Ishfaq A. Sheikh

Recent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds

Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS). Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB) in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimers disease, Parkinsons disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.

Protein Misfolding and Aggregation in Alzheimer's Disease and Type 2 Diabetes Mellitus

In general, proteins can only execute their various biological functions when they are appropriately folded. Their amino acid sequence encodes the relevant information required for correct three-dimensional folding, with or without the assistance of chaperones. The challenge associated with understanding protein folding is currently one of the most important aspects of the biological sciences. Misfolded protein intermediates form large polymers of unwanted aggregates and are involved in the pathogenesis of many human diseases, including Alzheimers disease (AD) and Type 2 diabetes mellitus (T2DM). AD is one of the most prevalent neurological disorders and has worldwide impact; whereas T2DM is considered a metabolic disease that detrementally influences numerous organs, afflicts some 8% of the adult population, and shares many risk factors with AD. Research data indicates that there is a widespread conformational change in the proteins involved in AD and T2DM that form β-sheet like motifs. Although conformation of these β-sheets is common to many functional proteins, the transition from α-helix to β-sheet is a typical characteristic of amyloid deposits. Any abnormality in this transition results in protein aggregation and generation of insoluble fibrils. The abnormal and toxic proteins can interact with other native proteins and consequently catalyze their transition into the toxic state. Both AD and T2DM are prevalent in the aged population. AD is characterized by the accumulation of amyloid-β (Aβ) in brain, while T2DM is characterized by the deposition of islet amyloid polypeptide (IAPP, also known as amylin) within beta-cells of the pancreas. T2DM increases pathological angiogenesis and immature vascularisation. This also leads to chronic cerebral hypoperfusion, which results in dysfunction and degeneration of neuroglial cells. With an abundance of common mechanisms underpinning both disorders, a significant question that can be posed is whether T2DM leads to AD in aged individuals and the associations between other protein misfolding diseases.

Molecular Linkages Between Diabetes and Alzheimer's Disease: Current Scenario and Future Prospects

After the revolutionary Rotterdam study that suggested there was an increased risk of developing Alzheimers disease (AD) in patients with type-2 diabetes mellitus (T2DM), a number of studies have provided direct evidence for the linkage between AD and T2DM. In recent years, AD is considered as a neuroendocrine disorder, also referred as type-3 diabetes. There is a growing list of evidence to suggest that, in addition to impaired insulin signaling, there are a number of additional factors that may act as mechanistic links between AD and T2DM. These factors mainly include hypercholesterolemia, dyslipidemia, hypercystinemia, inflammation, impaired insulin signaling and impaired central nervous response to the adipose tissue-derived hormone leptin. Increased cholesterol plays a crucial role in the abnormal metabolism of the amyloid precursor protein, leading to the accumulation of β-amyloid. In addition to impaired insulin signaling, diabetes has been found to accelerate the appearance of cerebrovascular inflammation and β-amyloid peptide (Aβ) deposition. Increased oxidative stress and production of advanced glycation end products are other probable marker linkages. However, the details of many of these molecular links still require extensive investigation. It is possible that a number of common molecular linkages exist between T2DM and AD. Understanding and analyzing the various molecular linkages between AD and T2DM may shed light on new tools that can be used for the early diagnosis and treatment of AD and also accelerate the identification of T2DM patients who are at high risk of AD.

Proteomics Approaches to Understand Linkage Between Alzheimer’s Disease and Type 2 Diabetes Mellitus

Alzheimers disease (AD) is a progressive neurological disease of the brain leading to the irreversible loss of neurons and intellectual abilities. Diabetes mellitus type 2 (T2DM) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. The prevalence of AD and T2DM is increasing at an alarming rate and has become a major public health concern worldwide. The clinico-pathological relationship between AD and T2DM has been debated for more than a decade. Recent epidemiological studies have provided direct evidence that T2DM is a strong risk factor for AD and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD as compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood and therefore are worth intensive research. The existence of proteomic links between AD and diabetes is an important topic currently under active debate. An understanding of the complex association between diabetes and AD is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases. This review aims to summarize what is currently known about the biological and especially proteomic relationships and similarities between these two age-related devastating diseases of modern day life. This study may also aid in future for the identification of a single or a panel of potential blood-based protein biomarkers for early diagnosis of AD and T2DM with high sensitivity and specificity.

Current view from Alzheimer disease to type 2 diabetes mellitus.

Alzheimers disease (AD) is a neurodegenerative disorder that leads to memory problems. It has been associated with type 2 diabetes mellitus at both the molecular and biochemical level. Pancreatic cells have molecular similarities to the brain at the transcriptomic and proteomic levels. Several genes have been reported to be responsible for both AD and diabetes. Currently, no proper treatment is available but various therapeutic approaches are utilized worldwide for the management of these disorders and may be nanoparticles and herbal treatment of Bacopa monnieri will make promise for the treatment of AD in future. The formation of amyloids in neurons and the formation of amylin in pancreatic cells are potential links between these two disorders, which can be silent killers.

Endocrine Disruption: Computational Perspectives on Human Sex Hormone-Binding Globulin and Phthalate Plasticizers.

Phthalates are a class of high volume production chemicals used as plasticizers for household and industrial use. Several members of this chemical family have endocrine disrupting activity. Owing to ubiquitous environmental distribution and exposure of human population at all stages of life, phthalate contamination is a continuous global public health problem. Clinical and experimental studies have indicated that several phthalates are associated with adverse effects on development and function of human and animal systems especially the reproductive system and exposures during pregnancy and early childhood are by far of utmost concern. Sex hormone-binding globulin (SHBG) is a plasma carrier protein that binds androgens and estrogens and represents a potential target for phthalate endocrine disruptor function in the body. In the present study, the binding mechanism of the nine phthalates i.e. DMP, DBP, DIBP, BBP, DNHP, DEHP, DNOP, DINP, DIDP with human SHBG was delineated by molecular docking simulation. Docking complexes of the nine phthalates displayed interactions with 15–31 amino acid residues of SHBG and a commonality of 55–95% interacting residues between natural ligand of SHBG, dihydrotestosterone, and the nine phthalate compounds was observed. The binding affinity values were more negative for long chain phthalates DEHP, DNOP, DINP, and DIDP compared to short chain phthalates such as DMP and DBP. The Dock score and Glide score values were also higher for long chain phthalates compared to short chain phthalates. Hence, overlapping of interacting amino acid residues between phthalate compounds and natural ligand, dihydrotestosterone, suggested potential disrupting activity of phthalates in the endocrine homeostasis function of SHBG, with long chain phthalates expected to be more potent than the short chain phthalates.

Multiple antigen peptide consisting of B- and T-cell epitopes of F1 antigen of Y. pestis showed enhanced humoral and mucosal immune response in different strains of mice

Yersinia pestis is a causative agent of plague. F1 and V antigen based vaccines have shown remarkable protection in experimental animals. In order to develop epitope based immunogen, three B and one T-cell epitopes of F1 antigen with palmitate residue at amino terminal were assembled on a lysine backbone as multiple antigen peptide (MAP or F1-MAP). MAP was characterized by SDS-PAGE, immunoblot and immunoreactivity with anti F1 sera. MAP was entrapped in PLGA (polylactide-co-glycolide) microparticles and humoral, mucosal immune responses were studied after intranasal immunization with/without CpG ODN 1826 (CpG)/murabutide in different strains of mice. Serum and mucosal washes were measured for MAP specific IgG, IgA, sIgA and IgG subclasses in three strains of mice. F1-MAP showed high serum antibody and mucosal IgG and IgA peak antibody titers. MAP with CpG showed significantly high (p<0.001) peak antibody titer ranging from 102,400 to 204,800 for IgG and 6400 to 12,800 for IgA. High mucosal sIgA and its secretary component detection confirmed generation of mucosal response in intestinal and lung washes. MAP antisera also showed significant immunoreactivity with individual peptides. Moreover, antibody specific activity (IgG, IgA and sIgA) positively correlates with peak antibody titers. Predominantly IgG2a/IgG2b subclass was observed with CpG formulation but in other formulation a mixed IgG1 and IgG2a response was observed. The present study highlights the importance of multiple antigen peptide approach of F1-antigen with CpG as an alternative approach for subunit vaccine.

Implication of the Nutritional and Nonnutritional Factors in the Context of Preservation of Cognitive Performance in Patients With Dementia/Depression and Alzheimer Disease

It has been postulated that Alzheimer disease (AD) is a systemic process, which involves multiple pathophysiological factors. A combination of pharmacotherapy and nonpharmacological interventions has been proposed to treat AD and other dementia. The nonpharmacological interventions include but are not limited to increasing sensory input through physical and mental activities, in order to modify cerebral blood flow and implementing nutritional interventions such as diet modification and vitamins and nutraceuticals therapy to vitalize brain functioning. This article highlights the recent research findings regarding novel treatment strategies aimed at modifying natural course of the disease and delaying cognitive decline through simultaneous implementation of pharmacological and nonpharmacological modulators as standardized treatment protocols.

Computational insights into the molecular interactions of environmental xenoestrogens 4-tert-octylphenol, 4-nonylphenol, bisphenol A (BPA), and BPA metabolite, 4-methyl-2, 4-bis (4-hydroxyphenyl) pent-1-ene (MBP) with human sex hormone-binding globulin

Environmental contamination has been one of the major drawbacks of the industrial revolution. Several man-made chemicals are constantly released into the environment during the manufacturing process and by leaching from the industrial products. As a result, human and animal populations are exposed to these synthetic chemicals on a regular basis. Many of these chemicals have adverse effects on the physiological functions, particularly on the hormone systems in human and animals and are called endocrine disrupting chemicals (EDCs). Bisphenol A (BPA), 4-tert-octylphenol (OP), and 4-nonylphenol (NP) are three high volume production EDCs that are widely used for industrial purposes and are present ubiquitously in the environment. Bisphenol A is metabolized in the human body to a more potent compound (MBP: 4-Methyl-2, 4-bis (4-hydroxyphenyl) pent-1-ene). Epidemiological and experimental studies have shown the three EDCs to be associated with adverse effects on reproductive system in human and animals. Sex hormone-binding globulin (SHBG) is a circulatory protein that binds sex steroids and is a potential target for endocrine disruptors in the human body. The current study was done in order to understand the binding mechanism of OP, BPA, NP, and MBP with human SHBG using in silico approaches. All four compounds showed high binding affinity with SHBG, however, the binding affinity values were higher (more negative) for MBP and NP than for OP and BPA. The four ligands interacted with 19-23 residues of SHBG and a consistent overlapping of the interacting residues for the four ligands with the residues for the natural ligand, dihydrotestosterone (DHT; 82-91% commonality) was shown. The overlapping SHBG interacting residues among DHT and the four endocrine disruptors suggested that these compounds have potential for interference and disruption in the steroid binding function.

Application of Proteomic Tools in Modern Nanotechnological Approaches Towards Effective Management of Neurodegenerative Disorders

Neurodegeneration is the progressive loss of structure or function of neurons leading to neuronal death, usually associated with ageing. Some of the common neurodegenerative disorders include Alzheimers disease, Parkinsons disease, Creutzfeldt-Jakob disease, and Huntingtons disease. Due to recent advancements in highthroughput technologies in various disciplines such as genomics, epigenomics, metabolomics and proteomics, there has been a great demand for detection of specific macromolecules such as hormones, drug residues, miRNA, DNA, antibodies, peptides, proteins, pathogens and xenobiotics at nano-level concentrations for in-depth understanding of disease mechanisms as well as for the development of new therapeutic strategies. The present review focuses on the management of agerelated neurodegenerative disorders using proteomics and nanotechnological approaches. In addition, this review also highlights the metabolism and disposition of nano-drugs and nano-enabled drug delivery in neurodegenerative disorders.