Can the aging influence cold environment mediated cancer risk in the USA female population?

Cancer is one of the most debilitating diseases worldwide. Cancer incidence and/or death depends on several intrinsic and extrinsic factors (e.g., dietary habits, socio-behavioral activities, physical inactivity, smoking, alcohol consumption, gender, races/ethnicities and age). Various studies have found that an inverse relationship subsists between environmental temperature and cancer risk. Furthermore, this negative relationship was found to be more consistent in the USA female population. This research mainly focuses on influence of aging on cold environment mediated cancer risk for overall and various anatomical site-specific cancers. Age-specific county-wise data of cancer incidence rate (CIR) in the USA female population was selected in this study. Statistical analysis found a negative correlation between the average annual temperature (AAT) and CIR in all anatomical sites (AAS; overall) as well as different anatomical site-specific cancers (e.g., breast, melanoma, leukaemia, pancreas, bladder, uterus, thyroid and non-Hodgkin's lymphoma (NHL), except for cervical cancer) in different age groups (e.g., less than 50 years, 50 plus years, less than 65 years and 65 plus years). In addition, an inverse relationship between the AAT and CIR was found in case of paediatric cancer. However, all the results obtained from the linear model based statistical analysis proposed that the older age-group of females particularly above 65 years seems to be more prone to cold temperature linked cancer risk. For example, age-specific cold linked cancer incidence appears to be more inclined in case of breast cancer in the age-group of 65 plus years. This study, for first time, proposes that aging may have a positive influence on the relationship between cancer incidence and environment temperature.

Magnesium and molecular crowding of the cosolutes stabilize the i-motif structure at physiological pH.

Most of the important genomic regions, especially the G,C rich gene promoters, consist of sequences with potential to form G,C-tetraplexes on both the DNA strands. In this study, we used three C-rich oligonucleotides (11Py, 21Py, and HTPy), of which 11Py and 21Py are located at various transcriptional regulatory elements of the human genome while HTPy sequence is a C-rich strand of human telomere sequence. These C-rich oligonucleotides formed i-motif structures, verified by Circular Dichroism (CD), UV absorption melting experiments, and native gel electrophoresis. The CD spectra revealed that 11Py and 21Py form i-motif structures at acidic pH values of 4.5 and 5.7 in the presence of 100 mM NaCl but remain unstructured at pH 7.0. However, 21Py can form stable i-motif structure even at neutral pH in presence of 1 mM MgCl2 . UV-thermal melting studies showed stabilization of 21Py i-motif at pH 5.7 in the presence of Na+ or K+ with increasing concentration of MgCl2 or CaCl2 from 1 to 10 mM. Significant shift in the CD peak of HTPy sequence was observed as the positive peak from 286 nm shifted to 276 nm while the negative peak from 265 to 254 nm. Further, inevitable necessity of 1 mM Mg2+ to form i-motif structure at neutral pH was observed. Under similar ionic conditions and neutral pH, all the three C-rich sequences were able to form stable i-motif structures (11Py, 21Py) or altered i-motif/homoduplex structures (HTPy) in the presence of MgCl2 and cell mimicking molecular crowding conditions of 40 wt% PEG 200. It is concluded that presence of Mg2+ ions and molecular crowding agents induce and stabilize i-motif structures at physiological solution environment.

Metal sensitive and DNA concentration dependent structural rearrangement of short oligonucleotide into large suprastructures.

Formation of higher order structures, such as G-quadruplexes and G-quadruplex based large suprastructures into long G-wires and liquid crystals is promising elements for use in healthcare for drug delivery as they are mechanically and thermally stable. In this study, we studied the structures of short 11-mer oligonucleotide 5'-G2AG5AG2-3'(11Pu) which is observed in 3'-UTR region of c-jun protooncogene. We used circular dichroism, UV-thermal melting, native gel electrophoresis and atomic force microscopy to determine the structure of 11Pu. CD results showed that 11Pu formed a mixed G-quadruplex in the presence of Na+ with and without Mg2+, while it formed a parallel G-quadruplex in the presence of 100 mM K+ with or without Mg2+. Cation selectivity in inducing the formation of large superstructures was observed in the presence of 100 mM K+ with 10 mM Mg2+. On the contrary, 10 mM Ca2+ did not induce the suprastructures. It was further demonstrated that Mg2+ at low concentration induced a parallel G-quadruplex of 11Pu, whereas at 10 mM Mg2+ induced a large suprastructure. AFM Images showed that 11Pu formed a G-wire, a liquid crystals and a crystalline lattice depending on the concentration of 11Pu and Mg2+. These insights may be employed to design G quadruplex-based nanowires for targeted drug delivery as well as interesting candidates for molecular nanowires. Communicated by Ramaswamy H. Sarma.

Selective recognition of human telomeric G-quadruplex with designed peptide via hydrogen bonding followed by base stacking interactions.

We described a novel synthetic peptide in which a glutamine residue binds through hydrogen bonding to a guanine-base and a trytophan residue intercalates with K+ resulting in stabilization of a human telomeric G-quadruplex with high selectivity over its complementary c-rich strand and a double-stranded DNA and its complementary C-rich strand. This peptide offers great potential for cancer treatment by inhibiting the telomere extension by telomerase.