Amyotrophic Lateral Sclerosis

The Current Concept for Stem Cell Therapy in Spinal Cord Injury

Spinal cord injury with neurological deficits is devastating to patients and their families. After the immediate treatment that may involve spinal decompression and stabilization surgeries, patients are typically left with long-term disability. Intense research has focused on spinal cord regeneration, tissue repair, and reinnervation to improve function. Stem cell-based therapies are at the center of this effort. This chapter summarizes common spinal cord injury (SCI) patterns, including complete and incomplete SCIs, and their classification-based prognosis and treatments. They review the types of stem cells used in preclinical and clinical trials in the treatment of SCI and the associated ethical concerns and summarize the current state of the art of stem cellbased SCI treatments.

Anesthetic Considerations for Patients with Chronic Neurologic Disorders

Chronic neurological disorders encompass a broad range of challenges for the surgical and anesthesiology team in the perioperative setting. According to the World Population Prospects 2019, by 2050, 1 in 6 people will be over 65, from 1 in 11 in 2019 [1]. As our population continues to age, our understanding and ability to provide medical and surgical services must improve as well. Perioperative strokes are rare, but they can greatly impact a patient's recovery and function when they occur. Dementia strongly predicts postoperative complications, higher hospital costs, and 30- day mortality [2]. Patients with Parkinson’s disease are at a higher risk of perioperative medical and surgical complications not to mention specific medication regimens that need to be adjusted to avoid worsening symptomatology. Although rare, a patient presenting with Amyotrophic lateral sclerosis (ALS), can present with a broad range of neurologic symptoms, and cardiovascular and pulmonary dysfunction that can be daunting for any anesthesia provider. In this chapter, we will explore the comprehensive approach to managing chronic neurologic disorders, including multidisciplinary care, early identification of potential complications, specialized medication management, and intraoperative considerations.

Pathogenesis of Atherosclerosis and Coronary Heart Disease: Epidemiology, Diagnostic Biomarkers and Prevention by Nutraceuticals, Functional Foods, and Plant-Derived Therapies

Atherosclerosis is characterized by hardening/narrowing of arteries and reduction of blood flow to vital organs. Animal models and human research show that endothelial dysfunction and plaque development precede the pathogenesis of atherosclerosis, and related coronary heart disease, neurological, and renal disorders. Cardiac CT-scans are used to detect atherosclerosis. Early diagnosis of atherosclerosis reduces mortality, morbidity, and healthcare expenditures. Biomarkers like C-reactive protein, IL-6, IL-8, phospholipase A2, cardiac troponin, MicroRNA, miR-21, and other endothelial inflammation biomarkers are novel targets for monitoring atherosclerosisrelated cardiovascular disorders. Anti-platelet and anti-cholesterol drugs are used in the treatment of atherogenesis and blood vessel clots. However, cholesterol-lowering drugs may cause serious adverse effects. Thus, safe and cost-effective non-pharmacological anti-atherogenic and anticoagulant therapies are urgently needed. Nutraceuticals, functional foods, plant-derived therapies, antioxidant/anti-inflammation, foods/fruits/vegetables, and lifestyle changes (e.g., physical activity, less alcohol, smoking cessation) reduce atherogenesis, diabetes mellitus, obesity, hypertension, LDL, and C-reactive protein in all age groups, especially younger people. Overwhelming evidence suggests that regular physical activity (30 min/day), cessation of cigarette smoking, and consumption of antioxidant nutraceuticals rich in flavonoids and retinoids, fresh vegetables and fruits, omega-3 PUFA, culinary spices, probiotics, Mediterranean-type diet, and “DASH DIET” lower the risk of atherogenesis and cardiovascular diseases. This review summarizes current advances in the diagnosis and management of atherosclerosis and related cardiovascular illnesses with plant-based and wholesome diets, including the Mediterranean diet, DASH DIET, and lifestyle changes. New preventative measures and alternative therapies, including dietary interventions and plant-based foods may be the most cost-effective ways to manage atherosclerosis and cardiovascular illnesses.

Recent Drugs Tested in Clinical Trials for Alzheimer´s and Parkinson´s Diseases Treatment: Current Approaches in Tracking New Drugs

Affecting more than 50 million people worldwide and with high global costs annually, neurological disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD) are a growing challenge all over the world. Globally, only in 2018, AD costs reached an astonishing $ 1 trillion and, since the annual costs of AD are rapidly increasing, the projections estimate that these numbers will double by 2030. Considering the industrial perspective, the costs related to the development of new drugs are extremely high when compared to the expected financial return. One of the aggravating factors is the exorbitant values for the synthesis of chemical compounds, hindering the process of searching for new drug candidates. In the last 10-year period, an average of 20 to 40 new drugs were approved per year, representing a success rate of less than 6%. However, the number of referrals for new drug orders and/or applications remained at approximately 700 each year, reinforcing the difficulty in the process of identifying and developing novel drugs. Regarding neurodegenerative diseases, the FDA (USA) approved 53 new therapies in 2019, including 48 new molecules and, from these, three are medicines and two are vaccines. The main drugs recommended for the treatment of these disorders are included in the following classes: Dopamine supplement (Levodopa), Monoamine oxidase (MAO) inhibitor (Selegiline, Rasagiline), Dopamine agonist (Apomorphine, Pramipexole), and Acetylcholinesterase inhibitor (Donepezil, Rivastigmine, Galantamine). Additionally, the current pharmacological treatments are not able to cure these patients and considering the etiological complexity and the prevalence of neurological disorders, scientists have a great challenge in exploring new therapies and new molecules to find an adequate and viable treatment for these diseases. Clinical trials are essential in this process and thus, this chapter describes the most important drugs that were targets of phase III and IV clinical studies in the last five years, associated with the most common neurological disorders worldwide, AD and PD. Information about mechanisms of action, experimental studies in other diseases that support their use, and chemical structure of the drugs are included in this chapter. Additionally, nature as a source of valuable chemical entities for PD and AD therapeutics was also revised, as well as future advances in the field regarding tracking new drugs to get successful results and critical opinions in the research and clinical investigation.

Impact of Abiotic Stresses on In Vitro Production of Secondary Metabolites

Climate change conditions affect plant growth, net primary productivity, photosynthetic capability, and other biochemical functions that are essential for normal metabolism. The stimulation of biosynthesis of secondary metabolites is an important strategy developed by plants to cope with adverse environmental conditions. Many of these metabolites display a wide array of biological and pharmacological properties (e.g., antioxidant, anti-inflammatory, antiproliferative, anti-allergic, antiviral, and antibacterial) and, thus, have valuable applications as pharmaceuticals, agrochemicals, cosmetics, fragrances, and food additives. The aim of this review is to present an overview of the impact of abiotic stress factors in the biosynthesis of secondary metabolites by in vitro cultures. Our literature survey showed that plant tissue culture has been an effective tool to understand plant response to abiotic stresses, such as drought, salinity, temperature, nutrient deficiency, or exposure to ultraviolet radiation, which is of particular interest in the actual scenario of climate change conditions. Furthermore, this technique appears as an environmentally friendly alternative for the production of high-value secondary metabolites for many applications.

MSCs as Biological Drugs: From Manufacturing to Commercialization

Mesenchymal stem/stromal cells (MSCs) can be used as a therapeutic agent in regenerative medicine, owing to their unique self-renewal, multi-lineage differentiation, and immunoregulation properties. The manufacturing of authorized MSC products should depend on good manufacturing practices (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP). Until now, many biotech companies have invested in developing the clinical application of MSC product all over the world. Meanwhile, the application of MSC products for human use must comply with regulations and guidance for a biotech company. In this chapter, we discuss the process and development of MSC products from production-manufacturing to commercialization.

Biomaterials and Mesenchymal Stem Cells

Mesenchymal stem/stromal cells are splendid cell sources for tissue engineering and regenerative medicine attributed to the unique hematopoietic-support and immunomodulatory properties as well as the multi-dimensional differentiation potential towards adipocytes, osteoblasts, and chondrocytes in vitro and in vivo. To date, MSCs have been identified from various approaches, such as perinatal tissues, and adult tissues, and even derived from human pluripotent stem cells (hPSCs). Longitudinal studies have indicated the ameliorative effect and therapeutic efficacy upon a variety of refractory and recurrent disorders such as acute-on-chronic liver failure (ACLF), acute myeloid leukemia (ACLF), premature ovarian failure (POF), and intractable wounds. To date, MSCs have been a to have various origins, including mesoderm, endoderm and ectoderm. In this chapter, we mainly focus on the concepts, and biological and therapeutic properties of MSCs, together with the standardizations for industrial transformation. Overall, the descriptions would help promote a better understanding of MSCs in disease pathogenesis and management and benefit the preclinical and clinical applications in the future.

Neural Stem Cells in Tissue Engineering

Neural stem cells (NSCs) are unique subsets of stem cells with self-renewal and multiple lineage differentiation potential, which are considered promising cell sources for neuron generation and complex cognitive and sensory functions, and the resultant NSC-based cryotherapy for regenerative purposes. Of them, distinguished from the small amount of activated subset, most of the NSCs are maintained in the quiescent state and reveal a low level of metabolic activity but a high sensitivity to the environment. The dynamic balance between quiescence and the activity of NSCs determines both the efficiency of neurogenesis and the long-term maintenance and self-renewal of the NSC pool as well as the neurogenic capacity of the brain. In this chapter, we mainly review the classification and biofunction of NSCs, and introduce the significant progress in the understanding of NSC-based applications and the underlying molecular mechanism for NSC quiescence, the dysfunction in neurogenesis, and the pathogenesis of neurological disorders. Collectively, these data will facilitate the development of NSC-based cytotherapy for a broad spectrum of refractory and recurrent diseases in the future.

Tubulin Modifying Enzymes as Target for the Treatment of Alzheimer's Disease: Old Perspective With A New Angle

Alzheimer's disease (AD) is a major cause of mental disability in the elderly, accounting for 50-60% of all dementia. While β-amyloid plaques as well as neurofibrillary tangles are neuropathological markers, inflammation plays a critical role in AD development. The aberrant detachment of microtubules (MTs) from axon MTs, cellular mislocalization, and hyperphosphorylation of tau are major factors in neurodegeneration death. Tau's ability to aggregate as well as form NFTs is assumed to be regulated by post-translational changes, which are regarded to be an essential regulatory mechanism. So far, drugs that target tau phosphorylation as well as aggregation have not shown therapeutic impact. It is now clear that tubulin PTMs cause tau dysfunction. High glutamylation and detyrosination levels in the neurons affect MT surface physicochemical characteristics. Further evidence for the relevance of such an enzymatic machinery in neurobiology comes from the recent discovery of harmful mutations in enzymes involved in surface MT modification. In this chapter, we discussed that targeting tubulin-modifying enzymes pharmacologically may be useful in treating neurodegenerative disorders.

Neurological Examination

A neurological exam, also called a neuro exam, is an evaluation of a person's nervous system that can be done in the physcians. It may be done with instruments, such as lights and reflex hammers. It usually does not cause any pain to the patient. The nervous system consists of the brain, the spinal cord, and the nerves from these areas. There are many aspects of this exam, including an assessment of motor and sensory skills, balance and coordination, mental status (the patient's level of awareness and interaction with the environment), reflexes, and functioning of the nerves. The extent of the exam depends on many factors, including the initial problem that the patient is experiencing, the age of the patient, and the condition of the patient.

Application of Nanomaterials in the Medical Field: A Review

Nanomaterials are particles in sizes from 1-100 nm. Nanomaterials have a wide field of applications in aviation and aerospace, chemical industries, optics, solar hydrogen, fuel cell, batteries, sensors, power generation, aeronautic industry, buildingconstruction industry, automotive engineering, consumer electronics, thermoelectric devices, pharmaceuticals, paints, and cosmetics. Also, efforts are being made to develop friendly alternate energy sources using nanomaterials. In this chapter, the main focus will be on the application of nanomaterials in various aspects of the medical field. Nanomaterials are used in various medical devices. Some of the nanomaterials used in the area of optical imaging are quantum dots, and in MRI are superparamagnetic iron oxide nanoparticles. Also, nanomaterials are applied in ultrasound imaging and radionuclide imaging. Due to the small size of batteries (e.g., for pacemakers) or electronic circuits and sensors utilized in medical devices presently made using nanomaterials. New ceramics consisting of materials derived from sintered nanopowders (comparable to 3D-printing) or having a specially designed surface are made from so-called nanostructures for teeth filling or screws for dental implants. For bio-detection of pathogens, detection of proteins, and phagokinetic studies, nanomaterials are also used. For fluorescent biological labels, drug and gene delivery, probing of DNA structure, tissue engineering, tumour destruction via heating (hyperthermia), separation and purification of biological molecules and cells, MRI contrast enhancement, osteoporosis treatment, infection prevention, bone regeneration are some of the applications of nanomaterials used in medicines. Cancer therapy, neurodegenerative disease therapy, HIV/AIDS therapy, ocular disease therapy, respiratory disease therapy, sight-restoring therapy, and gene therapy are various therapies nanomaterials are used Nanomaterials used in various surgeries are surgical oncology, thoracic surgery, replacement of heart with an artificial heart, vascular surgery, neurosurgery, radiosurgery, ophthalmic surgery, plastic and reconstructive surgery, maxillofacial surgery, orthopedic surgery, intracellular surgery by nanorobots. Although all applications of nanomaterials have pros and cons, care should be taken so that the cons can be minimized.

Drug from Marine Sampling to Factory

The marine world expresses a great scope for diverse novel scaffolds with unusual skeleton nature. Polyphenols, phycocolloids, pigments, fucoidans, peptides, pigments, and phlorotannins are the main classes of compounds provided by marine resources. Some of these structures displayed astonishing biological activities and successfully proceeded to marketed drugs for the treatment of different human diseases. There are many examples of successful commercially available marine-derived drugs such as cytarabine (Cytosar-U®) for acute myelocytic leukemia, trabectedin (Yondelis®) for ovarian cancer, Eribulin (Halaven®) for metastatic breast cancer, Ziconotide (Prialt®) for severe chronic pain, and Vidarabine (Ara-A) for viral infections. Oceans and their immense biodiversity have gifted humanity with a pathway out of the obstacles of health care. The constant need for innovation has been a great challenge for the pharmaceutical industry especially in finding new sources of active compounds. This chapter discussed the clinically approved marine-derived compounds and their impact on different diseases, focusing on those with granted approval in the last decade from 2011 to 2021. We also highlighted the underlying mechanism of actions through in vivo, in vitro, and computational in silico studies. Hopefully, this chapter will help scientists to develop a novel marine-derived drug.

References

Biosensors for Neurodegenerative Diseases

Since the conception of biosensor technology in biomedical research, this field is emerging as a promising and high-throughput tool for neuro-engineering and neurosciences research. It has been postulated that the accumulating property proteins are the basic cause of neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease and prion diseases. Thus, neurodegenerative diseases are also called “protein misfolding disorders”. Biosensors have a wide range of applications in biomedical research, including optical and electrochemical detection of biometal-protein interactions, detection of biomarkers, such as β-amyloids, apolipoprotein, and tau proteins, and microRNA in blood and cerebrospinal fluid in neurodegenerative diseases. These are composed of primary biological recognition elements that convert the chemical signal into the voltage or current that evaluates the physical signal by preparing a plot of sensor response against the analyte concentration. This chapter presents a bird’s eye view on various aspects of progress in biosensor development with special emphasis on their application, including metal-protein interactions studies, detection of neurotransmitters using aptamers and calixarenes, detection of biomarkers proteins, such as α-synuclein for Parkinson’s disease, apolipoprotein, tau and β-amyloid proteins for Alzheimer’s disease, and prion proteins. The chapter also summarizes the novel materials reported for improved biosensor performance. This chapter will be of high relevance to the biological scientists working in neuro-engineering and neurosciences research

Chromosome 20

Over the years, many scientists and doctors have been treating the deadly disease of cancer but are not able to find a permanent treatment for this disease. Also, sometimes it becomes very difficult to understand the mechanisms and causes of cancer as it is a very complex disease that involves many biological processes. Due to the redundancy in our biological system, cancer progression becomes very easy, thus making it difficult to cure. To find the root cause of this disease, we should know what genetic alterations are undergoing, which is causing cancer to progress, and know who is participating in these alterations, like proteins, signaling pathways, or genes. Cancer is caused due to various reasons; it can be due to genetics but mostly due to carcinogens, causing mutations in the genes, thereby making them an oncogene. The Proto-oncogenes are those genes that usually assist the growth of tumor cells. The alteration, mutation, or increased copy number of a particular gene may turn into a proto-oncogene which could end up completely activated or turned on. Many Tumor-causing alterations or mutations related to oncogenes are usually acquired and not inherited. These tumor-causing mutations often actuate oncogenes via chromosomal rearrangement, or alterations in the chromosome, which sequestrates one gene after another, thereby permitting the first gene to prompt the alternative. Search which genes are involved in different cancer types would help scientists proceed with new methods for finding a cure for this disease. This article will depict which genes and their location on which chromosomes, specifically on chromosome 20, are related to different types of cancer.

Chromosome 17

Cancer is a disease in which the body's cells divide disorderly and are likely to spread to other organs. It has always been one of the world's top causes of death. A growing population, low mortality rate, and lifestyle changes lead to an increase in the number of cancer cases. It can be caused by genetic or environmental factors or a combination of both. The risk of cancer increases with age as the body loses its ability to eliminate the damaged cells. Cancer-causing genes can be inherited or acquired due to exposure to carcinogens. Cancers are inherited when a mutation occurs in the germ cells. The carcinogens can alter the DNA of a normal gene (a proto-oncogene) converting it into a cancerous oncogene. Genes that slow cell division, fix DNA errors, or undergo programmed cell death (apoptosis) are tumor suppressor genes. Tumor suppressor genes that don't function properly can cause cells to develop out of control, leading to cancer. Cancer expresses itself differently in each individual, making it challenging to identify and treat. Studying the types of genetic mutations, as well as the genes, proteins, and signaling pathways involved in cancer formation will help better understand the underlying cause of cancer. Identifying which genes are expressed in various cancer types will enable scientists to develop novel techniques for curing the disease. This chapter will explain how different cancer types are linked to specific genes and their locations on chromosome 17.

Chromenes and Nutraceuticals

Nutraceuticals have received tremendous interest in the treatment or prevention of multiple diseases in modern times. Chromenes (Benzopyran), phytochemicals that are polyphenolic secondary metabolites, are one of the privileged scaffolds that occur in various natural products as essential structural components and also have beneficial nutraceutical properties. Chromenes are more correctly referred to as ‘nutraceuticals' due to their variety of pharmacological activities in the mammalian body. A better understanding of their mechanisms and biological activities suggests their ability as therapeutic agents and also for predicting and monitoring food quality due to their significance in food organoleptic properties and human health. In this chapter, the discussion will be on the diverse therapeutic actions of chromenes as well as the probable mechanisms of action that are responsible for their therapeutic activity. The origins of these chromenes, their extraction from these sources, and their use as nutraceutical components in various food items will also be discussed. The pharmacological relevance of chromenes, which may be added to staple foods to create various nutraceutical products, will also be discussed. As shall be evident after reading this chapter, chromenes as pharmacological agents have a wide range of targets. As a result, medicinal chemistry and quantitative structure-activity relationships should be used to focus on their specific biological action when developing new congeners of chromenes to be used as drugs.

Biological, Biomedical and Pharmaceutical Application of Cerium-based Materials

Cerium-based materials have established themselves as biologically active materials with a wide range of pharmacological benefits. In particular, Nanoceria has been proven to be the most versatile and effective therapeutic agent due to its surface area-to-volume ratio. In this chapter, we made an attempt to discuss all important therapeutic applications of Cerium based materials. Also, the mechanistic course of action of cerium-based materials has been emphasized in this chapter. Moreover, the possible toxicity of cerium-based materials in the biological system has been reviewed in the later section of this chapter.

Diseases and Disorders Associated with Immune System

The human immune system is one of the complex systems of the body, which works against both external and internal invasion. It has two parts: the innate and the acquired immune systems. We have been born with the innate system which gives a quick response for the invading pathogen non-specifically. To deal with the typical environmental antigens, immune system adapts to changes. The acquired (or adaptive) component develops over time and produces antibodies that “remember” invaders to fight them if they return. Failure of it could be due to genetic defect (weak natural immunity), inability to adapt to the change, hyper-responsiveness, or inability to distinguish self from foreign, leading to various diseases and disorders. Various genetic defects of the immune system are at the core of Primary Immune disorders (PIDs), while overactivity is responsible for allergic diseases. Autoimmune diseases are mostly due to malfunction of the adaptive immune system, while in Systemic Autoinflammatory Disorders (SAIDs), the innate immune system is affected. Advancements in technology and genetics have improved our understanding of the pathogenesis, diagnosis, and management of these diseases.

A Survey on Brain-Computer Interface and Related Applications

Brain Computer Interface (BCI) systems are able to communicate directly between the brain and computer using neural activity measurements without the involvement of muscle movements. For BCI systems to be widely used by people with severe disabilities, long-term studies of their real-world use are needed, along with effective and feasible dissemination models. In addition, the robustness of the BCI systems' performance should be improved, so they reach the same level of robustness as natural muscle-based health monitoring. In this chapter, we review the recent BCIrelated studies, followed by the most relevant applications. We also present the key issues and challenges which exist in regard to the BCI systems and also provide future directions.

Multi-functional Ligands and Molecular Hybridization: Conceptual Aspects and Application in the Innovative Design of Drug Candidate Prototypes for Neurodegenerative Diseases

The rapid increase in the incidence of dementia has enormous socioeconomic impacts and costs for governmental health systems all over the world. Despite this, finding an effective treatment for the different types of neurodegenerative diseases (NDs) so far represents a challenge for science. The biggest obstacles related to NDs are their multifactorial complexity and the lack of knowledge of the different pathophysiological pathways involved in the development of each disorder. The latest advances in science, especially those related to the systems biology concepts, have given new insights for a better comprehension of such multifactorial networks related to the onset and progression of NDs, and how Medicinal Chemists could act in the search for novel disease-modifying drug candidates capable of addressing the multiple pathological factors involved in neurodegeneration. The multi-target directed ligands (MTDLs) concept has captivated and opened new windows for the creativity and rationality of researchers worldwide in seeking innovative drug candidates capable of modulating different molecular targets by a single multifunctional molecule. In fact, in the last two decades, thousands of research groups have dedicated their efforts to the use of molecular hybridization as the main tool for the rational design of novel molecular scaffolds capable of expressing multi-target biological activity. In this way, this chapter addresses the most recent pathophysiological hallmarks of the most highimpact NDs, represented by Alzheimer’s, Parkinson’s, Huntington’s diseases, and amyotrophic lateral sclerosis, as well as the state-of-art in the design of new MTDLs, inspired mostly by natural products with improved druggability properties.

Applications of Taurine in the Central Nervous System Disorders Linked with Mitochondrial Impairment

Taurine (TAU) reaches a high concentration in the central nervous system (CNS). The physiological role of TAU in the CNS is the subject of many investigations. It has been suggested that this amino acid could act as a membrane stabilizer, a modulator of calcium signaling, a trophic factor for neuronal development, and even be proposed as a neurotransmitter in the CNS. Besides, several investigations revealed the neuroprotective properties of TAU in various experimental models. Multiple mechanisms, including the inhibition of the excitotoxic response, the blockade of cytoplasmic calcium overload, regulation of oxidative stress, and the positive effects of TAU on mitochondrial parameters, have been proposed for the neuroprotective properties of this amino acid. Today, it is well-known that mitochondrial function and energy metabolism play a pivotal role in the pathogenesis of various neurodegenerative disorders and xenobiotics-induced neurotoxicity. Hence, targeting mitochondria with safe and clinically applicable agents is a viable therapeutic option in various neurodegenerative disorders. In the current chapter, the effects of TAU on the CNS will be highlighted, focusing on the positive effects of this amino acid on mitochondrial parameters. The data could help the development of safe therapeutic agents against CNS complications.

Subject Index

Resveratrol: A Novel Drug for the Management of Neurodegenerative Disorders

Resveratrol is a naturally occurring polyphenol (stilbenoid) that works as a phytoalexin, a part of plants’ defense system against infection, ultraviolet radiation, stress and injury. Common dietary sources of resveratrol include grapes, berries, peanuts, red wine, and some herbal preparations. In animal models, resveratrol exhibits a wide spectrum of potential therapeutic activities, including antioxidant, antiinflammatory, neuroprotective, and longevity-promoting properties. Resveratrol mimics the antioxidant, anti-aging, and neuroprotective effects of caloric restriction, mainly mediated through the increased expression of genes encoding antioxidants and the anti-aging factors (AMPK and Sirtuin 1). Therapeutic strategies for the treatment of neurodegenerative diseases currently have several shortcomings. Naturally occurring compounds may play a significant role in augmenting these therapeutic options. Resveratrol has been shown to maintain homeostasis, protect the brain against oxidative stress, preserve neuronal function, and ultimately minimize age-related neurological decline. It has shown positive effects in animal models and cell culturebased experiments in treating Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, and other neurodegenerative diseases. Resveratrol enhances learning memory and neurogenesis and alleviates neural apoptosis in the hippocampus of AD mice. Beneficial effects of resveratrol in PD result from the inhibition of α-synuclein aggregation and cytotoxicity, lowering of total and oligomeric α-synuclein levels, reduction of neuroinflammation, and oxidative stress. Clinical trials are also evaluating the role of the drug in the major neurodegenerative disorders.

Tinospora cordifolia in Neurodegeneration: A Strong Antioxidant and Anti-inflammatory Phytotherapeutic Drug Candidate

Tinospora cordifolia is a Rasayana herb of Ayurveda, commonly known as “Heavenly Elixir” or “Amrita”, and one of the most exploited herbs in herbal medicines. T. cordifolia is well reported for its various pharmacological properties, such as anti-diabetic, anti-inflammatory, antipyretic, immunomodulatory, anti-cancer, cardioprotective, neuroprotective, and hepatoprotective activities. The prevalence of neurodegenerative diseases and other neurologic disorders is increasing worldwide. Oxidative stress and neuroinflammation are among the major pathologic mechanisms underlying neurodegenerative diseases. This chapter discusses the pieces of scientific evidence of the beneficial effects of T. cordifolia in various brain-related ailments. Various research groups have demonstrated the ability of T. cordifolia and its extracts to normalize oxidative stress and suppress the inflammatory response against various causative agents, and thus suggested that T. cordifolia has the potential to be a neurotherapeutic drug candidate in the future.

Modulations of SIRTUINs and Management of Brain Disorders

Neurodegenerative disorders are the conditions in which neurons of the central and peripheral nervous systems degenerate. Various cellular and molecular processes are associated with the progression of such degeneration, including inflammation, apoptosis, and axonal degeneration. Recently, SIRTUINs have emerged as one of the key factors associated with neurodegenerative disorders. SIRTUINs are involved in the regulation of several cellular and molecular processes in neurons of the nervous system through the deacetylation of target proteins. The chapter focuses on the modulatory role of SIRTUINs in neurodegenerative disorders and their potential therapeutic application.

Delineating the Neuroinflammatory Crosstalk in Neurodegeneration and Probing the Near Future Therapeutics

Neurodegenerative disorders are threatening mankind with significant health and economic burden. Neurodegeneration involves the deterioration of neurons in the central nervous system (CNS), resulting in decreased neuronal survival. Therefore, it is of utmost requirement to develop a promising pharmacological strategy to minimize or prevent the progression of the underlying disease pathogenesis. In neurodegenerative disease conditions, neurons and glial cells present in the specific brain regions are damaged and depraved, resulting in specified disease symptoms in the patients. Neuroinflammation plays a major role in the degeneration of neuronal cells by regulating the expression of interleukin-1 beta (IL-1β), IL-6, IL-8, IL-33, tumor necrosis factor-alpha (TNF-α), chemokines Cxcl3 (C-C motif) ligand 2 (CCL2), CXCL5, granulocyte-macrophage colony-stimulating factor (GM-CSF), glia maturation factor (GMF), substance P, reactive oxygen species (ROS), reactive nitrogen species (RNS), impaired tuning of immune cells and nuclear factor kappa-B (NF-κB). Considering this, it is very important to understand the in-depth role of neuroinflammation in the initiation and progression of various neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), as well as Multiple Sclerosis (MS). Recent shreds of evidence have suggested that using exogenous ligands to approach various biological molecules or cellular functioning that modulates the neuroinflammation, such as microglia response, P2X7 receptors, TLR receptors, oxidative stress, PPARγ, NF-κB signaling pathway, NLRP3 inflammasome, caspase-1 signaling pathway, and mitochondrial dysfunction, helps to combat neurodegeneration in a variety of diseases. Thus, targeting the neuroinflammatory drive could provide a beacon for the management of neurodegenerative diseases. Here, we have attempted to provide comprehensive literature suggesting the role of neuroinflammation in neurodegeneration and its implication in the development of near-future neurotherapeutics.

Natural Products: Antibacterial, Anti-fungal, and Anti-viral Agents

The existence of substantial evidence about the development of resistance to a drug among microbes has gained a lot of attention from the scientific world. To address this problem, researchers have been conducting experiments and testing strategies, including screening various molecules and using plant-derived natural products to ascertain if these substances can serve as an untapped source of antibacterial, anti-viral, and anti-fungal agents. The non-toxic, non-synthetic, causing minimal side effects, and cost-effective nature of these substances make the development of new anti-microbials heavily dependent on the use of many of these existing products and increase the demand for finding new natural products that are yet to be discovered. These plant-based natural products offer great promises to provide the best protection against infections and pathogenesis in many diseases. Furthermore, the biodegradable nature of many of these products increases their chances of being chosen by farmers and plant biologists to use to combat microbial pathogenesis. This chapter covers the current insights on the conflicts and opportunities of popular plant-derived natural anti-microbial compounds containing a reservoir of secondary metabolites, viz.. flavonoids, alkaloids, terpenes, coumarins, phenols and polyphenols. The chapter lists natural vegetable products, which serve as potent anti-bacterial and anti-fungal agents, and describes various plant extracts, which exhibit bacterial quorum sensing, biofilm as well as efflux pump inhibitory activity. Previous studies have demonstrated the effectiveness of these plant-based natural products in the treatment of neurodegenerative diseases as well. This chapter also summarizes the neuroprotective activity of these products and their potential to serve as therapeutic agents to block or delay the progression of disorders.

Sleep Medicine in the United Arab Emirates

Sleep disorders are increasingly being recognized as a major health problem in the UAE. The rising prevalence, potentially modifiable risk factors, and impact on global health outcomes have prompted the growth of sleep medicine. The burden of under-recognized disease has encouraged patient and physician-centric education. Supported by nationalized health insurance plans, the medical fraternity has adopted a multi-disciplinary approach to optimize resources and outcomes, while recognizing that these measures are initial steps in the unique challenges posed.

Modulation of Proinflammatory Cytokines by Flavonoids in the Main Age-related Neurodegenerative Diseases

Aging is a process associated with distinctive changes in physiological functions and physical appearance that result from progressive tissue degeneration, harming the structure and function of vital organs. Illnesses that are particularly frequent in people 65 years of age and older are generally grouped as age-related diseases or aging-related diseases and include neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), which are caused by progressive degeneration and/or neuronal death to produce debilitating conditions, and they have no cure. For these illnesses, the most important risk factor is aging. Aging involves changes in neuroendocrine and inflammatory responses and presents a stage with chronic and low-grade inflammation, characterized by a general increase in the production of proinflammatory cytokines, inflammatory markers, and cellular senescence. Herbal medicine, as well as various components of the human diet, including vegetables, cereals, and fruits, contain widely varied phytochemicals including flavonoids, which are the most common polyphenolic compounds. Epidemiological studies suggest that a higher intake of flavonoid-rich foods and beverages is associated with better cognitive outcomes, lower dementia rates, and reduced risk of neurodegenerative diseases. Moreover, numerous preclinical studies have shown that these compounds have a therapeutic effect on animal models of human degenerative diseases and highlight the anti-inflammatory effect of flavonoids by decreasing the activated glial cells and several proinflammatory mediators. Much modern scientific research has focused on establishing biological activities of purified single compounds to provide an evidence base for the rationale of traditional practice, and also to integrate these into modern medical practice.

Role of Withania somnifera (Ashwagandha) in Neuronal Health

Neurodegenerative disease refers to the progressive deterioration of neurologic function which leads to loss of speech, vision, hearing, and movement. It is also associated with seizures, eating difficulties, and memory impairment. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases due to the enormous adverse effects associated with pharmacological drugs. Withania somnifera (Ashwagandha) is a traditional Ayurvedic medicine, used in India as a general tonic. It contains withanolides, and phytochemicals that may have adaptogenic properties. Studies show that W. somnifera is a neuroprotective agent and can protect the brain from oxidative stress and inflammation. This explains its ability to protect from mood disorders. In this review, we have reviewed the available evidence of W. somnifera and its phytochemicals for neurodegenerative disorders.

Neuroprotective Effect of Ginkgo Biloba and its Role in Alzheimer’s Disease

Alzheimer's disease (AD) is a common age-related neurodegenerative disorder that results in cognitive defects. The disease is a progressive, age-associated, irreversible, neurodegenerative disease with severe memory loss, personality changes, unusual behavior and impairment in cognitive function. There is no cure for AD, and the drugs available for the treatment of the disease have limited efficacy. Medicine develops from the extract of medicinal plants have been the single most productive and common source for the development of drugs, and also, more than thousands of new products are already in clinical study. Different types of therapeutic strategies like herbal and synthetic approaches are being used against AD on the basis of understanding AD mechanisms. Ginkgo biloba extract (GBE) is the most effective and highly investigated, herbal medicine for AD and other cognitive disorders. One of the famous dietary supplements is GBE, consumed by the elderly population to improve memory and age-related loss of cognitive function. The exact mechanism of action of Ginkgo extract in AD is still not very clear. The phytochemical studies of the different plant parts of the G. biloba have revealed the presence of many valuable secondary metabolites, such as flavonoids, polyphenols, triterpenes, sterols, and alkaloids that shows a wide spectrum of pharmacological activities like anti-amyloidogenic, antiinflammatory and antioxidant effects. This book chapter gathers research on the G. biloba plant and its neuroprotective and phytochemical effects, which are used against AD. The summarized information concern pharmacological activities, neuroprotective effect, and biological and clinical applications of the Ginkgo plant.

Neuroprotective Alkaloids: Neuromodulatory Action on Neurotransmitter Pathway

Equilibrium in excitatory and inhibitory neurotransmitter signal transmission is necessary for the proper functioning of the brain, and alteration can stimulate the negative feedback mechanism that causes various neuropathogenesis. Disturbances like oxidative stress and alteration in the metabolism of neurotransmitters like γ- aminobutyric acid (GABA), acetylcholine (Ach), serotonin, dopamine, and glutamate, are important factors for the progression of neurodegenerative disorder (NDDs). Plant alkaloids have the potential to modulate the neurotransmitter signal transmission in the central nervous system and can provide a better alternative to the synthetic molecule. In the present chapter, we summarize the potential efficacy of plant alkaloids via functioning as anti-oxidant, monoamine oxidase (MAO) inhibitor, glutamate receptors- N-methyl-D-aspartate (NMDA) antagonist, acetylcholinesterase (AcHE) inhibitor and shows potential therapeutic effects against NDDs.

Phytochemicals from Indian Medicinal Herbs in the Treatment of Neurodegenerative Disorders

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis are the major cause of disability and mortality. These disorders are appearing in the current era due to aging and stress-full lifestyles. For the treatments of these disorders, several conventional drugs are available but due to higher cost and dangerous adverse effects. Therefore, scientists are focusing more on medicinal herbs containing phytochemicals because these medicinal herbs are more effective, low cost, and show less harmful side effects to cure neurodegenerative disorders. Indian medicinal herbs are the most effective medicines and indigenous to India. Since ancient times, medicinal herbs have been used for treating neurodegenerative disorders. Indian medicinal herbs containing phytochemicals possess beneficial therapeutic effects for the treatment of neurodegenerative disorders, majorly having various compounds such as alkaloids, sesquiterpenes, triterpenoids, polyphenols, flavonoids, saponins, and essential oils which show anti-inflammatory and anti-oxidative properties. In this chapter, we highlighted and discussed the importance of some Indian medicinal herbs, such as Bacopa monnieri (Brahmi), Centella asiatica, Curcuma longa (turmeric), Allium sativum (garlic), Terminalia chebula (haritaki), Celastrus paniculatus (Jyotishmati), Glycyrrhiza glabra (Licorice), and Acorus calamus (Vacha) containing phytochemicals with their mechanism of action on neurodegenerative disorders.

Recent Development of Hybrids and Derivatives of Resveratrol in Neurodegenerative Diseases

Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons in different regions of the nervous system, being Alzheimer’s disease (AD) and Parkinson’s disease (PD) the most common NDs. Despite their high incidence, the pharmacological treatments are mainly symptomatic. For this reason, in recent years, the research has been focused on the discovery of new molecules able to target neuropathological pathways involved in NDs. In the last decades, several researchers investigated the neuroprotective actions of naturally occurring polyphenols, such as resveratrol, that has attracted special interest since its ability to interact simultaneously with the multiple targets implicated in NDs. Thanks to the structural simplicity of the stilbene core, the broad spectrum of possible modifications, and the improved synthetic strategies, resveratrol is an attractive chemical starting point for the searching of new entities with extended therapeutic uses in NDs. In this review, a systematic update of the stilbene-based hybrids and derivatives, and SAR analysis were provided for the development of new drugs potentially useful as NDs multitarget directed ligands.

Polyphenols and Flavonoids: Chemical, Pharmacological and Therapeutic Aspects

Polyphenols and flavonoids represent a group of compounds characterized by a large assortment of phenolic structures, which can be naturally found in vegetables, roots, stems, flowers, grains, and fruits. Thanks to their biological activities, molecules belonging to these classes of compounds, besides their nutritional role, have found applications in several fields such as pharmaceutical, cosmetic, and nutraceutical. In fact, like many natural derivatives from plants, they possess several therapeutic properties, including antitumor, anti-oxidative, anti-neurodegenerative, antimicrobial and anti-inflammatory effects. Nowadays, the growing interest in polyphenolics and flavonoids translates into constant research to better define their pharmacological mechanism of action. Extraction studies in order to obtain pure compounds with a more defined biological activity, as well as pharmacokinetic studies to understand the bioavailability, the involved metabolic pathways and the related active metabolites, are carried out. Molecular docking studies are also continuously in progress to expand the field of application. Moreover, toxicity experiments to clarify their safety and studies about the interaction with other compounds to understand their selectivity of action are continuously forwarded and deepened. Consequently, many recent studies are aimed at introducing polyphenols, more specifically flavonoids, and their semi-synthetic derivatives, in the prevention, management and treatment of several diseases.

Subject Index

Genome-Wide Association Studies (GWAS)

Genome-wide association studies (GWAS) are designed to find associations between genomic variants and a phenotype, usually a complex multifactorial disease. The idea for association studies in a large cohort was floated after linkage analysis, which proved extremely successful in the identification of causative genes for rare disorders, but it did not come up to expectations in the case of common complex disorders where causative alleles are less frequently aggregated in families. Ever since their advent in 2005, GWAS have transformed gene identification ventures in complex disease genetics over the past fifteen years, giving rise to several powerful associations for complex traits and disorders. Association studies are based on the “common disease common variant” hypothesis which assumes that genomic variation with low penetrance and high population frequency are involved in the causation of common complex disorders. Although GWAS, complemented with the downstream functional assessment of the variants, have been successful in identifying novel disease-causing genes and biological mechanisms, the field has also received intense criticism over the years, especially its failure in tracing the so-called ‘missing heritability’. Therefore, further functional studies are mandatory to precisely establish a link between risk alleles and a phenotype. This chapter broadly covers an introduction of GWAS, their successes and limitations, and various important factors affecting the design and results, followed by challenges in the post-GWAS era.

The Fluoride Adsorption Isothermal Studies of Activated Alumina Modified with Different Materials: A Critical Review

Fluoride in drinking water has become a global problem that has a profound effect on teeth and bones, fostering various health problems. Adsorption is a potential defluoridation technique because of flexibility, cost-effectiveness, environmental friendliness, simplicity in design, relative ease of operation, and capability of producing high water quality. Although activated alumina is an appropriate adsorbent, it has a narrow favorable pH range, a tendency to form toxic aluminum fluoride complexes, and the problem of aluminum metal leaching. This article critically reviews the applicability of activated alumina and its modification by metal oxides, rare earth elements, organic materials, alkaline earth metals, and acid treatment. The effect of process parameters like pH, contact time, adsorbent dose, initial fluoride concentration, and the presence of coexisting ions on the adsorption capacity of fluoride ions is discussed. The adsorption reaction rates were discussed by fitting various rate models into the experimental data and the model equations. The adsorption isotherm models like Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich tested on the adsorption equilibrium data to identify the best fit model for adsorption isotherm are discussed in this chapter. The chapter finally discusses the advantages, disadvantages, and future prospects of all the adsorbents in order to improve their fluoride removal capacity.

Bioactive Compounds as Therapeutic Intervention in Neurodegenerative Diseases

Neurodegenerative disorders have been implicated as the cause of many devastating diseases that are characterized by gradual loss of susceptible neurons, that are increasingly rising the prevalence of neurodegenerative diseases globally; however, therapeutics for them are lacking. There is an urgent need to develop an effective therapy that can combat the menace caused by disorders of neurodegenerative origin such as Alzheimer's and Parkinson’s diseases, stroke, and traumatic brain injury. Peerreviewed articles were explored for the purpose of this review. Several natural products from medicinal plants have been reported to have phytochemical components with bioactive effects in addition to nutritional value. An appropriate bioactive component is essential for a healthy lifestyle as it plays a significant role in the modulation of neurodegenerative diseases. This review covers the mechanism of action of neurodegenerative disorders and highlights selected classes of bioactive compounds and their effects on neurodegenerative disorders. The use of bioactive compounds in the management of neurodegenerative diseases could solve the problem of the nonavailability of therapy.

Treatment of Thoracic Meningioma with Spinal Canal Decompression under Spinal Endoscopy

Extramedullary benign tumors of the spine may cause spinal cord compression. Patients may present with motor weakness and sensory loss in the extremities causing gait abnormalities. Surgical treatment is indicated when symptoms are no longer manageable. In this chapter, the authors present an 87-year-old female's case as an illustrative example of how the spinal endoscopy platform can be safely and effectively deployed in the treatment of such lesions. The example patient suffered from spinal cord compression from a large meningioma at the T7 level. The tumor was successfully removed via an endoscopic working cannula. The patient's symptoms improved, and a nine-month follow-up MRI scan showed adequate and maintained spinal cord decompression. This case example demonstrates that spinal endoscopy may be applied to an increasing number of surgical indications beyond the scope of degenerative disease. Further clinical investigation will need to show this technology's limits when treating benign tumors of the spine.

A Pathophysiological Approach To Current Biomarkers

Biomarkers are necessary for screening and diagnosing numerous diseases, predicting the prognosis of patients, and following-up treatment and the course of the patient. Everyday new biomarkers are being used in clinics for these purposes. This section will discuss the physiological roles of the various current biomarkers in a healthy person and the pathophysiological mechanisms underlying the release of these biomarkers. This chapter aims to gain a new perspective for evaluating and interpreting the most current biomarkers.

Reproductive Cloning

Hearing the name “Dolly” was and still stirs the minds of professionals and non-specialists towards the term “cloning”, but the way of producing dolly is not the only aspect of cloning. Cloning is defined as the techniques through which identical or virtually identical individuals can be produced. Based on this definition, in this chapter, we are trying to clarify the different applications, aspects, and techniques of cloning such as gene cloning, therapeutic cloning, but to focus on reproductive cloning. Reproductive cloning is the method of making a genetically similar clone of a whole organism. Then it is needed to be discussed with all the scientific thoughts around it, advantages, disadvantages, legal or illegal, and comparing it to other aspects and this is our aim in this chapter.

Brief Description of Public Health and Burden of Neurodegenerative Diseases

Physical and mental well-being is treasure for mankind in a competitive and progressive global scenario. For a country, result oriented tasks can be accomplished only with its healthy population. Along with many diseases of global concern, neurological disorders have drawn concern globally as these are sharing an increasing proportion in global burden of diseases. Further cases of neurodegenerative disorders, majorly affecting aged population, have been recently reported to record a considerable increase which has complicated the health and care-giving (old age homes) services as part of public health. Many public health policies have been laid down by many developed and developing countries in accordance of WHO guidelines which in turn based on GBD studies, made till date. Major share of neurodegenerative disorders is contributed by Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis & Multiple Sclerosis. The recent past has witnessed growing number of deaths and disability adjusted life years, DALY, caused by neurodegenerative diseases. Public health services and related government policies are not enough, according to WHO, to properly address the current situation. Lack of public awareness towards neurological disorders of all kind, is one of the major challenges to Figure out actual data; for prevalence of neuro-disorders.

Emerging Therapeutic Approaches for Neurodegenerative Diseases

The most common neurodegenerative diseases (ND) include Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), as well as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Protein misfolding and aggregation are the key hallmarks of these neurodegenerative diseases, which may lead to cell death, axonal regeneration failure, demyelination, and overall neuronal structural and functional deficits. Usually, ND is diagnosed at a very advanced stage and conventional therapies are directed at treating neurological symptoms but have no effect on disease progression. In general, several pathological processes contributes to misfolding proteins/protein aggregates and their postconsequences, including impairment of autophagy, microtubule destabilization, neuroinflammation, proteostasis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, calcium homeostasis, and neurogenesis impairment. Indeed, several signaling pathways critically linked with these pathological processes are now becoming attractive targets and investigated for their beneficial effects by restricting the progression of ND. In particular, certain signaling mechanisms and proteins found to show an integral involvement in the pathogenesis of ND and had shown promising results in preclinical and/or clinical contexts. For ex; novel autophagy stimulators, drugs acting on mTOR, NRF2, TLR, purinergic signaling; drugs acting on neuroinflammatory signaling pathways, Heat Shock Proteins (HSP), sestrins, sirtuins, some PDE-inhibitors, miRNA’s have gained a lot of attention in the therapy of ND and are included in the following discussion.

Omics for Biomarker Investigation in Neurodegenerative Diseases

Neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and the spinocerebellar ataxias is major health threat specifically in the elderly population. Currently, the disease diagnosis and progression is tracked through the clinical estimation which only gives a rough estimate of the disease severity. So the biomarkers serve as an essential tool in the disease diagnosis and disease progression. High-throughput omics-based technologies have facilitated the discovery of new biomarkers. The analytic methods underlying the basic omics-based technologies, genomics, transcriptomics, and metabolomics are now been extensively useful in the identification of novel biomarkers. These new candidate biomarkers are helpful in the clinical management of neurological disorders.

Role of Reactive Oxygen Species in Neurodegenerative Diseases

The altered redox state leads to oxidative stress through the extravagant synthesis of reactive oxygen species (ROS) and inhibition of the antioxidant system. The high oxygen demand in nervous tissue makes it vulnerable to ROS, and the presence of peroxidation-prone lipid cells worsens the situation. We now understand that oxidative stress plays a role in the pathophysiology of neurodegenerative diseases such as Parkinson's disease, Motor neuron disease, and Alzheimer's disease. In spite of the fact that there is no lasting cure for any of these diseases, antioxidant treatments have been promoted as ways to treat and discourse neurodegenerative diseases. However, the results regarding their efficacy are contradictory. This chapter examines the role played by oxidative stress in the etiology of neurodegenerative diseases and how they lead to brain dysfunction in people. It will later provide an overview of antioxidants as a therapeutic option for oxidative stress-induced damage.

Protein Aggregation in Neurodegenerative Diseases

Protein aggregation-related diseases primarily affect the central nervous system and are involved in the pathogenesis of multiple neurodegenerative diseases as well as several rare hereditary disorders that involve the deposition of protein aggregates in the brain. These diseases include Alzheimer's, Parkinson, Huntington's disease, Prion diseases, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, etc. The aggregates usually consist of fibers containing misfolded protein with a betasheet conformation. As a result, proteins’ secondary structures change from α-helix to β-sheet, leading to the accumulation of harmful misfolded protein aggregates in the CNS. The misfolding, subsequent aggregation and accumulation of proteins in neurodegenerative diseases lead to cellular dysfunction, loss of synaptic connections and brain damage. This chapter discusses some of the important neurodegenerative diseases resulting from protein misfolding and explains the pathological mechanisms behind brain damage.

Neurodegenerative Diseases Involve Multifactorial Interplay of Genetics and Environmental Factors

Neurodegenerative diseases are one of the leading causes of morbidity and disability worldwide, afflicting millions of individuals. These diseases emerge as a result of multiple factors, sharing pathogenic pathway that includes mitochondrial dysfunction, misfolded protein aggregation, and oxidative stress. Genetic and environmental factors have been identified to play a key role in neurodegeneration and modifying the risk of the disease. The association of neurodegenerative diseases to genetic factors and environmental agent’s exposure is not well conclusive. As a consequence, studying the interplay of genetic and environmental factors in neurodegenerative diseases can help researchers better understand gene and therapy and disease progression. In this chapter, an attempt has been made to discuss the multifactorial degenerative process and the role of genetic and environmental factors in common neurodegenerative diseases. Understanding the mechanisms of disease initiation and progression is crucial for disease prevention and modification of disease risk. These information would be helpful in the exploration of therapeutic options against these diseases.

Subject Index

Modulation of Mesenchymal Stem Cells, Glial Cells and the Immune System by Oligodeoxynucleotides as a Novel Multi-target Therapeutic Approach Against Chronic Pain

Despite our growing understanding of chronic pain mechanisms, an

alarming proportion of patients worldwide remains refractory to treatment. Chronic

pain is complex, involving the interaction of both neuronal and non-neuronal systems.

Several studies focused on immune, glial and mesenchymal stem cells (MSCs) have

recently revealed key roles of these non-neuronal players in the initiation and

perpetuation of chronic pain. The complexity of chronic pain is reflected by the

difficulty of its therapeutic control, in particular when using mono-target drugs. A good

proportion of these drugs target neuronal pathways, and serious concerns arise when it

comes to the use of opioids and abuse liability. In contrast, novel pain drugs targeting

non-neuronal components of chronic pain are scarce. Exceptions include classical nonsteroidal

anti-inflammatory drugs, or those modulating trophic factors, although their

use remains restricted to the presence of appropriate targets. Synthetic

oligodeoxynucleotides have been used as immune system modulators for the last 15

years. One of them, IMT504, a non-CpG oligodeoxynucleotide, exhibits remarkable,

long-lasting anti-allodynic and anti-inflammatory properties upon single-dose systemic

administration in rodent models of inflammatory or neuropathic pain. Mounting

evidence suggests that the beneficial effects of IMT504 relate to actions on the immune

system, glial cells and MSCs. In this state-of-the-art chapter, we address the current

knowledge of the role of IMT504 over non-neuronal cells, its impact on chronic pain,

and its translational potential. We also propose that further analysis on its mechanisms

of action will be key to the identification of novel and effective multi-target pain drugs

without abuse liability.

Neurotrophic Factors to Combat Neurodegeneration

Conditions caused by the lesion and progressive death of neuronal cells in

the organism include neurodegenerative disorders and neuropathic pain. They represent

the major causes of disability in Western countries. These conditions are more common

in elderly people, and their prevalence, therefore, is expected to grow in the future

because of the aging population. Currently, curative therapies against

neurodegenerative disorders and neuropathic pain are not available. Existing treatments

may provide temporary symptomatic relief to some patients but fail to stop neuronal

degeneration, protect and restore damaged neurons. Neurotrophic factors are small

secretory proteins whose main function is to support the survival of neurons. Therefore,

they hold considerable promise for disease-modifying treatment of neurodegenerative

disorders and neuropathic pain. However, despite promising results in preclinical

studies, clinical translation of neurotrophic factors has so far achieved limited success.

Neurotrophic factors are different from traditional chemical compounds used as drugs

in the majority of cases, and this complicates their clinical use. Biology of neurotrophic

factors and their absorption, distribution, metabolism, excretion, and pharmacokinetics

properties dictate special requirements to clinical trials design. Patients taking part in

clinical trials, delivery system, delivery paradigm, and the dose of neurotrophic factor

should be carefully considered in trial design in order to ensure that the treatment will

improve the condition of patients.

In the present chapter, the author summarizes the available literature regarding

signaling of neurotrophic factors, provides the data about their preclinical evaluation in

animal models of neurodegenerative disorders and neuropathic pain, describes the

results of clinical trials conducted with neurotrophic factors in patients, and discusses

the limitations of these trials and translational problems faced by researchers and

clinicians in this field. The author will further discuss emerging alternatives to

neurotrophic factor proteins with improved translational perspectives, such as mutant

proteins, small molecules, and peptides targeting the receptors of neurotrophic factors.

The author will review attempts of clinical translation of glial cell line-derived

neurotrophic factor family ligands for the treatment of Parkinson’s disease and

neuropathic pain. The author will briefly describe the non-conventional cerebral

dopamine neurotrophic factor tested in Phase I/II clinical trial in patients with
Parkinson’s disease. The author will also describe the data concerning the clinical evaluation

of other neurotrophic factors in the above-mentioned conditions.

NMR Spectroscopy For The Characterization of Photoprotective Compounds in Cyanobacteria

Cyanobacteria are ubiquitous in nature as they efficiently tolerate various

extreme climatic conditions for survival, such as increasing effects of solar radiation,

salinity, temperature, etc. Cyanobacteria are important sources of secondary

metabolites, which enable them to withstand these harsh environmental conditions.

Small-molecular-weight secondary compounds are primarily implied in the defense

mechanisms in case of biotic and abiotic stresses. Various beneficiary secondary

compounds are extracted from cyanobacteria, such as UV-screening pigments

(mycosporine-like amino acids, scytonemin, carotenoids, etc.), phytohormones,

cyanotoxins and antioxidants. Bioactivity-directed isolation techniques are used to

identify these molecules from complicated matrices in pharmacognosy (discovery of

biologically active compounds from natural sources). NMR spectroscopy has appeared

as a specific major analytical technique applied in metabolomics. The easy sample

preparation, the expertise to evaluate metabolite quantity, the notable investigational

reliability, and the innately non-destructive quality of NMR spectroscopy have made it

the first-line option for significant scientific metabolic analyses. Unlike some mass

spectrometry methods, NMR is not discriminatory, depending on the metabolites'

precursors or their ionization potential. Screening of metabolites needs maximum

sensitivity, and it is a process with a broad scope. In this chapter, we have discussed the

usage of NMR spectroscopy in the identification of photoprotective compounds and its

advantages and disadvantages for metabolomic studies. We have also explored several

new NMR techniques that have recently become available in order to fortify its

advantages and overcome its inherent limitations in metabolomics applications.

Aluminium and other Metals Exposure Cause Neurological Disorders: Evidence from Clinical/ human Studies

Exposure to Aluminium and other heavy metals has become a serious concern in today’s modern life. Due to excessive use and improper disposal of heavy metals, the entire food chain is being contaminated, which is imposing various health risks for humans and other living organisms. These heavy metals particularly induce oxidative stress through different mechanisms which can ultimately interfere with the normal physiological activities. Brain is highly prone to oxidative stress due to its rich polyunsaturated content and high oxygen consumption than the periphery. Therefore, emphasis has been given to neurotoxicological effects produced by exposure to heavy metals. In this regard, the effects of both essential and non-essential heavy metals have been investigated in various clinical studies which are demonstrating them as a serious threat to normal brain function. This chapter summarizes the neurotoxicological effects of heavy metals which have been revealed in various human studies.

Role of aluminium in Post-Translational Modifications and Neurological Disorders

Increased exposure or elevated levels of aluminium(Al) in humans cause various detrimental pathological processes especially affecting the central nervous system. Al-induced neurotoxicity predominantly leads to impaired motor coordination, cognition and learning and memory deficits. Significant association of chronic Al exposure with several neurological disorders, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) Parkinson's disease (PD) and multiple sclerosis (MS) is evident where it instigates aberrant expression of various proteins via alterations in post-translational modifications (PTMs). In depth understanding of mechanism of action of Al, effect of altered PTMs and their detection methods is essential to revert anomalies induced by Al in these neurological disorders. The present chapter will attempt to summarize the role of Al in modulation of significant PTMs including phosphorylation, methylation, oxidation, ubiquitination and provide insights into its involvement in various neurological disorders.

Co-Exposure of Aluminium with other Metals Causes Neurotoxicity and Neurodegeneration

Metals are key players in maintaining and regulating gene expression, antioxidant response, cell structure and neurotransmission. Their presence in the human body is required in trace amounts to perform these functions, however, excessive accumulation of these metals in various organs, including the brain, leads to detrimental neurological consequences by altering oxidative stress, protein misfolding, mitochondrial dysfunction, DNA fragmentation and apoptosis. These events over a course of time contribute to mild cognitive impairment, movement related disorders, learning and memory deficits which can further progress to neurodegeneration. According to some epidemiological and clinical findings, there is strong evidence of metal exposure and its correlation with a number of neurological diseases like Alzheimer’s diseases (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Guillain-Barre disease (GBD), Parkinson’s disease (PD) and multiple sclerosis (MS), etc. Moreover, metal ions tend to exacerbate the accumulation of neurotic plaques in AD associated pathologies. It has been observed that metals like iron, zinc, copper and Aluminium are elevated in AD brains, causing damage to the synapses. Such metal ions imbalances are associated with aging related neuropathies and disease progression. Some other factors contributing to neurodegeneration include predisposition to ApoE allele, the interaction and synergistic effect of multiple metals together, the impact of cholesterol, amyloid precursor protein (APP) processing, and increased total tau along with Aβ production play a key role in increased biosynthesis of reactive oxygen species in the brain. Such events tend to reduce neuronal viability and function, thus causing cognitive decline.

Biochemical Mechanisms of Aluminium and Other Metals Exposure, Their Brain Entry Mechanisms, Effects on Blood Brain Barrier and Important Pharmacokinetic Parameters in Neurological Disorders

Evolution of life has resulted in a strong association between environmental metals and the biological processes taking place in the human body. Some of these metals are essential for the survival of human life, while many others can pose harmful effects on the body if exposed continuously. These toxic metals include Aluminium (Al), Arsenic (As), Lead (Pb), Mercury (Hg), Cadmium (Cd) etc. Upon entry into the brain, these metals lead to the development of many neurological disorders by increasing the levels of ROS, disturbing calcium ion efflux, causing mitochondrial dysfunction and activating an immunogenic response. These metals also cause a decrease in the levels of certain antioxidants in the brain like glutathione, superoxide dismutase and catalase. Moreover, the decrease in the level of certain genes like brain derived neurotropic factor (BDNF) due to metals neurotoxicity can also cause depletion of the memory and other cognitive functions leading to many neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), etc. The following chapter explains the pharmacokinetic mechanisms involved in metals induced neurotoxicity leading to different neurological disorders.

Veterinary Nutraceutics, Pharmaceutics and Vaccine

Animals have been utilized extensively as part and parcel of pharmaceutical and vaccine development. Many studies from animal models for human diseases have re-affirmed inventions in the field of medicine. Animal nutraceuticals of biological origin have marked exceptional promise by enhancing the production and performance of commercial animals. Transgenic animals have helped transform laboratory-scale developments into clinical applications. The nutraceutical potential of animal products is a fascinating area of research with considerable anti-microbial, anti-cancer, antiinflammatory, anti-diabetic and neuroprotective functions. Vaccines in veterinary sciences have been revolutionized based on the efficacy demonstrated by animal models. Vaccines are being routinely used against bacteria, viruses and some parasites at commercial levels. Third-generation vaccines that were thought to be very expensive in the last century are now being commercially produced and marketed worldwide for animal health. Most recently, many avenues have opened that encourage the use of biologically derived pharmaceuticals and vaccine products. This chapter deals with a very comprehensive contrast of history and recent trends in veterinary pharmaceuticals and vaccines. It concludes that more research focus is required to come up with more efficient treatment and prophylactic approaches amidst mutating pathogens of concern.

Neuroprotection with the Functional Herbs from the Lamiaceae Family

The growth of the average lifespan of the global population is accompanied by a progressive increase in the prevalence of neurodegenerative disease (NDD). Common NDDs such as Alzheimer’s, Parkinson’s, Huntington’s diseases, and others are known to be strongly related to aging. The prevalence of NDD is expected to increase steeply with the increment in life expectancy. The currently available therapeutic interventions are mainly symptomatic, and most have failed to reverse or slow down the disease progression. Hence, new treatments and preventive measures are urgently needed. Plants from the Lamiaceae family have reported several neuroprotective effects attributed to the abundance of secondary metabolites that could target multiple pathways of the cellular death mechanism. Owing to the multifactorial nature of NDDs, the abundance of secondary metabolites in plants has attracted the attention of researchersto the neuroprotective potentials of natural products. The neuroprotective effects and bioactive constituents of common herbs such as Perilla frutescens (Perilla), Sideritis scardica (Ironwort), Ocimum sanctum (Holy basil), Origanum syriacum (Lebanese oregano), Satureja bachtiarica (Bakhtiari savory), Orthosiphon stamineus (Cat whisker), Prunella vulgaris (Prunella), Pogostemon cablin (Patchouli) and Stachys sieboldii (Japanese artichoke) from the Lamiaceae family are discussed in this chapter. The neuroprotective property of these herbs relied on their ability to target the underlying mechanisms of neuronal cell death, such as aberrant protein aggregation, excessive oxidative stress, neurotransmission system dysfunction, neuroinflammation, and others. The multi-targeting ability of these plants is attributed to their complex chemical compositions with different bioactive compounds. Thus, the incorporation of these plants and herbs into the management of NDD should be further explored. Their role as dietary supplements to preserve the function of the nervous system is also strongly advocate.

Neuroprotective Effects of Polyphenols

Phenolic compounds, the bioactive phytochemicals, are abundantly found in a huge variety of food items, including fruits, vegetables, cereals, legumes, and herbs. Phenolic compounds are often called phenols, phenolics, and polyphenols. They are secondary metabolites of plants and are considered an integral part of both animal and human diet. Natural phenolic compounds have acquired increasing attention in the last few years because of their countless health-related therapeutic interventions. Biological activities of phenolic compounds include anti-oxidative, anti-inflammatory, antiallergic, and anti-hypertensive are found to play their role in neuroprotection. All of these above mentioned properties of different phenolic compounds play a critical and central role in preventing the progression of neurodegenerative, neurological disorders and brain injuries. A list of phenolic compounds including resveratrol, quercetin, rutin, curcumin, baiclein, luteolin, and (-) Epigallocatechin-3-gallateon have been discussed in detail in the context of their neuroprotective action. The present chapter describes a brief and comprehensive overview of the physiological activities of phenolic compounds along with their potential neuroprotective approach.

Tau-Targeted Therapy in Alzheimer's Disease - History and Current State

The two main histopathological hallmarks still required for the diagnosis of Alzheimer's disease are the presence of amyloid plaques and intraneuronal neurofibrillary tangles formed mainly of tau protein. Normally, tau protein regulates intracellular trafficking and provides microtubule stability. However, in AD as well as in other tauopathies, there is a disruption in the normal function of tau, leading to the development of neurofibrillary tangles with disease-dependent ultrastructure of the tau filaments.

After several failures of trials with drugs trying to prevent the accumulation of amyloid, tau protein became another target of molecules designed to modify the course of AD.

Each stage in the development of tau pathology, from the expression of tau protein to its post-translational modifications, with the protein’s aggregation and impaired clearance, presents opportunities for therapeutic intervention: reducing tau expression with antisense oligonucleotides, reducing tau phosphorylation with kinase inhibitors, inhibiting tau acetylation, tau deglycosylation, tau aggregation, modulating tau degradation, stabilizing the microtubules, as well as active or passive anti-tau immunotherapies (with various monoclonal antibodies), have been attempted or are still in trials, with rather inconclusive results so far. It appears that an efficient diseasemodifying therapy is not yet available. Given the complex pathophysiology of Alzheimer’s disease, most likely, a multi-targeted approach would be more effective.

The Possibilities of Safe Lithium Therapy in the Treatment of Neurological and Psychoemotional Disorders

Lithium is a type of psychotropic drug, belonging to the normothymics classification group. It is used in the treatment of affective disorders such as manic and hypomanic phases of bipolar disorder and severe and treatment-resistant depression. It also has anti-suicidal properties and a neuroprotective effect on neurodegenerative diseases. This article presents findings regarding the effects of lithium in experimental pathology of the central nervous system in mice and rats. In clinical practice, lithium is the standard for pharmacological treatment of bipolar disorders. The drug is also effective in treating depression. It suppresses aggressiveness and is a therapeutic agent in the treatment of chronic neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease. Lithium salts however can be highly toxic even in relatively low doses. The mechanism of action of lithium salts can be realized through the inhibition of glycogen synthase kinase -3β (GSK-3β) and inositol monophosphatase 1 (IMAP1). Inhibition of GSK-3β is considered to be one of the fundamental mechanisms in the implementation of the action of lithium ions on the body. Lithium stabilizes adenylate cyclase activity and acts as an antagonist of sodium ions in nerve and muscle cells. One of the ways to deliver lithium to target organs is to combine lithium salts with a sorbent (a solid porous carrier). This approach made it possible to create modified sorbents for the prolonged delivery of components such as lithium and silver. A new drug – a complex of lithium citrate and a sorbent – aluminum oxide and polydimethylsiloxane (lithium complex) was created at the Research Institute of Clinical and Experimental Lymphology – a branch of the Institute of Cytology and Genetics SB RAS. Its anxiolytic and adaptogenic effects were observed over the course of preclinical studies. The lithium complex improved cognitive functions in experimental animals, influenced the electrophysiological activity of the brain and had positive effects on the behavior of mice in the experimental model of chronic social stress. The lithium complex is therefore a promising drug for the treatment of neurological and psychoemotional disorders.

Revaluation of Thyrotropin-Releasing Hormone and Its Mimetics as Candidates for Treating a Wide Range of Neurological and Psychiatric Disorders

Thyrotropin-releasing hormone (TRH) is a neuropeptide having many biological and pharmacological activities. TRH (protirelin tartrate) has been used for the treatment of persistent disturbance of consciousness disorder because of its amelioratory effect. However, therapeutic use of TRH entails problems, such as its low lipophilicity, short half-life times due to specific degradation enzymes, and low penetration of the blood-brain barrier (BBB) for access to the central nervous system (CNS). To overcome such problems, a large number of TRH mimetics have been developed for the treatment of various neurological and psychiatric disorders, including spinocerebellar degeneration (SCD), cognitive impairment, and Alzheimer’s disease (AD), given by non-oral routes such as intravenous (iv) administration. However, orally effective TRH mimetics are needed to help improve the quality of life (QOL) of patients. As the first orally active TRH mimetic for the treatment of SCD, Taltirelin (Ceredist) has been launched in Japan for administration twice a day. Recently, rovatirelin reported to have high oral bioavailability (BA), was developed for SCD as a potentially effective treatment option in clinical trials by oral administration once a day. This would allow treatment with TRH and its mimetics to be moved from the hospital to outpatient or homecare facilities, and their use for a wider range of disorders. In the near future, TRH and its mimetics should become available as one of the key treatments for various neurological and psychiatric conditions, such as AD, Parkinson’s disease (PD), depression and so on.

Clinical Milestones in Nanotherapeutics: Current Status and Future Prospects

An aging population and poor clinical solutions for several diseases have propelled the rapid emergence of nanotherapeutics. Advanced drug delivery has turned out to be an important aspect of the medical field. A targeted delivery system transports the drug to the place of action hence, minimizing its adverse side effects on other vital tissues. Cell-specific targeting can be achieved by coupling drugs to specially framed carriers. Various nanoparticles, including solid lipid nanoparticles, nanosuspensions, nanoliposomes, micelles, polymeric nanoparticles, magnetic nanoparticles, dendrimers, carbon nanotubes, and fullerenes have been developed as carriers in drug delivery systems. In this chapter, the aforementioned nanocarriers and their clinical milestones achieved in various arenas including cancer, CNS disorder, rheumatoid arthritis, thyroid, cardiac diseases, ocular drug delivery, and vaccines so far, are scrutinized. This chapter outlines the current status of pharmacological and clinical studies of nanoparticles in the development process.

Artificial Intelligence Played an Active Role in the COVID-19 Epidemic in China

This perspective aims to summarize the COVID-19 experience of the Chinese people, which included psychological assistance and open datasets. We hope that countries across the world can utilize the lessons learned and tools developed by China in response to the COVID-19 pandemic and share their fighting experience in academic publication freely so the world can solve this crisis. This perspective focuses on psychological assistance and open datasets in China's COVID-19 pandemic; they played an important role in fighting with COVID-19 and acquired major contributions to calm people in the restless environment. We hope other countries can absorb the quintessence from this experience and utilize their situation to prevent and protect citizens from being infected and get rid of sequela in the COVID-19 epidemic.

Applications and Implementations of 6G Internet of Things

The Internet of things (IoT) has been the information infrastructure of a digitalized society and drives the newest wave of industrial development. With the rise of smart vehicular IoT applications, such as intelligent transport, smart navigation, and automatic driving, vehicular IoT is gaining some new features that cannot be fully addressed by current 5G networks. This chapter presents an overview of the vehicular IoT developing trend and discusses its relationship to 5G and the coming generation. It also presents some survey results from recent literature on the challenges and promising technologies for vehicular massive IoT.

Intestinal Microbiota and its Implications in Pathology

The intestinal microbiota develops as a results of various genetic, nutritional and environmental factors, becoming very specific for each individual. It totalizes more than 100 trillions of bacteria with a piece of genetic information more than 100x greater than the human genome. The functions of the microbiota can be grouped into metabolic, protective and structural. The microbiota-derived metabolites signal to distant organs of the host, which enable the microbiota to connect to the brain, the immune and endocrine system, metabolism and other functions of the host. These microbiota-host communications are essential to maintain the vital functions and health of our organism. So, microbiota, in eubiosis and especially in dysbiosis, has multiple effects on the human organism. The therapeutic possibilities for this are the administration of nonabsorbable antibiotics, pre-, pro, syn- or symbiotics, as well as FMT, which is in principle a complex human probiotic. The most important digestive effects of microbiota are in Clostridium difficiledetermined pseudomembranous colitis, in IBS, IBD, diverticulitis, functional dyspepsia, and in different digestive cancers: gastric, colorectal, liver and pancreatic cancer. Alcoholic liver disease is also influenced by microbiota. The extra-digestive effects of microbiota are very complex. In some metabolic diseases, like obesity, NAFLD, atherosclerosis, dyslipidemias and T2D, special types of dysbiosis have important pathophysiologic implications. Microbiota has also implications in Alzheimer's disease, osteoporosis, CKD, different psychiatric disorders and some extra-digestive cancers. In conclusion, it may be stated that the intestinal microbiota has multiple effects, even in diseases that apparently have no relation with the intestinal flora.

Basal or Nonspecific Plant Defense

Non-specific defense against plant pathogens can be passive (constitutive) or active (induced by microbes). The activation of general resistance follows the perception of the pathogenic threat. The first class of plant receptors recognizes molecular patterns associated with pathogens / microbes (PAMPs / MAMPs) in a nonspecific way. These are resident membrane receptors, also called pattern recognition receptors, PRRs. Plant PRRs are the source of extremely complex molecular signaling immune machinery. A transmembrane receptor that binds to a ligand then triggers the signalling would be the most simplistic scenario. Yet, in many cases, the recognition scheme would also include co-receptors, as well as regulatory proteins, which activate PRRs leading to the signal trasduction intiation. It is, therefore, reasonable that our current knowledge is only touching the surface of a remarkably intricate immune strategy.

Type 2 Reaction (T2R)

Type 2 reaction (T2R), also called erythema nodosum leprosum (ENL), is a reactional phenomenon that occurs in response to Mycobacterium leprae antigens in patients with borderline lepromatous or lepromatous forms of leprosy. T2R usually occurs after starting treatment and can affect any parasitic tissue in the body, causing neuritis, arthritis, painful lymphadenitis, buccopharyngeal lesions, laryngitis, hepatomegaly, splenomegaly, bone injuries, iridocyclitis, uveitis, orchitis, glomerulitis with proteinuria, and hematuria. Recognition of the histopathological characteristics of T2R is important for guiding early treatment of the reaction process, decreasing the likelihood of developing serious sequelae, especially when T2R affects the nerves, and to exclude different diseases that can simulate T2R over leprosy lesions during the course of the disease. In this chapter, the histopathological characteristics that allow T2R diagnosis are described, and some of its differential clinicopathological diagnoses and their possible pathophysiological mechanisms are discussed.

Laboratory Diagnosis

Due to the high potency of P. aeruginosa in pathogenesis and diffusion in the human body, it can be diagnosed in a variety of clinical specimens. For this purpose, the unique properties of P. aeruginosa are used. In general, the appearance of the bacterium under the microscope and its features on culture media as well as biochemical tests are widely used for the initial diagnosis of P. aeruginosa in the clinical laboratories. In this section, the diagnostic routine tests are briefly discussed so the readers can easily use them.

Subject Index

Impact of Nano-Formulations of Natural Compounds in the Management of Neuro degenerative Diseases

Neurodegenerative disorders (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), are caused by oxidative stress, inflammation, and proteinopathy. These are further characterized by loss of neurons and, consequently, impaired cognitive functions. However, the exact mechanisms of the pathogenesis of these diseases are still unknown. Nowadays, natural compounds like curcumin, quercetin, resveratrol, and piperine, among others, have been explored for the treatment and prevention of neurological disorders. There are various in vivo studies and clinical trials conducted for alleviating neurological disorders using natural compounds encapsulated in nanocarrier systems. Nanoparticles such as lipidic, polymeric, quantum dots help to enhance the bioavailability, specificity, and targeted delivery of these compounds in the brain. Various simple and reproducible methods are reported to synthesize the nanoparticles in the literature. In this chapter, we will explore the role of nanotechnology and natural compounds to treat and prevent neurodegenerative disorders.

Novel Therapeutic Targets in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis is an adult-onset, irremediable, and fatal neurodegenerative disease marked by the advancement in the loss of motor neurons in the spinal cord, brain stem, and motor cortex. Etiology is blurred, but it is thought to be multifactorial, which contributes to the heterogeneity and complexity of the disease. Core knowledge of primary etiology and pathological mechanisms can pave the way towards treatment. This chapter examines mechanisms that may contribute to motor neuron degeneration, among which oxidative stress, mitochondrial dysfunction, protein aggregation, axonal transport are potential novel therapeutic targets for ALS treatment.

Therapeutic Efficacy of Mushroom in Neurodegenerative Diseases

Mushrooms are used not only for culinary purposes, but also for the treatment of various chronic diseases. It shows vital therapeutic activity in several neurodegenerative disorders such as, Alzheimer's and Parkinson's diseases. These diseases are non-communicable as well as age-related. Currently, no drug therapy is available to treat such neurodegenerative disorders; instead, it is best to delay progression of these diseases. Accumulated evidence has suggested that culinary or medicinal mushrooms may play a significant role in the prevention of these disorders, as mentioned earlier, and dementia. Therefore, daily consumption of mushrooms in the diet may improve memory and cognitive functions, including mushrooms such as, Hericium Erinaceus, Ganoderma lucidium, Pleurotus giganteus, Dictyophora indusiata, Sarcodon scabrosus, Antrodia camphorata Termitomyces albuminosus, Paxillus panuoides, Mycoleptodonoides aitchisonii, Lignosus rhinocerotis, and numerous other species. These mushrooms show potent antioxidative, antiinflammatory, and memory-enhancing activities. This chapter deals with the therapeutic activity of mushrooms and their bioactive components for different neurodegenerative diseases. Thus, mushrooms can be considered supportive and promising candidates for treating or preventing neurodegenerative diseases.

Potential of Gut Microbiome in the Diagnosis and Treatment of Alzheimer’s and Parkinson’s Disease

Neurodegenerative diseases (NDD) are a heterogeneous group of disorders characterized by a progressive, selective loss of physiologically related neuronal systems. Some prominent diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS), and Huntington’s disease (HD). It is believed that oxidative stress-induced cellular degeneration, inflammation, mitochondrial involvement, and dysfunction are important aspects in the pathogenesis of NDDs. Despite many decades of research and intensive studies, it has been an unending struggle to discover the root cause and a cure for these life-threatening ailments. However, the emerging domains of research provide evidence that probiotics and human gut microflora have a peculiar relationship with health and the pathogenesis of several diseases, including NDDs. Microbiome and nutrients have a profound impact on the brain by influencing their development and function in health and diseases. The gut ecosystem and any modulation thereof exhibit a significant impact on the physiological and psychological health of an individual. The present chapter discusses the effect of the beneficial gut microbial community versus pathogens on the overall human health and its role in the development, diagnosis, and management of NDDs, especially Alzheimer’s disease (AD) and Parkinson’s disease (PD). Furthermore, the potency of probiotics and prebiotics as a gut-friendly therapeutic agent to treat these disorders is highlighted.

Role of Phytochemicals in Neurodegenerative Disorders

Neurodegenerative disorders (NDs) are one of the leading serious problems worldwide, not only for developed countries but also for developing countries. NDs can be described as a progressive loss of neurons of the central nervous system that leads to cognitive impairment in individuals. The generation of excess reactive oxygen species is one of the reasons for the pathogenesis of NDs. From the various study, it has been established that the use of antioxidants may reduce the onset of NDs. The treatment of these diseases is very costly; for example, the cost of AD worldwide is estimated to be~ $800 billion in 2015. Moreover, in 2017 the cost of PD is reported to have been greater than ~$14 billion in the United States. Now, the researchers have focused on the screening of phytochemicals that have a huge antioxidant effect and neuroprotective ability. Phytochemicals are plant-derived biochemical, and they are described to have a protective effect on oxidative stress (OS), inflammation and provide better mental health. In this chapter, we have incorporated some important phytochemicals that have a great capacity to protect our brain cells and slow down or inhibit NDs pathogenesis.

Recent Advancement in the Treatment of Neurodegenerative Diseases by Ayurveda

Neurodegenerative diseases (NDDs) are not the only diseases but a key term for a range of conditions that mainly affect the neurons in the human brain resulting in progressive degeneration or death of the nerve cells, which is a deadly and debilitating state. It affects millions of people worldwide. The most common NDDs worldwide are Parkinson’s disease (PD) and Alzheimer's disease (AD). According to De Lau & Breteler et al., the incidence of PD is about 10 million globally (i.e., approximately 0.3% of the world population) and 1% of those above 60 years. Management of NDDs has become a big challenge in the modern system of medicine & public health at present because of demographic changes worldwide. There is no specific therapy for the conventional management of NDDs in the modern system of medicine. The absence of specific and complete therapy for NDDs in the present era makes Ayurveda more important to consider some alternative and complementary system of medicine for the treatment. Ayurveda is an Indian system of medicine that comes under AYUSH and treats the NDDs since its inception, which is mainly described under the VataVyadhi (neurological disorder) context. In this chapter, the recent advancement in Ayurvedic medicinal plants, RasaAusadhies (herbo-mineral drugs) & combined drugs, Panchkarma therapies (bio-purification procedures), and Yoga & Asanas (bodily postures) that successfully treat the various common NDDs worldwide will be described.

An Introduction to Neurodegenerative Diseases and its Treatment

In the 21st century, a lot of progress has been made in the treatment against different kinds of Neurodegenerative disorders (NDs). Antioxidant therapy is one of the most common types of therapy for NDs. Among Antioxidant therapy, reduced GSH delivery systems are widely utilized. Gut-microbiome based treatment is also widely accepted. The blood-brain barrier (BBB) is one of the major hurdles that reduce the efficacy of several neuroprotective drugs. That is why nanoformulation based drug is currently trending to potentially treat the neurodegenerative disease. 3D organoid model is employed to mimic the in vivo condition for the development of drugs for NDs. Target specific surgical interventions are also utilized to improve the symptoms of neurological diseases. Chemical compound mediated protection only provides symptomatic relief. In long term usage, this chemical compound causes several side effects. Herbal plant-mediated therapy is a better alternative for the same. Diet is a basic part of our life. By manipulating our diet in such a way that include several beans may be very helpful in the treatment of several NDs. Accordingly, this chapter explores some important recent advancement in the treatment of different NDs.

Blood and Toil

In this chapter, you will learn about the amazing work done with bone marrow transplants to treat leukaemia and blood disorders. This is not an easy process for either the patient or the healthcare professional, but it is a tried and tested treatment for otherwise deadly diseases. There is also a discussion about the nature and importance of clinical trials using bone marrow stem cells to treat a whole range of disease, which is followed by a note of caution to anyone considering such treatment provided by some private clinics outside of registered clinical trials and in areas of the World where regulation of such technology is either weak or non-existent.

Interplay Between Oxidative Stress and Meta- Inflammation in Obesity-Related Neurodegeneration

Neurodegeneration refers to the gradual deterioration of neuron structure and function and can lead to debilitating neurological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Common pathogenic mechanisms on which many neurodegenerative disorders (NDDs) are based include abnormal protein dynamics of malfolding, degradation, proteasomal instability, and aggregation; often with molecular chaperone actions and mutations; free radical/reactive oxygen species (ROS) formation and OxS; bioenergetic weakness, mitochondrial dysfunction and damage to DNA, neuronal Golgi system fragmentation, disruption of the movement of cellular/axonal, neurotrophin (NTF) dysfunction and neuroinflammatory/neuroimmune processes. Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of ROS/reactive nitrogen species (RNS) and/or a deficiency of enzymatic and nonenzymatic antioxidants. Oxidative stress can be a result, but also an obesity trigger. It has shown that obesity is coupled with an altered redox state and increased metabolic risk. Antioxidant defenses in obese patients are decreased compared to the control group, and their concentrations correlate inversely with core adiposity. Moreover, obesity is also defined by increased concentrations of reactive oxygen or nitrogen species. Metabolic changes caused by weight are associated with damage to the central nervous system (CNS), which can result in neuronal death, either through apoptosis or cell necrosis, or by modifying the neuron's synaptic plasticity. Adipose tissue dysfunction associated with obesity has been correlated with abnormal brain metabolism, neuroinflammation, brain atrophy, neural impairment, diminished mood, and cognitive decline. Due to their high metabolic rate, visceral fat tissues function as endocrine organs, which secrete adipokines (leptin, adiponectin, visfatin, resistin, apelin, and plasminogen activator inhibitor type 1) and cytokines (TNF-α, IL-6, IL-1β). Inflammatory cytokines bind to their receptors by activating the pathway of the nuclear factor-kappaB, which induces a pro-inflammatory state. Inflammatory pathways and DNA damage may also be triggered by nutritional imbalance, adversely affecting redox control [via glutathione peroxidase (GPx); glutathione (GSH), and oxidized glutathione (GSSG) levels] and thus fostering oxidative stress. Obesity also impacts the glucose and energy metabolism of brain cells, and by secreting pro-inflammatory agents causes neuroinflammation primarily in the brain's hypothalamic area. The general effect is the loss of neuronal activity and its internal molecular machinery, resulting in intracellular or extracellular or both aberrant protein deposition, contributing to neurodegeneration.

Diagnostics for Neurodegenerative Disorders

Neurodegenerative diseases (NDDs) stem from the loss of neurons and related progressive disruption of psychological, cognitive, and motor functions. The development of NDDs results from either disruption or dysfunction of normal nervous tissues or the accumulation of pathologically altered proteins in the brain. Traditionally, the diagnoses are based on clinical presentations, with limited sensitivity for early diagnosis and specificity for differential diagnosis. However, advancements in the research of biomarkers and biosensing techniques have led to additional promising strategies for the molecular diagnosis of NDDs.

In this chapter, we have reviewed the clinical features, diagnostic criteria and known genetic and protein biomarkers of common NDDs. We have also discussed the importance of bioenergetics in the development of NDDs. Finally, we have placed emphasis on current developments in the detection and diagnosis of NDDs, including neuroimaging, metabolome profiling, and biosensors for NDD biomarkers. Biosensing provides a noninvasive way to diagnose NDDs at an early stage to detect alterations and abnormal products in the blood and brain tissues with high sensitivity and selectivity. This chapter is expected to provide an overview of the recent advances in diagnosing NDDs, as well as pointing out the current progress and challenges in the evaluation and treatment of NDDs and beyond.

Subject Index

Anti-angiogenic Mechanism, Biochemical Factors’ Roles, Therapeutic Agents, and Under Clinical Trial Drugs for Breast and Prostate Cancers

The genesis of new blood vessels is the culmination of angiogenic activity which is responsible for the spreading of the tumors and other malignant masses. The blood supply also provides nourishment to non-malignant tissues and helps in their maintenance, growth, and proliferation. The major biological factors that significantly favor the angiogenic processes includes vascular endothelial growth factors (VEGFs), tumor necrosis factors (TNFs), and fibroblast growth factors (FGFs). The disruption and inhibition of angiogenic growth factors and their biochemical pathways during the cancer cycle are among the obvious choices to control the growth and proliferation of cancers. The current work deals in details about the growth factors, their roles, contextual biomechanics, and approaches to control angiogenesis through different inhibitory mechanisms involving biochemical pathways, growth factors, and structural motifs, playing part in the angiogenesis. The approaches to find novel molecular templates, new chemical entities, bio-macromolecular substrates, and probable drug leads for anti-angiogenic pharmacology are discussed. The chapter enlists various antiangiogenesis drugs, under clinical trials, new chemical entities, and other biochemical and recombinant therapeutic agents, used either as mono or as combination therapy in treatment of various forms of cancers, especially breast and prostate cancers.

Subject Index

Hampering Essential Tremor Neurodegeneration in Essential Tremor: Present and Future Directions

Essential tremor (ET) is one of the most prevalent neurological disorders worldwide. ET presents mainly with kinetic and action tremor in upper limbs. Tremor may also affect the head and some patients develop an ataxic gait, as well as cognitive/affective symptoms. ET significantly impacts the quality of life. There is accumulating evidence that ET is a slowly progressive neurodegenerative disease, driven by both genetic and environmental (possibly dietary) factors. Both the olivocerebellar pathways and the cerebellar cortex are critically involved, with particular impairments in the morphology of the Purkinje neurons (Purkinjopathy) as well as the surrounding micro-circuitry. Dysfunctional cerebello-thalamo-cortical loops probably result in bursts of tremor. So far, only few symptomatic medications are available, including beta-blockers, primidone and drugs aiming to modulate GABAergic transmission such as topiramate or gabapentine. Surgery (deep brain stimulation, thalamotomy) is proposed to refractory cases but carries the risk of infection, bleeding in the brain and several technical issues related to the mispositioning of electrodes. MRI-guided focused ultrasound is a promising technique, but long-term follow-up is missing. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are encouraging non-invasive techniques but no consensus on optimal protocols has been reached so far. It is remarkable to observe that none of the available therapies targets the neurodegenerative process affecting in particular the cerebellum, the masterpiece of progression of the disease. This chapter focuses on the pathogenesis of ET and discusses possible novel avenues for therapy and prevention. In particular, the impact of environmental toxins such as beta-carboline alkaloids (βCAs), possibly generated from Maillard-type reaction products, is discussed. Animal models of ET, toxicokinetics and neurotoxic effects of βCAs are presented, with an emphasis on the neuroprotective pathways that are candidates to block the neurodegenerative process. Moreover, we consider a group of enzymes that could be neuroprotective, especially GAD65 and GAD67, involved in GABA synthesis/neurotransmission, and MAOA/MAOB. Finally, we emphasize the potential interest of dietary phytochemicals (such as phenolic acids, catechins, flavonoids, anthocyans, stilbenoids, curcuminoids) and herbal therapies (based i.e. on Bacopa monnieri, Ginkgo biloba) as neuroprotective approaches to hamper the neurodegenerative process in ET.

Metals Linked to Alzheimer's Disease

Exposure to metals including copper, zinc, aluminum, and iron ions occurs inevitably. Any disturbance in metal homeostasis develops diseases and abnormalities. Metal ions undergo an electric charge balance via gaining or losing electrons from surrounded biomolecules. They bind to amyloid fibrils or tau proteins in the brain in a way that links to the development of neurodegenerative diseases including Alzheimer's disease (AD). For several decades, scientists have been exploring possible links between metals imbalance and AD. However, very little is known about the exact mechanisms governing the links of metals to AD. This book chapter summarizes recent thoughts in the research studies that focus on the links between metals and AD. Most of the current results suggested that metal binding to amyloid binds affects the architecture of the protein fibrils and rate of propagation.

Modeling Neurodegenerative Diseases Using Transgenic Model of Drosophila

From the past several decades, neuroscientists have been focusing on understanding the mechanisms of various human neurodegenerative diseases using different models such as Mouse, Rat, Zebrafish, worm and the Drosophila. Among them, the Drosophila, with a short generation time and genetic amenity, has emerged as a vital and prevailing model system to explore multiple aspects of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, etc. In this chapter, we have presented various molecular, genetic and therapeutic approaches employed to model human neurodegenerative diseases using Drosophila. Furthermore, we also present the worldwide prevalence of neurodegenerative diseases, along with a survey of published literatures of research conducted in the last two decades on major neurodegenerative diseases employing transgenic Drosophila, to evaluate where we stand.

Reprogramming of Adipose-Derived Stem Cells to Neuronal-Lineage Cells is Regulated by Both Cell Signalling and Redox Status

The generation of specific neuronal-lineages for cellular therapies hold great promise for nervous system disorders. Stem cells can offer regenerative and replacement therapies of the nervous system through cell signalling, which is directed by the addition of cytokines and neuronal growth factors. Adipose-derived Stem Cells (ASCs) are capable of differentiating into neuronal and glial cells through induced cell signalling pathways and altered redox status. In this chapter, we addressed the dynamic changes within ASCs in response to the changes in its milieu - a pre-requisite for transdifferentiation in vitro. We considered the functional use of ASCs as a regenerative tool in recovering neuronal cells by focusing on ligand expression and their effects on transmembrane receptors. We also discussed various levels of cell signalling capable of modifying epigenetic programming for trans-differentiation processes. Finally, we underlined the fact that harnessing of Reactive Oxygen Species (ROS) and ROSmediated cellular signalling is a secret recipe for successful differentiation of stem cells in vitro.

Toward Induced Pluripotent Stem Cells for Clinical Use: Sources, Methods and Selection

Since their development by Yamanaka in 2007, much progress has been made in the last decade toward the use of human induced pluripotent stem cells (iPSCs) in clinical practice. In this review, we will focus on the various sources of somatic cells for human iPSC generation, the methods used for generating human iPSCs, their characterization, and the progress on directed differentiation toward several cell types. We will also describe current efforts to prevent culture-driven mutations and the selection of nontumorigenic cells for clinical use. A comprehensive comparison of such methods will aid in the establishment of standardized techniques and highlight areas in which further research is still needed.

Autonomous Immunity

Autonomous immunity is a set of immune mechanisms present in practically every cell of a multicellular organism. They include immune mechanisms based on nuclear acids, such as RNA interference (RNAi). Small RNAs generated from pathogen dsRNAs guide nucleases to the pathogenic nucleic acids. In addition, RNAi restricts the expression of transposable elements by establishing transcriptionrepressing chromatin over DNA regions that encode such elements. Other autonomous mechanisms prevent the entry of viruses into cells, detect and destroy non-self nucleic acids, restrict pathogen growth and replication, prevent pathogen release, and induce regulated cell death if the infection cannot be suppressed. Infected cells release interferons and other cytokines that alert neighboring cells and preventively induce defensive mechanisms in them. Pathogens express pathogen-associated molecular patterns (PAMPs), which are recognized by pattern-recognition receptors (PRRs). These receptors also recognize damaged “self” molecules expressing damageassociated molecular patterns. Infection can also be sensed indirectly through changes in the functioning of some key cellular molecules. Stress and infection can lead to the formation of inflammasomes triggering production and secretion of pro-inflammatory cytokines.

Polyphenols and Cancer

A solid and useful connection exists among eating regimen and malignancy. An inaccurate diet may increase the incidence of all types of cancer from 10% to 70%. Polyphenols are found in more than 700 foods, particularly foods grown on the ground (such as herbs), flavorings, and even nuts and cocoa items. Many food items considered superfoods; top superfoods include blueberries, apricots, grapes, olives and olive oil, artichoke, herbs (e.g., oregano, peppermint, and cloves), nuts and seeds (e.g., walnuts, almonds and flaxseeds), and green tea. Polyphenolic compounds can lead to epigenetic modification of chromatin and modulation of membrane organization; they can also interfere with interaction of the various macromolecules and regulation of the telomerase activity. They play crucial roles in modulating the multiple cellular pathways individually. Pure polyphenolic agents may be used as therapeutic agents, in combination with conventional therapy for improved cancer treatment. This chapter summarizes the anticancer efficacy of major polyphenolic compounds and discusses the potential mechanisms of action based on epidemiological studies.

Potential Biological Mechanisms with Prophylactic Action in Rapid Cognitive Impairment in Late- Onset Alzheimer's Disease

Given the alarming increase in the Alzheimer's Disease (AD) related costs and the number of patients, significant importance of the research of dementia in elderly people is represented by the early detection of dementia signs and identifying ways to slow down the cognitive decline that should be done by the entire medical community, not only by specialists in psychiatry, neurology and geriatrics. An integrated, multidisciplinary approach can only be achieved by recognizing some clinical-biological parameters that may represent an early signal for a potential onset of AD, or that may speed up the cognitive impairment. Dysfunctional neurobiochemical mechanisms in AD engaging in multimodal pathogenic processes of cognitive impairment, are correlated with the presence of clinical, imaging or biological markers. Identifying risk factors for the progression of cognitive impairment in AD will bring significant improvement in primary and secondary prophylaxis in late-onset AD with improved quality of patient life and a significant decrease in the cost of care associated with this pathology. The patient's assessment should consider multiple somatic comorbidities, associated with cognitive impairment: neurobiochemical vulnerabilities (acetylcholine, dopamine, serotonin and noradrenaline deficiency), traumatic brain injury, disruption of the blood brain barrier, insomnia, depression, cardiovascular diseases, diabetes, hepatic steatosis, infectious pathology. The etiology of late-onset AD and the rapid progression of cognitive decline are complex, multifactorial and incomprehensible, the genetic component is less involved, and is a real challenge for research on the pathology of cognitive impairment. These considerations make it difficult to diagnose early and develop effective therapeutic strategies.

Novel Molecular Targets of Tauopathy; Therapeutic and Diagnostic Applications

Neurodegenerative diseases (NDDs) are heterogeneous group of disorders that lately become among the most life-threatening disorders affecting the elderly people. The neurodegenerative disorders that are collectively grouped under the term of tauopathies are featured by the presence of abundant neurofibrillary lesions made by accumulation of abnormal hyperphosphorylated microtubule associated protein tau inside the neurons and/or glial cells. Undoubtedly, tau protein plays a fundamental role in axonal microtubule network stabilization however, the flexible unfolded structure of tau enables modification of tau by several intracellular enzymes which in turn extends tau function and interaction spectrum. The distinctive characteristics of tau protein alongside the essential role of tau interaction partners in the development and progression of neuronal neurodegeneration suggest tau and its binding partners as potential drug targets for the treatment of neurodegenerative diseases. This chapter aims to discuss interaction between mitochondria and tau, and the key molecular players that interfere with tau proteins in physiological and pathological conditions. We outline the putative molecular targets and address the mitochondrial critical role based on research efforts that previously identify their influence on diseases models. Taken together, no solitary player would trigger the whole pathogenic pathway, we attempted to give a detailed description of structure, functions and interactions of tau protein in order to provide insight into potential therapeutic targets for treatment of tauopathies.

Through the Perspective of Histology - The Alzheimer’s Disease Promotion by Obesity and Glucose Metabolism: Type 3 Diabetes

Since the 1990s The World Health Organisation (WHO) has stated that “… obesity should now be regarded as one of the greatest neglected public health problems of our time…” and defined the global epidemic of being overweight and obese as “globesity”. A positive energy balance, which consists of an imbalance between energy intake and calorie expenditure is the main cause of obesity, however, genetic, environmental, socioeconomical, behavioral and psychological factors may also be the inducing factors when it comes to obesity. The excess of adiposity has an enhancing effect on the development of hypertension, cardiovascular diseases and type 2 diabetes mellitus (T2DM) as a result of the resistance to insulin-mediated glucose disposal. T2DM which represents a common disease associated with obesity and often aging is characterized by high blood glucose levels, impaired insulin production and peripheral insulin resistance. Homeostatic degradation of glucose affects the cerebral functions directly or indirectly because glucose is a significant metabolic substrate for all cells and also for the cells of the brain. Insulin has a key effect on the regulation of energy metabolism of neurons and neuronal recovery, which acts as a growth factor on all cells including neurons in the central nervous system. Therefore, simply put, impairment in neuronal homeostasis which occurs as a result of insulin deficiency. These are considered to be a risk factor for Alzheimer’s disease (AD) development. Indeed, many studies have shown that glucose intolerance and impairment of insulin secretion are associated with a higher risk to develop dementia or AD. It is worth remembering that AD is associated with brain insulin resistance and deficiency, whereas T2DM is associated with peripheral insulin resistance. In short, it can be said that T2DM causes AD-type neurodegeneration in the brain. T2DM and AD share several molecular processes that underlie the degenerative developments. Dysregulated glucose metabolism, abnormalities in insulin signaling, the formation of advanced glycation end products, oxidative stress, the activation of inflammatory pathways and abnormal protein processing are the common characteristics of T2DM and AD. The misfolding of proteins plays an important role in both diseases, so as the aggregation of amyloid peptides. AD is characterized by the deposition of amyloid within neurons and amyloid plaques. Also in AD, the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects induced by a dysfunction of the proteasome. According to one study which was conducted on T2DM rats, T2DM-dependent decreases in p62 (a known cargo molecule that transports polyubiquitinated tau to proteosomal and autophagic degradation systems) transcription which is a primary mechanism underlying increased AD-like pathology. In some studies, brain amyloid deposition occurs as a result of increased blood-brain barrier permeability in case of diabetes conditions. In the recent years, according to some members of the diabetes community, AD is seen as a neuroendocrine disorder and the term “Type 3 Diabetes” defines the insulin deficiency and resistance in the brain of those with AD. In the context of these information, in this chapter, we propose a study about “Type 3 Diabetes” with the underlying mechanisms through the perspective of histology.

Ru(II)-polypyridyl Complexes as Potential Sensing Agents for Cations and Anions

Design, synthesis and applications of cation and anion sensing selective Ru(II)- Polypyridyl complexes have attracted a considerable attention because of their multipurpose and promising biological insinuation. Ruthenium(II)-polypyridyl ligands such as 2,2-bipyridine (bpy), 1,10-phenanthroline (phen), and/ or ortho-phenanthroline etc. on reaction with Ru(II) forms Ru(II)-polypyridyl complexes which have various significant benefits like metal-to-ligand charge transfer based on excited visible light and emission intensity, high chemical and photochemical stabilities, high shifts in Stokes (particularly more than 150 nm), greater response efficiency, low cytotoxicity and good water solubility. Owing to the MLCT emission, Ru(II) polypyridyl complexes were mostly used as essential materials in electro-generated chemiluminescence analysis offers unique properties like high rigidity, selectivity and less sensitive to environment. The multifaceted nature of Ru(II) polypyridyl-complexes in sensing is found as electrochemical sensors, solid state sensors, amperometric sensors, and straightforward chemosensors. A methodical report of different Ru(II) polypyridylcomplex chromophores emphasizing fluorophore frame work has been thoroughly discussed in this chapter. The binding mechanism has been proposed precisely. Unlike other metal complexes, the versatility and uniqueness of Ru(II) polypyridyl-complexes as chemosensor is observed in sensing of less common analytes which are rarely detected according to the literature. Polypyridyl Ru(II)-complexes being covalently bonded with photo conducting polymer may also be used as photosensitizers.

Phytochemicals in Asteraceae Leafy Vegetables

Knowledge about quantitative and qualitative characterization of phytochemical contents in Asteraceae leafy vegetables is continuously increasing due to the strong interest from scientists and consumers. This chapter deals with leafy vegetables of Lactuca sativa, Cichorium intybus and C. endivia species, given their relevance within the botanical family. It gives an overview of the wide differences occurring in genotype panels, in bioactive compound types and levels, focusing on phenolics, carotenoids and sesquiterpenes lactones. It also provides information on their biosynthesis pathways in plants together with health effects, bioaccessibility and bioavailability of diverse phytonutrient classes. Finally, it outlines the effects of the main pre-harvest and post-harvest factors affecting the amount and status of final products intended for dietary intake, and reports on some genetic aspects and biotechnologies aimed to biofortification of these species.

Intracellular Transport System in AD

The maintenance of intracellular trafficking is essential to neuron survival. Well-organized intracellular events contribute to synapse effectiveness and efficient communication between cells. Changes in microtubule trackers, vesicles, mitochondria or autophagosomes can lead to neurodegeneration. Protein aggregates containing amyloid-beta peptides and hyperphosphorylated tau are hallmarks of Alzheimer’s disease and they impair intracellular trafficking. Moreover, dysfunction of intracellular transport might increase the formation of protein aggregates. In this chapter it is discussed the association between intracellular trafficking and Alzheimer’s disease with emphasis in protein aggregation, cholesterol transport, molecular motors, rab proteins, autophagy, endoplasmic reticulum, mitochondria and calcium homeostasis.

Alterations of Membrane Composition in Alzheimer´s Disease

Biological membranes are a vital component of all living cells. They consist mainly of lipids and proteins. The proteins are embedded into the lipid structure, whose distribution in an aqueous environment forms a bilayer. The biological membranes have an average thickness of 30Å, determined by the size of the carbon chain of lipids, which range from 14 to 24 carbons. The lipid portion of biological membranes is also fundamental to determine their physicochemical properties such as membrane order, fluidity, and hydrophobicity. As Alzheimer’s disease pathology is mainly due to actions of Aβ peptides on the plasma membrane, its modifications are of great importance. In fact, membrane lipids, such as cholesterol, ceramides, gangliosides, and fatty acids, have been implicated in the molecular mechanisms of various stages of Alzheimer’s disease pathology. The following chapter describes the main changes in membrane lipid composition in Alzheimer’s disease (AD).

Subject Index

Unravelling Mesenchymal Stem Cell Signature in Regenerative Medicine

Mesenchymal stromal/stem cells (MSCs) represent suitable candidates for regenerative medicine purposes given their ability to differentiate in several cellular lineages, to migrate to site of injury, to secrete soluble factors crucial for cell survival and proliferation, as well as to modulate immune response. Although the exact mechanisms of action are still under investigation, several MSC- based clinical trials developed for various diseases, including organ injuries, systemic diseases, chronic inflammatory and autoimmune pathologies are ongoing. Recently, the possibility of using less immunogenic and more specific MSC by-products (i.e. microvesicles and exosomes) to overcome MSC transplantation criticisms and side effects is currently under consideration.