The Essentials of Biochemistry of the Proteins as Related to Alzheimer’s Disease: A Review

Amyloid plaques and Tau tangles, constitute the pathological hallmarks of the brains of the patients suffering from Alzheimer’s disease. They are identified as far back as 1996 by Alois Alzheimer, a German psychiatrist and neuropathologist, but till this date, how they produce neuronal death remained an enigma. The amyloid cascade theory held its sway until recent times until the emphasis is shifted to the metabolites of amyloid Beta precursor protein (APP). Several metabolites of APP are formed depending on by which pathway, the APP is metabolized, either by the non - amyloidogenic pathway (forming ? - C terminal fragment - CTF? / C83 and the N - terminal fragment sAPP? / P3 and the APP intracellular domain AICD). Or amyloidogenic pathways. ( Forming extracellular A? and APP intracellular domain - AICD). The hyperphosphorylation is held responsible for the tau protein tangles. The over activity of the tau kinases or the failure of inhibition by the tau phosphatases i s implicated, in tau tangle deposits. These biochemical aspects of AD assumed importance in connection with the interventional therapeutic strategies that are developed in the years bygone, as well as those still are in the developing stage. In keeping with this fact, it is attempted to review the essentials of the biochemical aspects of the involved proteins, as related to AD, in this article

Studies on Alzheimer Disease - Metformin Connection - A Brief Review

Metformin is the widely prescribed first line oral antidiabetic drug used in diabetes mellatus, type 2 . The global sales turnover of metformin runs into millions of dollars. The Increased risk of metformin (Met) users for developing Alzheimer disease (AD)is reported first in a study conducted in 2011. Since then, the subject has attracted the attention of the researchers as well as the pharmaceutical industry, resulting in a number of studies, both clinical as well as experiments on animals. Confusing results poured in , ranging from confirmation of the risk of AD to protection against developing AD , making the scenario, all the more intriguing . Added to the confusion, is the diversity of various studies as well as the parameters interpreting their results. Of the many clinical trials, some are retrospective cohort studies(Tseng Chin-Hsiao 2019) , case controlstudies (Imfeld P, et al.) Randomised studies (Hsu CC, et al.),double blind , cross over pilot studies. (Aaron Koenig et al.)and some longitudinal studies (Ng TP, et al.) , besides studies doing meta analysis .Of these studies most of the trials estimate the risk of development of dementia withmetformin alone (Tseng Chin-Hsiao 2019) or in comparison with other OHAs (Hsu et al,Chenget al.) .The other studies studied the effect of metformin on the cognition. (Moore EM, et al.).These trials have different out come measures, (like Hazard ratio, (HR) Odds(OR) ratio, relative risk (RR) etc.)which don’t mean one and the same. So the multiplicity of the types of studies and different out-comes with different conclusions will be surely baffling to an average reader who tries to take cognisance of the involved issues. The article attempts to take stock of the overall developments in this regard. The author adopted a reader friendly approach which is discussed in the article, at the outset. Finally, it is reiterated that future prospective studies only can resolve the conflict of opinion on the nexus between metformin and Alzheimer’s disease

Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

Fibrates are a class ofmedication that mainly lowers theblood triglyceride levels. Theyreduce the LDL andincrease the levels of HDL C, in the blood.Clofibrate,the first member to bediscovered in 1962, and introduced in USA in 1967, is withdrawnin 2002, due to unexplained hepatomegaly,hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular diseaseand diabeticretinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density LipoproteinCholesterol Intervention Trial) , FIELD trail. (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study,ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and BIP (Bezafibrate Infarction Prevention Study) trial andangiography trials, like LOCAT(LopidCoronary Angiography Trial) and BECLAIT(Bezafibrate Coronary Atherosclerosis Intervention Trial)demonstrated thebeneficial effects of gemfibrozil and fenofibrate.Their mechanism of action remained obscure for three decades,ie till 1990s, when theirmode of actionwas found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL)modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involvingthevariousenzymes like LCAT (Lecithin-cholesterol acyl transferase)andCYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochromeP450 7A1 (CYP7A1)) , transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP,OATP (Na+-dependent taurocholate transporter/ organic anion transporters) . These are the.) andnuclear factors like LXR, PPAR alfa etc. (liver orphan receptorα , and peroxisome proliferative nuclear factor) , in relation to the mechanismsof action of fibrates are discussed . Areas of current interests in literature are briefed.

Molecular Basis of Pathogenesis of Ectopic Fat Deposition in DM2 – An Overview

The presence of fat, beyond physiological limits, in organs, other than the adipose tissue, like the liver, the skeletal muscle, the heart and the pancreas etc is called ectopic fat. It causes specific organ dysfunction in the tissues concerned. The importance of the ectopic fat is that it is connected to peripheral tissue insulin resistance, obesity, metabolic syndrome etc. Though the molecular mechanisms underlying the specific organ dysfunctions are understood, still grey areas exists as to the source ofthe ectopic fat and how it finds it’s way to the specific sites of the target organs (intra-myocellular in skeletal muscle, hepatocyte cytoplasm of liver,epicardial surface andcoronary arteries of heart etc.).The molecular mechanisms involving the actualectopic deposition fat, are not clear. This article focuses on some of the grey areas in the pathogenesis of the ectopic fat deposition, besides reviewing brieflythe factsalready known in the literature about ectopic fat deposition.

Molecular Basis of Pathogenesis of Diabetes Mellitus Type 2- a New Perspective

Decreased insulin secretion due to beta cell dysfunction of the pancreas and defective utilization of insulin due to insulin resistance / Hyperinsulinemia are two important issues in the pathogenesis of DM2. There are many explanations in the literature to account for these two observed phenomena and their interrelationship. DM2 is believed to occur due to a complex interplay of environmental andBehavioural factors in genetically predisposed persons. Among the prominent theories explaining the pathogenesis of DM2, the viscera- Portal hypothesis, the Ectopic fat hypothesis and the adipose tissue as an endocrinal gland are prominent. Besides, the role played by oxidative stress, metabolic stress, mitochondrial dysfunction, endoplasmic reticulum stress, etc. are also advanced. It is felt that basic to and at the core of all the observed facts, is the shift of energy metabolism from normal glycolysis to B- oxidation of fats. Hence, how B - oxidation prevails over glycolysis is the fundamental issue to be addressed together with its interrelationships with insulin resistance, as to which is the cause and which is the effect. At the molecular level, an attempt to find answers to the above questions is made in this paper.To this extent, the Randle fatty acid cycle (Substrate competition theory of Randle) is suitably modified and applied to explain the switch of Energy metabolisms in DM2 .Defective disulfide bond formation of the insulin receptor which makes it physiologically ineffective, is suggested as the cause of the insulin resistance where as the prevailing molecular mechanisms stress on post-receptor signaling defect. The cause and effect of both are discussed. This line is considered to be a departure from traditional approaches broached above and briefly outlined in this article.