Sasmita Das

Retinoic acid signaling pathways in development and diseases.

Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging.

Boron chemicals in diagnosis and therapeutics

Advances in the field of boron chemistry have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade(®)), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkins lymphoma. Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry. It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the development of boron-based compounds as diagnostic and therapeutic agents in humans.

Acute and subchronic effects of clozapine on licking in rats: tolerance to disruptive effects on number of licks, but no tolerance to rhythm slowing

In order to assess the effects of the atypical neuroleptic clozapine on orolingual competence in rats, tongue function was measured by quantitating the rhythm of tongue movements after acute (1.0, 3.0, 6.0 mg/kg) or subchronic intraperitoneal treatment (1.5, 3.0, 4.5 mg/kg, each dose for at least 7 days) with the drug. Thirsty rats were trained to lick water from a force-sensing disk by thrusting the tongue through a 12-mm-diameter hole to strike the horizontal disk located 5 mm below the hole. Number of licks in 2 min and rhythm of tongue movements (as determined by Fourier analysis of the force-time signal) were each dose dependently reduced in the acute dose-effect phase of the study. In the subchronic study number of licks exhibited tolerance, but the slowing of lick rhythm did not show tolerance. An acute dose range of the serotonin antagonist ritanserin (0.5, 1.0, 2.0, 4.0 mg/kg) was also studied in the same rats. Ritanserin had no effect on any of the measures of orolingual function. The clozapine result was replicated in a second study using younger, drug naive rats. The results for clozapine were contrasted with previous reports indicating that haloperidol has little effect on lick rhythm. Additional discussion evaluated the possible contribution of neurotransmitter receptors on motor neurons of the hypoglossal nucleus to the observed rhythm slowing induced by clozapine.

The Role of Tau Protein in Diseases

Amyloid-β peptide (Aβ) and tau protein deposits in the human brain are the pathological hallmarks of Alzheimer’s disease (AD). Tau is a class of proteins that are abundant in nerve cells and perform the function of stabilizing microtubules. However, in certain pathological situations, Tau proteins become defective and fail to adequately stabilize microtubules, which can result in the generation of abnormal masses that are toxic to neurons. This process occurs in a number of neurological disorders collectively known as Tauopathies. Tau protein is the major factor of the intracellular fi lamentous deposits that relate to a number of neurodegenerative diseases which includes the progressive supranuclear palsy (PSP), Pick’s disease, and Parkinsonism. The identifi cation of mutations in Tau established that dysfunction or misregulation of tau protein is suffi cient to cause dementia and neurodegeneration. In this review article, we discussed the etiology of the tau formation and role in AD and subsequently therapeutic approach for disassembling and Tau inhibition. Research Article The Role of Tau Protein in Diseases Bhaskar C Das1,2*, Sribidya Pradhan1, Devi Prasana Ojha1, Arpita Das1, Narayan S Hosmane3 and Sasmita Das4 1Departments of Medicine and Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 2Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA 3Department Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA 4Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA *Address for Correspondence: Bhaskar C Das, Departments of Medicine and Pharmacological Sciences, Department of Surgery, Weill Cornell Medical College of Cornell University, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Email: Bhaskar.Das@mssm.edu Submitted: 22 March 2018 Approved: 06 April 2018 Published: 09 April 2018 Copyright: 2018 Das BC, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Das BC, Pradhan S, Ojha DP, Das A, Hosmane NS, et al. The Role of Tau Protein in Diseases. Ann Adv Chem. 2018; 2: 001-016. https://doi.org/10.29328/journal.aac.1001010 Introduction The need for a new approach to treatment of Alzheimer’s disease is urgent. Alzheimer’s is the most common age-related dementia and the number of cases in the United States is expected to increase from the current number of about ive to six million to 15 million by the year of 2050. The costs to family life and on the health care system are enormous. Alzheimer’s and other dementias are projected to cost the United States approximately

Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats

226 billion in 2015 alone (estimated 44.4 million, in 2013), with that number rising to as high as

Synthesis of a Water Soluble Carborane Containing Amino Acid as a Potential Therapeutic Agent

1.1 trillion in 2050 (approx. 135.5 million in 2050) [1,2]. Tau protein is the major factor of the ilamentous deposits that relate to AD alongside various other neurodegenerative disorders. Tau protein belongs to a group of proteins referred to as Microtubule-Associated Proteins (MAPs), that in common are heat resistant and limited affected by acid treatment without loss their function [3]. Six isoforms of tau protein differ according to the contents tubulin binding domains. These isoforms, which vary in size, are related to the presence or absence of sequences encoded by exons. Because each of these isoforms has explicit physiological roles, they are differentially expressed during the development of the brain. Tau has been said to interact with a number of other proteins besides tubulin/microtubules [4], although the biological relevance of many of these interactions is not clear. Structure of Tau Tau is an unusual protein that has long stretches of charged (positively and The Role of Tau Protein in Diseases Published: April 09, 2018 2/16 negatively) regions that are not bene icial for intermolecular hydrophobic association [5]. Of the four microtubule binding repeats in tau, the predicted amino acids having β-structure are concentrated. Tau is a hydrophilic protein that has been widely categorized in solution where, by analysis of the circular dichroism spectra [6], it appears as a random coiled protein. With its sedimentation coef icient, tau has been suggested to be a highly irregular protein, compatible with the long rod structure observed by electron microscopy [7]. Tau is encoded by a single gene, MAPT, which lies on human chromosome 17. In the human brain, tau is expressed as six molecular isoforms, which are the result of alternative splicing of exons 2, 3 and 10 in its premRNA. The six isoforms of tau differ from one another in containing zero (0N), one (1N), or two (2N) amino-terminal inserts of 29 amino acids each, and the presence of three (3R) or four (4R) microtubule-binding domain repeats in a assumable length of 352 to 441 amino acids [8-11]. In the adults, it consists of a family of four to six related polypeptides with apparent mol. wts of 50,000 68,000 daltons [12]. Tau changes in the neuronal morphology Neurons are cells with a very complex morphology; the microtubules become stabilized in speci ic directions that develop two types of cytoplasmic extensions that will become the axon and the dendrites, and tau is preferentially localized and active in distal portions of axons where they stabilize microtubules as well as providing lexibility. In Figure 1a,1b [9], the expression of tau in cells promotes the stabilization of microtubules, leading to the formation of cytoplasmic extensions as shown by the arrows. Neural transmission occurs through these processes, and any changes in neuronal morphology may affect the behavior and produce pathological events. In pathological situations, tau has additionally been shown to be capable of forming aberrant ibrillary polymers as shown in Figure 1c and Figure 2 (courtesy NRN poster 2008). Figure 1: (Courtesy [9] and modifi ed by us) The expression of tau in non-neural cells (a and b) promotes the stabilization of microtubules, leading to the formation of cytoplasmic extensions (arrows) that are not normally seen in those cells that are not expressing tau. c: Fibers assembled in vitro from the pro-aggregant Tau repeat domain. Figure 2: (Courtesy NRN poster 2008 and modifi ed by us) The image on the left shows a view of the binding of tau to a tubulin dimer. The right shows a description of the differences between a healthy neuron versus a diseased neuron and the result of a of the tau hyperphosphorylation. The Role of Tau Protein in Diseases Published: April 09, 2018 3/16 Formation of how Tau proteins Tau proteins are produced through alternative splicing of a single gene called MAPT (Microtubule-Associated Protein Tau). The proteins work together with a spherical protein called tubulin to stabilize microtubules and aid the assembly of tubulin in the microtubules. Tau proteins achieve their control of microtubule stability through isoforms and phosphorylation. These six tau isoforms are generated by alternative mRNA splicing from a single gene in human brain [13,14]. Tau is a phosphoprotein that normally contains 2-3 phosphates/molecule, but it is abnormally hyperphosphorylated with a stoichiometry of 9-10 moles of phosphate per mole of protein in Alzheimer’s disease (AD) brain [15,16]. To date, more than 30 phosphorylation sites have been identi ied in AD hyperphosphorylated tau, some of which are not phosphorylated in normal tau. Hyperphosphorylation (mechanisms used by the cell to regulate mitosis) of tau proteins can cause the straight ilaments to tangle which is referred to as neuro ibrillary tangles. These tangles contribute to the pathology of Alzheimer’s disease. When a brain affected by Alzheimer’s disease is examined, all six isoforms of tau are often found hyperphosphorylated in paired helical ilaments. Deposits of abnormal aggregates enriched with tau isoforms have also been reported in some other neurodegenerative diseases. Certain aspects of Alzheimer’s pathology also point at some similarities being shared with prion diseases. Tau protein was discovered by studying factors necessary for microtubule formation. Tau protein promotes tubulin assembly into microtubules, one of the major components of the neuronal cytoskeleton that de ines the normal morphology and provides structural support to the neurons [17,18]. Tubulin binding of tau is regulated by its phosphorylation state, which is regulated normally by coordinated action of kinases and phosphatases on tau molecule [19,20]. Taupathies Tauopathies are considered as a group of disorders that are the consequence of abnormal tau phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations in the tau gene. In some tauopathies, like Alzheimer’s disease or Downs syndrome, the tau pathology is associated with other cerebral changes. The majority of neurodegenerative diseases are characterized by the deposition of insoluble protein in cells of the neuromuscular system. Advances in molecular neuropathology have allowed a classi ication system of neurodegenerative diseases based on this protein accumulation. Microtubule-associated tau is one protein that has important functions in healthy neurons, but forms insoluble deposits in diseases as tauopathies. Tauopathies encompass more than 20 clinicopathological entities, including Alzheimer’s disease, the most common tauopathy. There are important clinical, pathological, biochemical and genetic similarities in the range of these diseases and they have helped to advance our understanding of the factors that initiate neurodegeneration and tau accumulation. Alzheimer disease is the most common and the best-studied tauopathy in which two main pathological structures form in the brains of patients: senile plaques (composed of the β-am

Similarity of clozapine's and olanzapine's acute effects on rats' lapping behavior

RationaleThe low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding.ObjectiveThe objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats.MethodsLevels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats.ResultsHS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LS rats, but not in HS animals, while high-dose cocaine augmented activity only in HS rats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HS rats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors.ConclusionsDiminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HS rats and an altered dose-effect relationship for cocaine-induced locomotor activity.