HSD17B7 gene in self-renewal and oncogenicity of keratinocytes from Black versus White populations.

Human populations of Black African ancestry have a relatively high risk of aggressive cancer types, including keratinocyte-derived squamous cell carcinomas (SCCs). We show that primary keratinocytes (HKCs) from Black African (Black) versus White Caucasian (White) individuals have on average higher oncogenic and self-renewal potential, which are inversely related to mitochondrial electron transfer chain activity and ATP and ROS production. HSD17B7 is the top-ranked differentially expressed gene in HKCs and Head/Neck SCCs from individuals of Black African versus Caucasian ancestries, with several ancestry-specific eQTLs linked to its expression. Mirroring the differences between Black and White HKCs, modulation of the gene, coding for an enzyme involved in sex steroid and cholesterol biosynthesis, determines HKC and SCC cell proliferation and oncogenicity as well as mitochondrial OXPHOS activity. Overall, the findings point to a targetable determinant of cancer susceptibility among different human populations, amenable to prevention and management of the disease

DNA damage in obesity: Initiator, promoter and predictor of cancer

Epidemiological evidence linking obesity with increased risk of cancer is steadily growing, although the causative aspects underpinning this association are only partially understood. Obesity leads to a physiological imbalance in the regulation of adipose tissue and its normal functioning, resulting in hyperglycaemia, dyslipidaemia and inflammation. These states promote the generation of oxidative stress, which is exacerbated in obesity by a decline in anti-oxidant defence systems. Oxidative stress can have a marked impact on DNA, producing mutagenic lesions that could prove carcinogenic. Here we review the current evidence for genomic instability, sustained DNA damage and accelerated genome ageing in obesity. We explore the notion of genotoxicity, ensuing from systemic oxidative stress, as a key oncogenic factor in obesity. Finally, we advocate for early, pre-malignant assessment of genome integrity and stability to inform surveillance strategies and interventions

Signaling pathways and gene-gene network interaction in the pathogenesis of Oral submucous fibrosis: a precancerous condition

A prominent count of world’s population is affected from the oral malignancies and the number is increasing at an alarming rate (90.3 million cases being recorded annually), due to lack of effective control of the malady. These malignancies are almost always preceded by inflammatory oral lesions such as Leukoplakia (LPK), Erythroplakia (EP), Oral lichen planus (OLP) and Oral submucous Fibrosis (OSF) with malignant transformation rates of 15%,14.3%-50%, 0.4%-5.6% and 3%-19% respectively (Mithani et al. 2007). The WHO monograph on Head and Neck Tumors (2005) used the term “Epithelial precursor lesions” for such pre-malignant lesions. In May 2005, the term “Potentially Malignant disorders” was recommended by workshop coordinated by the WHO Collaborating center for Oral Cancer and Precancer in UK as it conveys that not all disorders described under this term may transform into cancer (Warnakulasuriya et al. 2007). The current study comprises the analysis of genetic alteration involved in OSF which is a major concern especially in south Asian countries. Worldwide estimates of OSF in 1996 indicated 2.5 million people being affected; whereas according to 2002 statistics, 5 million cases were reported from Indian subcontinent alone (Rajalalitha et al. 2005). Though current statistics are not available, but the discrete case studies reporting the prevalence of OSF among younger population makes OSF a major health concern among the south Asian countries. This is supported by the widespread use of areca nut and tobacco, which has been implicated as principal etiological factors of OSF, in these countries

In-silico prediction of dual function of DksA like hypothetical protein in V. cholerae O395 genome.

Cholera, an acute infection of the small intestine, is caused by Vibrio cholerae. The present study identified a hypothetical protein in V. cholerae O395, which was predicted to be acquired through horizontal gene transfer the origin of which was found to be from a phage. Its expression was further confirmed by RT-PCR. Homology based 3D model of the hypothetical protein indicated DksA like homologue. Protein binding site of 3D-model revealed a deep cleft which may influence the dimer formation and interaction with ds-DNA molecule. Also, canonical function of direct interaction with RNA polymerase (RNAP) holoenzyme in complex with ppGpp suggests its dual role in the pathogenesis of cholera

Characterization of Homology Model of VCO395_1035.

<p>A. The cartoon representation of 3D modeled structure of VCO395_1035 using PDB ID: 3STJ. Helix (blue), sheets (Purple) and loops (Sky Blue). B. The β-barrel like structure of protease Domain of VCO395_1035 showing active site loops LD: Activation loop, L1: Oxyanion loop, L2: Substrate specificity and L3: Regulatory loop along with interdomain linker (IDL) helix. ML 1: Modeled loop 1 in Protease domain (residue 79–89) on FALC-Loop server indicated as α1-helix. C. The PDZ1 Domain of VCO395_1035, showing flexible carboxylate binding loop (CBL) and interacting clamp (IC). ML 2: Modeled loop 2 in PDZ1 domain (residue 176–189) on FALC-Loop server indicated as α6-helix.</p

Active site and Protein-substrate interaction using Hex 5.0.

<p>A. The surface view of protease domain containing active site showing the oxyanion hole and properly oriented shallow S1 hydrophobic pocket. B. The surface view of PDZ1 containing hydrophobic binding groove formed by CBL and α7-Helix showing shallow P₀ and P₋₂ substrate binding pocket. C. The C-terminal of poly-alanine peptide substrate (blue) docked into active side of protease domain. D. The C-terminal of poly-alanine peptide substrate (blue) docked into active side of PDZ1 domain via β-aggumentation. E. The superimposition of substrate docked into the protease active site (blue) with respective to template (3STJ) substrate (red). F. The superimposition of substrate docked into the active site PDZ1 domain (blue) with respective to template (3STJ) substrate (red).</p

Surfactant modulated aggregation induced enhancement of emission (AIEE)—a simple demonstration to maximize sensor activity

A new type of easily synthesized rhodamine-based chemosensor L3, with potential NO2 donor atoms, selectively and rapidly recognizes Hg2+ ions in the presence of all biologically relevant metal ions and toxic heavy metals. A very low detection limit (78 nM) along with cytoplasmic cell imaging applications with no or negligible cytotoxicity indicate good potential for in vitro/in vivo cell imaging studies. SEM and TEM studies reveal strongly agglomerated aggregations in the presence of 5 mM SDS which turn into isolated core shell microstructures in the presence of 9 mM SDS. The presence of SDS causes an enhanced quantum yield (φ) and stability constant (Kf ) compared to those in the absence of SDS. Again, the FI of the [L3–Hg]2+ complex in an aqueous SDS (9 mM) medium is unprecedentedly enhanced (∼143 fold) compared to that in the absence of SDS. All of these observations clearly manifest in the enhanced rigidity of the [L3–Hg]2+ species in the micro-heterogeneous environment significantly restricting its dynamic movements. This phenomenon may be ascribed as an aggregation induced emission enhancement (AIEE). The fluorescence anisotropy assumes a maximum at 5 mM SDS due to strong trapping (sandwiching) of the doubly positively charged [L3–Hg]2+ complex between two co-facial laminar microstructures of SDS under pre-miceller conditions where there is a strong electrostatic interaction that causes an improved inhibition to dynamic movement of the probe-mercury complex. On increasing the SDS concentration there is a phase transition in the SDS microstructures and micellization starts to prevail at SDS ≥ 7.0 mM. The doubly positively charged [L3–Hg]2+ complex is trapped inside the hydrophobic inner core of the micelle which is apparent from the failure to quench the fluorescence of the complex on adding 10 equivalents of H2EDTA2− solution but in the absence of SDS it is quenched effectively

Comparison of the catalytic triad residues and active site arrangement of active and inactive form of the protease domain.

<p>Comparison of the catalytic triad residues and active site arrangement of active and inactive form of the protease domain.</p