Mechanism involved in insulin resistance via accumulation of ß-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer's disease.

The pathophysiological link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has been suggested in several reports. Few findings suggest that T2DM has strong link in the development process of AD, and the complete mechanism is yet to be revealed. Formation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) are two central hallmarks in the AD. APs are the dense composites of ß-amyloid protein (Aß) which accumulates around the nerve cells. Moreover, NFTs are the twisted fibers containing hyperphosphorylated tau proteins present in certain residues of Aß that build up inside the brain cells. Certain factors contribute to the aetiogenesis of AD by regulating insulin signaling pathway in the brain and accelerating the formation of neurotoxic Aß and NFTs via various mechanisms, including GSK3ß, JNK, CamKII, CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, PPP, and P70S6K. Progression to AD could be influenced by insulin signaling pathway that is affected due to T2DM. Interestingly, NFTs and APs lead to the impairment of several crucial cascades, such as synaptogenesis, neurotrophy, and apoptosis, which are regulated by insulin, cholesterol, and glucose metabolism. The investigation of the molecular cascades through insulin functions in brain contributes to probe and perceive progressions of diabetes to AD. This review elaborates the molecular insights that would help to further understand the potential mechanisms linking T2DM and AD.

Thioacids - synthons for amide bond formation and ligation reactions: assembly of peptides and peptidomimetics.

The synthesis of α-amino thioacids and peptide thioacids and their applications in chemoselective amide bond formation, ligation of peptides/proteins/glycopeptides and synthesis of peptidomimetics are reviewed. A variety of successful methods including both C-terminal and N-terminal activations for the coupling of α-amino thioacids and peptide thioacids have ascertained the thioacid-based protocol as a benign alternative to some of the traditional methods of amide/peptide bond formation which employs carboxyl activation. In addition to the couplings involving unprotected peptide fragments and solid phase synthesis, their use in the synthesis of different classes of peptidomimetics such as thioxopeptides, imide conjugates and acylsulfonamide-peptide conjugates only illustrates the versatility of this functionality in generating diverse classes of molecules, some of which are relevant to drug discovery and chemical biology. A note on more reactive seleno counterparts of thioacids, which can be useful in selective cases, is provided.

A facile one pot route for the synthesis of imide tethered peptidomimetics.

A simple and efficient method for the synthesis of N,N'-orthogonally protected imide tethered peptidomimetics is presented. The imide peptidomimetics were synthesized by coupling the in situ generated selenocarboxylate of N(α)-protected amino acids with N(α)-protected amino acid azides in good yields. The protocol was also successfully applied for the synthesis of hybrid tripeptidomimetics bearing both amide and imide functionalities. In addition, coumarinic imide conjugates of amino acids have been accomplished by employing this protocol. The present method provides a convenient and easy access to imide tethered peptidomimetics and is compatible with common protecting groups employed in peptide chemistry.

Orthostatic hypotension in healthy elderly: Is it a myth?

BACKGROUND: Orthostatic hypotension (OH) is common among older people and is more prevalent in elderly with various disorders and on medications. AIMS: The objective of the study was to know the prevalence of orthostatic hypotension in healthy geriatric subjects. SUBJECTS AND METHODS: The study group comprised of healthy non hypertensive, non diabetic elderly individuals aged 60 years and above (n=80) and another group, healthy aged 30 to 50 years age (n=80, mean age39.2±5.3). Orthostatic hypotension was defined as a decline in systolic/diastolic blood pressure of ≥20/10 mmHg when an individual changed from a supine to a standing position within 3 minutes of standing. Systolic and Diastolic blood pressure was measured in supine position and within 3 minutes of standing. RESULTS: 1 out of 80 (1.25%) in the elderly subjects was found to have orthostatic hypotension. CONCLUSION: The study concluded that the orthostatic hypotension is less prevalent in healthy elderly subjects without any illness or without on any medications.