Bioreducible polyethylenimine core-shell nanostructures as efficient and non-toxic gene and drug delivery vectors.

Low molecular weight branched polyethylenimine (LMW bPEIs 1.8 kDa) have received considerable attention for the fabrication of nucleic acid carriers due to their biocompatible and non-toxic nature. However, due to the inadequate nucleic acid complexation ability and transportation across the cell membrane, these show poor transfection efficacy, limiting their clinical applications. Therefore, to overcome these challenges, in this study, we have grafted bPEI 1.8 kDa with a disulfide bond containing hydrophobic moiety, 3-(2-pyridyldithio) propionic acid (PDPA), via amide linkages through EDC/NHS-mediated coupling to obtain N-[3-(2-pyridyldithio)] propionoyl polyethylenimine (PDPP) conjugates. The best formulation for nucleic acid transfection was evaluated after preparing a series of PDPP conjugates by varying the amount of PDPA. In an aqueous environment, these PDPP conjugates self-assembled to form spherical shaped core-shell PDPP nanostructures with size ranging from âˆ¼188-307 nm and zeta-potential from ∼ +3 to +19 mV. The positively charged surface of the core-shell nanocomposites helps in the binding of plasmid DNA (pDNA), its transportation inside the cell, and protection against enzymes. Evaluation of PDPP/pDNA complexes on mammalian cells revealed that all these complexes showed significantly improved transfection efficacy without hampering cytocompatibility. Amongst all, the pDNA complex of PDPP-2 exhibited the best transfection efficiency (i.e. >6-fold) in comparison to pDNA complex of the native bPEI. The nanocomposites exhibited the redox responsive behavior advantageous for therapeutic delivery to the tumor cells. The core of the nanostructures facilitate the encapsulation of a hydrophobic model drug, ornidazole. In vitro drug release analysis showed a faster release rate in response to a reductant mimicking the cellular environment. Altogether, these nanostructures have great potential to co-deliver both drug and gene simultaneously in response to tumor cell reductive microenvironment in vitro and could be used as the next-generation delivery system.

O6-methylguanine repair by O6-alkylguanine-DNA alkyltransferase.

O6-alkylguanine-DNA alkyltransferase (AGT) repairs O6-methylguanine (O6mG) in DNA that is known to cause mutation and cancer. On the basis of calculations performed using density functional theory involving the active site of AGT, a mechanism for catalytic demethylation of O6mG to guanine has been proposed. In this mechanism, roles of six amino acids, i.e., Cys145, His146, Glu172, Tyr114, Lys165, and Ser159 in catalytic demethylation of O6mG are involved. This mechanism has three steps as follows. At the first step, Cys145 in the Cys145-water-His146-Glu172 tetrad is converted to cysteine thiolate anion while at the second step, abstraction of the Tyr114 proton by the N3 site of O6mG occurs in a barrierless manner. In the third step, abstraction of Lys165 proton by deprotonated Tyr114 and transfer of the methyl group of O6mG to the thiolate group of Cys145 anion occur simultaneously. As AGT is a major target in cancer therapy, identification of the roles of the different amino acids in demethylation of O6mG is expected to be useful in designing efficient AGT inhibitors.

[Evaluating the health of the elderly and well-being of relatives caring for the elderly]. / Beurteilung der Gesundheit alter Menschen und Wohlbefinden pflegender Angehöriger.

Facilitating a realistic appraisal of physical and psychiatric health parameters of a diseased family member has shown to be most important in counseling families with frail elder relatives. It is a prerequisite for adequate coping strategies to reduce caregiver burden, e.g. for the relief available using professional help. Data of a study on 140 families with a diseased elder relative (Bruder et al.) (1) are used to identify 6 types of families that differ maximally with regard to estimation of the old person's state of health (denial, realistic view or aggravation of disease by the caregiver and/or by the old person) by means of cluster analysis. A multiple regression of "caregiver wellbeing" on the elderly's "objective health status", on "family type" and on an interaction term "objective health status" by "family type" accounts for roughly 33% of the variance of caregiver wellbeing. A highly significant effect of the interaction term proves denial and/or aggravation of the elder person's state of disease to be detrimental to caregiver wellbeing given a certain grade of disease of the old person. A negative effect of the patient's disease on caregiver wellbeing is found especially for families a) with old person and caregiver misjudging physical deficits in opposite directions and b) with caregivers denying organic brain deterioration in their frail relative. A concept for counseling families reaching from information, support during the process of grieving about loss of the elder's capacities up to psychotherapeutically oriented help for family members is briefly described.