial substrates requires strict control over the material's surface properties, because the initial response of the cultured cells to the biomaterials mainly depends upon the surface characteristics of the engineered material. Since most of the cells in the body are arranged in distinct patterns during development, it would be beneficial if one could create patterned environments in-vitro for regulating cell behavior, for applications in vivo, in particular for CNS neurons. Accordingly, in this article, we provide design strategies and methodologies developed for nano- and micro-scale surface patterning and the subsequent control of cellular responses in-vitro.

Black tea polyphenols modulate xenobiotic-metabolizing enzymes, oxidative stress and adduct formation in a rat hepatocarcinogenesis model.

The present study was designed to investigate the modulatory effects of black tea polyphenols (Polyphenon-B) on phase I and phase II xenobiotic-metabolizing enzymes and oxidative stress in a rat model of hepatocellular carcinoma (HCC). Liver tumours induced in male Sprague-Dawley rats by dietary administration of rho-dimethylaminoazobenzene (DAB) increased cytochrome P450 (total and CYP1A1, 1A2 and 2B isoforms), cytochrome b(5), cytochrome b(5) reductase, glutathione S-transferase (GST total and GST-P isoform) and gamma-glutamyltranspeptidase (GGT) with decrease in quinone reductase (QR). This was accompanied by enhanced lipid and protein oxidation and compromised antioxidant defences associated with increased expression of the oxidative stress markers 4-hydroxynonenal (4-HNE), anti-hexanoyl lysine (HEL), dibromotyrosine (DiBrY) and 8-hydroxy 2-deoxyguanosine (8-OHdG). Dietary administration of Polyphenon-B effectively suppressed DAB-induced hepatocarcinogenesis, as evidenced by reduced preneoplastic and neoplastic lesions, modulation of xenobiotic-metabolizing enzymes and amelioration of oxidative stress. Thus, it can be concluded that Polyphenon-B acts as an effective chemopreventive agent by modulating xenobiotic-metabolizing enzymes and mitigating oxidative stress in an in vivo model of hepatocarcinogenesis.

Processing nanoengineered scaffolds through electrospinning and mineralization suitable for biomimetic bone tissue engineering.

Processing scaffolds that mimic the extracellular matrix (ECM) of natural bone in structure and chemical composition is a potential promising option for engineering physiologically functional bone tissue. In this article, we report a novel method, by combining electrospinning and mineralization, to process a series of nano-fibrous scaffolding systems with desirable characteristics suitable for biomimetic bone tissue engineering. We have chosen two types of polymers, namely collagen and poly (lactic-co-glycolic acid) (PLGA), natural and synthetic of its kind, respectively, to electrospin into nano-fibrous scaffolds. The electrospun scaffolds have high surface area, high porosity and well connected open pore network. In order to mimic the chemical composition of native bone ECM, the electrospun scaffolds were subjected to mineralization under optimal conditions. From the experimental results, we observed that the formation of bone-like apatite into collagen was relatively abundant and significantly more uniform than PLGA. The major finding of this study has suggested that the surface functional groups of the scaffolding material, such as carboxyl and carbonyl groups of collagen, are important for the mineralization in vitro. In addition, this study revealed that the mineralization process predominantly induce the formation of nanosize carbonated hydroxyapatite (CHA) during collagen mineralization, whilst nanosize hydroxyapatite (HA) is formed during PLGA mineralization. These findings are critically important while selecting the material for processing bone scaffolding system.

9-Ethyl-2,3-dihydro-9H-carbazol-4(1H)-one.

In the title compound, C(28)H(30)N(2)O(2), the cyclo-hexene ring system adopts a sofa conformation. The crystal structure is stabilized by C-H⋯O inter-actions between methyl H atoms of the ethyl substituents and the O atoms of carbonyl groups of adjacent mol-ecules, and by an inter-molecular carbon-yl-carbonyl inter-actions [3.207 (2) Å].

(E,E)-1,5-Di-2-thienylpenta-1,4-dien-3-one.

In the title compound, C(13)H(10)OS(2), the dihedral angle between the thio-phene rings is 14.3 (1)°. The mol-ecular structure is stabilized by C-H⋯π inter-actions between a thio-phene H atom and an adjacent thio-phene ring, and by inter-molecular C-H⋯O hydrogen bonds.

Ethyl 4'-ethenyl-2'-oxo-4-phenyl-2-(3,4,5-trimethoxy-phen-yl)spiro-[pyrrolidine-3,3'-indoline]-5-carboxyl-ate monohydrate.

In the title compound, C(31)H(32)N(2)O(6)·H(2)O, the pyrrolidine ring adopts an envelope conformation. The ethyl C atoms of the ethoxy-cabonyl group are disordered over two positions with occupancies of ca 0.80 and 0.20. Intra-molecular N-H⋯O hydrogen bonds form S(5) and S(6) ring motifs. Mol-ecules are linked into a three-dimensional framework by O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds, and by C-H⋯π inter-actions.

(Z)-3-(4-Fluoro-phen-yl)-1-[4-(methyl-sulfon-yl)phen-yl]-2-tosyl-prop-2-en-1-one.

In the title compound, C(23)H(19)FO(5)S(2), two of the phenyl ring C atoms and a sulfonyl O atom of the phenyl(methylsulfonyl) group are disordered over two positions with occupancies 0.522 (17):0.478 (17). The methyl-phenyl and fluoro-phenyl rings are essentially planar, with maximum deviations of 0.0059 (8) and 0.0047 (9) Å, respectively. The crystal packing is stabilized by C-H⋯F inter-actions.

Design strategies of tissue engineering scaffolds with controlled fiber orientation.

Tissue engineering is an emerging area of applied research with a goal of repairing or regenerating the functions of damaged tissue that fails to heal spontaneously by using cells and synthetic functional components called scaffolds. Scaffolds made of nanofibers (herein called "nano-fibrous scaffolds") play a key role in the success of tissue engineering by providing a structural support for the cells to accommodate and guiding their growth in the three-dimensional space into a specific tissue. The orientation of these fibers is considered as one of the important features of a perfect tissue scaffold, because the fiber orientation greatly influences cell growth and related functions. Therefore, engineering scaffolds with a control over fiber orientation is essential and a prerequisite for controlling cell orientation and tissue growth. Recent advances in electrospinning have made it possible to create nano-featured scaffolds with controlled fiber orientation. Electrospinning is a straightforward, cost-effective, and versatile method, which is recently applied in engineering well-defined nano-fibrous scaffolds that hold promise in serving as a synthetic extra-cellular matrix (ECM). This article reviews the current trends in electrospinning nano-fibrous scaffolds with fiber orientation. A detailed mechanism involved in the spinning process is discussed, followed by experimental examples that show how the fiber orientation influences cellular growth behavior. This review is expected to be useful for readers to gain knowledge on the state-of-the-art of scaffold engineering by electrospinning.

Modulatory effects of black tea polyphenols on oxidant-antioxidant profile and expression of proliferation, apoptosis, and angiogenesis-associated proteins in the rat forestomach carcinogenesis model.

BACKGROUND: Chemoprevention by dietary constituents has emerged as a novel approach to control stomach cancer incidence. We therefore evaluated the chemopreventive effects of black tea polyphenols (Polyphenon-B) on oxidant-antioxidant status, cell proliferation, apoptosis, and angiogenesis during N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis. METHODS: Male Wistar rats were divided into four groups. Rats in group 1 and 2 were given MNNG (150 mg/kg body weight) by intragastric intubation three times at 2 week intervals and followed for 26 weeks. Rats in group 2 received in addition a basal diet containing 0.05% Polyphenon-B. Group 3 animals were given 0.05% Polyphenon-B alone. Group 4 animals served as controls. The status of lipid peroxidation and antioxidants and the expression of the lipid peroxidation marker 4-hydroxy nonenal (4-HNE), proliferating cell nuclear antigen (PCNA), glutathiones-transferase (GST)-pi, Bcl-2, Bax, cytochrome C, caspase 3, cytokeratins, and vascular endothelial growth factor (VEGF) were used as biomarkers. RESULTS: Intragastric administration of MNNG induced well-differentiated squamous cell carcinomas that showed diminished lipid and protein oxidation and an increase in antioxidant status. This was associated with increased cell proliferation, angiogenesis, and invasive potential coupled with apoptosis evasion as revealed by upregulation of PCNA, GST-pi, Bcl-2, cytokeratins, and VEGF and downregulation of Bax, cytochrome C, and caspase 3 protein expression. Dietary administration of Polyphenon-B effectively suppressed MNNG-induced gastric carcinogenesis, as evidenced by modulation of oxidant-antioxidant status, inhibition of cell proliferation and infiltration, and angiogenesis associated with apoptosis induction. CONCLUSIONS: The present study provides evidence that Polyphenon-B exerts multifunctional inhibitory effects on MNNG-induced gastric carcinogenesis and suggests that it can be developed as a potential chemopreventive agent.

Nanobiomaterial applications in orthopedics.

Advancements in nanobiotechnology are revolutionizing our capability to understand biological intricacies and resolve biological and medical problems by developing subtle biomimetic techniques. Nanocomposites and nanostructured materials are believed to play a pivotal role in orthopedic research since bone itself is a typical example of a nanocomposite. This article reviews current strategies using nanobiomaterials to improve current orthopedic materials and examines their applications in bone tissue engineering. Preliminary investigations support the potential of nanobiomaterials in orthopedic applications; however, significant advancements are necessary to achieve clinical use. Overall, current trends in nanobiotechnology foreshadow a bright future through the use of nanobiomaterials in the orthopedic domain.

Nano-featured scaffolds for tissue engineering: a review of spinning methodologies.

Tissue engineering is a multidisciplinary field that is rapidly emerging as a promising new approach in the restoration and reconstruction of imperfect tissues. In this approach, scaffolds play a pivotal role in supporting the cells to accommodate and guide their growth into a specific tissue; therefore, designing scaffolds that are favorable to cellular growth is of great importance. Electrospinning is a straightforward, cost-effective, and versatile technique that has been applied recently for the fabrication of nano-featured scaffolds suitable for tissue engineering. By mimicking a natural extracellular matrix, it offers many advantages over conventional scaffold methodologies. This paper reviews the current state of art of designing nanostructure scaffolds by using the electrospinning technique. Furthermore, an overview of this technique and its spinning mechanism is described, with special attention to areas of interest to the readers.

Biomimetic nanocomposites for bone graft applications.

Allograft bone, dematerialized bone matrix and calcium-based synthetic materials have long been used as bone graft substitutes. First-generation bone graft substitutes as stand-alone graft substitutes have not developed as hoped. It remains a great challenge to design an ideal bone graft that emulates nature's own structures or functions. To further improve the performance of such bone graft substitutes, scientists are investigating biomimetic processes to incorporate the desirable nano-features into the next generation of biomaterials. In this regard, nanostructured biomaterials less than 100 nm in at least one dimension, in particular nanocomposites, are perceived to be beneficial and potentially ideal for bone applications, owing to their nanoscale functional characteristics that facilitate bone cell growth and subsequent tissue formation. In fact, bone itself is a nanocomposite system with a complex hierarchical structure. This review reports the impact of biomimetically derived nanocomposite biomaterials for use in bone applications and provides possible suggestions for future research and development.