Encephalomyelitis

Appendix

The NLRP3 Inflammasome as a Target for Antiinflammatory Drugs

The Nod-like receptor protein 3 (NLRP3) inflammasome plays a vital role in the nonspecific immune response to inflammatory triggers such as cellular infections, injury, or stressors, and it has also been associated with several inflammation-related diseases. NLRP3 inflammasome activation results in the production of proinflammatory cytokines, contributing to an increased risk of inflammatory conditions, such as cardiovascular, metabolic, infectious, and neurodegenerative diseases. Several signaling pathways and cellular events involved in the NLRP3 inflammasome assembly and activation have been studied, and inhibitory mechanisms have been identified. NLRP3 inflammasome inhibition decreases inflammation and inflammasome-mediated cell death. In prospecting for novel anti-inflammatory therapeutics, signaling molecules upstream or downstream on the NLRP3 inflammasome pathway can serve as viable drug targets. Effective inhibition of these molecules culminates in the downregulation of the expression of proinflammatory cytokines like interleukin-1beta (IL-1β) and IL-18. This chapter elucidates the various classes of NLRP3 inflammasome inhibitors, their resultant anti-inflammatory effects, and various mechanisms of action.

Modulatory Mechanism of NLRP3 Inflammasome in Heart Diseases: “An Enigma Wrapped in a Riddle”

Despite breakthroughs in therapy over the prior two decades, heart failure is considered the foremost cause of mortality globally. The inflammasome plays a pivotal role in the advancement of heart failure, abdominal aortic aneurysm, atherosclerosis, diabetic cardiomyopathy, hypertension, dilated cardiomyopathy, cardiac remodeling and calcific aortic valve disease. The NLRP3 inflammasome is a crucial multi-protein signaling platform that tightly regulates inflammatory responses. It regulates antimicrobial host defense, which causes pyroptosis through caspase-1 activation by the eventual production of pro-inflammatory cytokines. The investigation of the NLRP3 inflammasome in various cardiovascular diseases may reveal critical disease triggers and endogenous modulators, leading to the development of new therapeutic interventions in the future. The target of this chapter is to summarise the recent literature describing the activation mechanism of the NLRP3 inflammasome by implicating different inflammatory pathways in the pathophysiology of heart failure.

Immunomodulating Botanicals: An Overview of the Bioactive Phytochemicals for the Management of Autoimmune Disorders

Immunomodulation refers to the mechanism by which the response of the immune system is modified by the regulation of antibody synthesis, leading to either an increase or a decrease in its levels in the circulation and body organs. Owing to their immunomodulation and remedial benefits, a broad range of herbal remedies have been shown to be effective in the treatment of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, myasthenia gravis, and systemic lupus erythematosus. The ancient Indian system of Ayurveda and different other alternative therapeutic methods have acknowledged the potential benefits of herbal-based remedies to upregulate or suppress the immune response in the human body. The conventional pharmacotherapies used for the management of autoimmune ailments are documented to cause serious drug-induced adverse reactions (ADRs). Whereas, some phytotherapies have proven safe, reliable, and efficient alternatives for the existing drug regimens with lesser ADRs. For instance, Withania somnifera, Andrographis paniculate, Tinospora cordifolia, Glycyrrhiza glabra, and Berberis arista are a few herbs whose bioactive phytoconstituents have been reported to possess powerful immunomodulation properties. Based on their purported immunomodulatory mechanisms, they can be used for the management of autoimmune conditions. The focus of this review is to highlight the key inflammatory biomarkers such as TNF-α and interleukin 1, 6 involved in the distortion of the immune system in humans. Also, we will discuss the usefulness of animal models for understanding the underlying mechanisms of autoimmune disorders. In addition, we will describe the patents of phytomedicine formulations filed by different manufacturers for the management of autoimmune disorders, as well as futuristic opportunities that should be explored for discovering the therapeutic functions of alternate remedies for treating autoimmune diseases.

Antimicrobial Peptides from Marine Invertebrates

This chapter centers on the novel marine metabolites from marine organisms, especially peptides and other therapeutic agents. The major component of the innate immune defense system, also regarded as the first line of defense, is the antimicrobial peptide, which not only boosts resistance but also displays promising curative properties. The isolation, potential antimicrobial activity, various properties, mechanism and sources of diversified antimicrobial peptides distributed in various phyla of marine invertebrates, along with their potential role in the therapeutic arena, are explored. The most popular conotoxin peptide Zincnotide was available as a drug (Prialt®) and entered the market as a potent analgesic agent. Ethionamide (Trecator®), a nicotinamide derivative, isolated from porifera possessing antibacterial activity, is used to treat tuberculosis. Similarly, a number of peptides have been reported for exhibiting antimicrobial activities in marine organisms. Hence, the present chapter is mainly focusing on the list of marine invertebrates’ antimicrobial peptides and their therapeutic applications.

Plant Cardenolides: Multifunctional Medicinal Agents

Cardenolides are a class of compounds steroidal in nature, belonging to the cardiac glycoside group of secondary metabolites. They consist of a sugar part and a non-sugar part consisting of a steroidal cyclopentanoperhydrophenanthrene ring with lactone substitution at the β-17 position. Cardenolides are found in angiosperm plant families like Plantiginaceae, Asclepiadaceae, Apocynaceae, Brassicaceae, Cruciferae, Liliaceae, Moraceae, Ranunculaceae, and Scrophulariaceae. These include some important glycosides, such as digitoxin, digoxin, Ouabain, Calotropin, etc. with profound pharmacological potential. Moreover, cardenolides have toxic effects for which these have been used in poison arrows and for self-harm purposes. Traditionally, these were used to treat congestive heart failure. However, recently they have emerged as promising agents to exhibit anticancer, antiviral, anti-inflammatory, neuroprotective, and various other therapeutic roles. Cardenolides like Digoxin and Digitoxin have been used in the treatment of heart failure and atrial fibrillation. Toxicarioside A, and Calotropin have been reported to suppress tumor growth and are used as anticancer agents, Strophalloside and Oubain are reported to be involved in apoptosis. Oleandrin is an antiproliferative agent and can inhibit IL-8 which is responsible for cystic fibrosis.

Biological Significance of Steroids

Steroids display varied biological functions and play a crucial role in the fascinating fields of biology, chemistry, and medicine.Steroids encompass wideranging natural products which are abundantly encountered in eukaryotic organisms. These exhibit a pivotal role in regulating the cellular functions of animals, plants, and fungi. Furthermore, they act as chemical messengers in the human body and get secreted in the systemic circulation and extracellular fluids, where they regulate metabolic, immune, and reproductive functions. Steroids are the fundamental components of cell membranes and serve primarily as signalling molecules. This chapter gives a comprehensive overview of physiologically active steroids in various organisms.The biological activities of various steroid classes have been discussed in detail. Glucocorticoids are a class of steroid hormones that regulate the metabolic processes involving the formation of glucose from amino acids and fatty acid deposition of glycogen in the liver. Another important group of hormones, called mineralocorticoids, helps in balancing water and electrolyte content in the body and primarily affects the kidney. The principal class of steroids viz. the sex hormones are essentially crucial for the development and maintenance of reproductive function and cause stimulation of secondary sexual characteristics in humans. To summarize, steroids stabilize and regulate the structure and functions of cellular membranes and play a crucial role in regulating growth and development.

COVID-19 Pandemic: Outbreak, Epidemiology and Immunology

The SARS-CoV-2 virus-led COVID-19 pandemic jolted the whole world at different levels. Severe acute respiratory syndrome (SARS) caused death in severe cases leading to millions of mortalities. This chapter attempts to present an overview of the whole fiasco created by the spread of the virus along with the historical background, structural features and important proteins of the virus, modes of infection and transmission and different diagnostic means like viral and antibody tests. The authors have presented the latest statistical data on the number of cases and mortalities reported across the globe and also elaborated on the probable remedial interventions like the different antiviral, antimalarial drugs which are being explored for treatment and also explored the utility and applications of drug repurposing and computational strategies for drug development. The authors have also elaborated on the different vaccines developed to curb the disease and explained the development of COVID-19 vaccines for children. Overall the chapter has summarized key facts associated with COVID-19 in a nutshell and it may prove beneficial to the readers to understand the disease more clearly

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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.

Malaria

The World Health Organization (WHO) defines cerebral malaria (CM) as an otherwise unexplained coma in a patient with asexual forms of malaria parasites on the peripheral blood smear. Malaria is a severe, devastating illness characterised by respiratory distress, severe anemia, and cerebral malaria (CM). Altered consciousness, convulsions, ataxia, hemiparesis, and other neurologic and psychiatric impairments are noted in cerebral malaria. Thus, cerebral malaria is defined as a condition in which a human has Plasmodium falciparum, a parasite in peripheral blood, followed by neurological complications of any degree. CM accounts for 300,000 deaths per year, and almost any survivors there display severe neurological manifestations. Coma is the outcome of CM, which is again due to brain hypoxia due to inflammation, edema, Brain swelling, and vascular blockage, are all due to the sequestration of pRBCs in brain microvasculature [1, 2]. In Ugandan children with CM infected with P.falciparum, severe cognitive impairment, behaviour problems such as hyperactivity, inattentiveness, aggressive behaviour, loss of speech, hearing loss, blindness, and epilepsy were noted (Irdo et al. , 2010). Heme offered protective responses to ECM, by dampening the activation of microglia, astrocytes, and expression of IP10, TNFa, and IFNg [3].

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.

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Advent of Pharmabiotics as a Promising Therapeutic Tool for Human Health and Diseases Management

With the recent advances in understanding the role of the gut microbiome and human health, it has become evident that pharmabiotics have huge potential in the therapeutics as well as supplement industries for conditions leading to impaired microbiota. Pharmabiotics can be referred to as a class of microbial therapeutic probiotics which could be live bacterial cells of human origin or their products with clinically proven pharmacological activities found to be beneficial in human disease conditions. So, the mechanism by which bacteria produce synergistic beneficial effects on health could help us to develop a scheme to understand the delicate relationship between the gut microbiome and human health. In this chapter, we will emphasize the role of gut microbiota, the pharmabiotics they produce and how it affects different physiological and metabolic and host-microbe interactions leading to the production of bioactive chemicals with health benefits, eventually leading to the establishment of a healthy immune system. The chapter will also discuss the repercussions of disturbed gut microbiota on overall human health, including host psychiatric health. The fact that pharmabiotics acting as antimicrobial agents will produce no resistant variety is also an added bonus that increases the scope for discovery of such novel therapeutic agents.

Nanomedicine Technology Trends in Pharmacology

Nanotechnology deals with materials that are 1–100 nm in size. Nanomaterials are prepared in different ways such as physical, chemical, and biological methods. They exhibit fascinating features that allow them to perform numerous physiological tasks. They have higher surface area to volume ratios and show typical nanoscale quantum confinement characteristics. They play a critical role in biomedical research. They're quite versatile and used in a variety of medical applications. The demand for nanomedicine drugs with improved performance and reduced toxicity has been steadily increasing in recent years. Nanomedicine is the new area of nanoscience and nanotechnology. Pharmaceutical nanosystems are classified, synthesized, and characterized using procedures based on their size, shape, and functionality. This book chapter focuses on recent trends of nanomedicine technology in pharmacology, particularly on the application of nanomaterials in medicine. Antibacterial characteristics, multicolor medical imaging, disease diagnostics, medication administration, vaccines and biomolecules (peptides, proteins, and genes), therapies, cancer treatment, tissue engineering, and clinical aspects are discussed. Advancements in nanomedicine technology will not only aid in the early diagnosis of infectious and viral disorders, but also in the treatment of infections such as Alzheimer's disease, tuberculosis, and Parkinson's disease. The benefits and constraints of commercializing nanomedicine technology products for pharmacology applications, as well as the hazards and obstacles in developing nanomaterials for medical research are highlighted in this chapter.

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Nanocarriers For Drug Targeting

Drug targeting specific cells/tissues of the body without their becoming a part of the systemic circulation is a prominent area of research in drug delivery, with the main emphasis on improvement in formulation and development. Drug-targeting can improve the viability, lower/minimize the adverse/side effects, and can become cost-effective. Certain limitations like short circulating half-life, bioavailability issues, rapid metabolism and degradation, poor tissue distribution and penetration in the blood-brain barrier, intestinal absorption barriers, etc., are associated with the delivery of various therapeutic agents. Nanocarriers have arisen in the field of drug targeting with valuable delivery of drugs to site-specific/desired areas which is a significant therapeutic advantage since it keeps drugs from being conveyed to some unacceptable spots. Nanocarriers prevent the obstacles in clinical utilization of the therapeutic agents as they decrease the serious and critical side/adverse effects by targeted drug delivery and provide slow and sustained drug release. Nanocarriers bring new trust to drug targeting by upgrading the efficacy, defeating resistance, and minimizing toxicity. This chapter mainly focuses on the role and benefits of nanocarriers in drug-targeting and nanocarriers as prominent systems for targeting and delivering drugs to achieve maximum effects with improved therapeutic response.

An Overview on Nanoparticulate Drug Delivery System for its Specific and Targeted Effects in Various Diseases

In modern-day medicine, nanoparticles and nanocarriers are rapidly evolving fields in therapeutics and are the building blocks of nanomedicine, which emphasize the use of nanoscale particles that have a wide array of functions from working as a diagnostic tool to the screening, monitoring, and controlling of various diseases to the delivery of drugs at specific targets in a controlled manner. With the advancement in technologies, it is proven that nanoparticles have a greater potential in wide biomedical applications. Due to their ability to bind with both hydrophobic and lyophilic substances, lower particle size, higher carrier capacity, nanoparticles serve as a favorable platform for specific and targeted drug delivery in disease treatment. Nanoformulations can improve the safety, pharmacokinetic characteristics, and bioavailability of administered drugs, and can improve the therapeutic effect when compared with conventional therapies. Besides, nanoparticles may also be effective in delivering nucleotides, vaccines, and recombinant proteins. Several varieties of nanoparticles are available: different metal and polymeric nanoparticles like gold/silver nanoparticles and micelles, dendrimers. Carbon-derived nanoparticles like quantum dots, carbon tubes, and many other nano assemblies. Numerous nanocarriers, nanoparticle-based drug delivery systems, and drug targeting systems are either developed or under development. In this chapter, we will emphasize mainly the specific and targeted nanoparticles and the use of various nanocarriers for the targeted delivery of drugs in various diseases. The opportunities and challenges of using nanoparticles/nanocarriers in targeted delivery along with its clinical applications are also discussed here.

Immunomodulatory Potential of Bioactives from Selected Ayurvedic Plants

The history of usage of herbal medicine is as old as human civilization. Plant-based drugs have been an invaluable and incredible source for several medical treatments in the traditional system of medicine. With technological advances, it has become possible to get a clear understanding of active compounds behind the therapeutic effectiveness of these drugs. Plant-derived immunomodulators are one such class of compounds, considered safe alternatives than synthetic immunomodulators which cause serious side effects. These agents can increase the body’s immune responsiveness against pathogens by activating both the innate and adaptive immune systems. Phyto drugs have gained more interest due to their multi-pharmacological potential of being antioxidant, adaptogen, etc. along with immunomodulator. The current book chapter focuses on a few extensively scrutinized immunomodulatory phytocompounds from medicinal plants such as Tinospora cordifolia, Andrographis paniculata, Curcuma longa, Zingiber officinale, Allium sativum, Terminalia chebula, and Piper longum. Phytomedicines from these plants have displayed significant immunomodulatory potential in a variety of experimental (in vitro and in vivo) models, few compounds have exhibited good therapeutic potential in clinical trials also.

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.

Immune-Endocrine Perspectives of Breast Cancer

Cancer is the consequence of the recalcitrant multiplication of the transformed cells. Cancer cells grow and proliferate at a fast pace and do not follow normal regulation of cell division. Breast cancer is a heterogeneous group of diseases, which is the second leading cause of death among women. Although androgen is primarily considered a male steroid hormone, it also has an important role in the female reproductive system. The literature evidence suggests the role of androgen receptors (AR) in the normal development of the breast. At puberty, the expression of AR is even more than ER, suggesting its importance during the process of sexual development; its activity maintains the ER-induced cell proliferation and normal development of the breast. Epidemiological studies have suggested a positive correlation between high endogenous androgens and the risk of breast cancer in both pre- and postmenopausal women. In both ER and PR-positive breast cancers, AR is expressed in 60-70% of the cases. AR is also reported to be co-expressed with ER in around 80-90% of breast cancer cases and is considered an independent prognostic factor of ER-positive breast cancers. Tumor-microenvironment has a complex role in tumor initiation, progression, and metastasis. Tumor-infiltrating and resident cells secretes a variety of inflammatory and anti-inflammatory cytokines, which in turn either inhibit or promote tumor growth. Immunosuppressive and immuno-inductive effects of androgen have been reported in various studies. Androgens have been reported to influence the adaptive immune system more than the innate immune system in many ways. Crosstalk of androgen and cytokine signaling has many effects in breast cancer epidemiology. So, in this chapter, we will discuss the various immune-endocrine perspectives of breast cancers.

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Updates on Pediatric Demyelinating Disorders

Myelin is a protective layer that enwraps the axonal terminals and is an essential component of the central nervous system white matter. Loss of myelin leads to conduction block in the axon leading to demyelinating disorders. Inherited poor formation of myelin is known as hypomyelination, and abnormally formed myelin is called dysmyelination. Demyelinating disorders exclude diseases where degeneration of the axon is the initial event and myelin is degraded secondarily. Most neurologists use the term demyelination only for acquired forms of loss of myelin with relative preservations of axons due to inflammation such as multiple sclerosis. Demyelinating disease in children may be monophasic (e.g., acute disseminated encephalomyelitis, optic neuritis, and transverse myelitis) or chronic (multiple sclerosis and neuromyelitis optica). Pediatric multiple sclerosis is the most common demyelinating disorder in children. Recent genetic and clinical researches have significantly improved our understanding of the diverse spectrum of pediatric demyelinating disorders. In this chapter, an updated summary of the current knowledge on the categories, diagnosis, as well as management of pediatric demyelinating disorders has been presented.

Neurodegenerative Disease: Prevention and Treatment Through Plant Extracts Therapy

Neurodegenerative diseases such as Parkinson's, Alzheimer’s, Huntington’s

etc. have their root in damaged nerve cells followed by the loss of their functions.

Though the exact reason for different neurodegenerative diseases is still unknown,

degradation and accumulation of proteins in neurons, oxidative stress, inflammation,

defects in mitochondria, genetic mutation etc., are said to be the general factors that

leads to this disease. The old ages are the worst affected group due to the rise in human

life expectancies. Although there is no complete cure for this disease, some drug

treatments have been found to be useful for reducing few of the physical or mental

symptoms associated with neurodegenerative diseases. In fact, most neurodegenerative

disorders show multiple symptoms;a promising result can be achieved only through the

combination of different compounds like natural plant extracts which have many

disease targets. Antioxidants are proven to have the capacity to act against the

oxidative stress developed in the cells. So, antioxidant rich plant extracts can be

utilized for the treatment of neurological related disorders. Several studies are being

carried out on the effect of various plant extracts on the neurodegenerative disease

prevention, management as well as treatment. This chapter will discuss the in vitro, in

vivo and clinical studies conducted on the effect of various plant extracts for the

treatment and prevention of different neurodegenerative disease conditions.

Experimental and Clinical Studies on the Effects of Nigella Sativa and its Constituents on Allergic and Immunological Disorders

Various pharmacological effects were shown for Nigella sativa (N. sativa),

including anti-inflammatory, antioxidant, and immunomodulatory properties. The plant

also has been used in traditional medicine for the treatment of various diseases. In this

chapter, the effects of N. sativa and its constituents in allergic and immunologic

disorders based on the experimental and clinical studies are provided. Articles

published on the effect of N. sativa and its constituents on allergic and immunologic

disorders in the experimental and clinical studies were searched until July 2020. For

this purpose, keywords including; Nigella sativa, black seed, thymoquinone, alphahederin,

carvacrol, allergic disorders, and immunology disorders were searched in

different databases such as PubMed, Science Direct, Scopus, and Google Scholar.

Experimental studies showed various immunologic effects of N. sativa extracts and

their constituents, including their effects on Th1/Th2/ balance. Treating patients with

N. sativa seed, alleviate symptoms of allergic rhinitis and decrease the body

temperature in allergic patients which is due to immunomodulatory properties of the

plant. Treatment of Vitiligo patients with N. sativa also reduced the Vitiligo Area

Scoring Index (VASI). Various studies showed that N. sativa and its constituents

showed significant effects on allergic and immunologic disorders. Therefore, N. sativa

and its constituents could be good candidate drugs for treating allergic and

immunologic disorders.

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Infections Caused by SARS: Main Characteristics, Targets and Inhibitors

SARS-coronavirus (SARS-CoV) originated in China from 2002 to 2003 and caused a global outbreak with 8098 cases and 774 confirmed deaths. More than 15 years later, in less than a year, the new coronavirus (2019-nCoV) has infected more than 44 million people and killed more than 1 million. The COVID-19 pandemic has brought serious consequences for several countries and a worldwide alert about coronaviruses. Severe acute respiratory syndrome (SARS) is an emerging infectious viral disease characterized by severe clinical manifestations of the lower respiratory tract that lead to severe lung damage and the spread of the virus to several other organs. Phylogenetic analyzes demonstrate that SARS-CoV-2 shares a 79% identity with SARS-CoV, and just as there was no effective treatment against SARS-CoV, it does not yet exist against SARS-CoV-2. However, researchers from all over the world are dedicating themselves to several studies in an attempt to find the best treatment and prevention against the coronavirus. Thus, this book chapter addresses the main characteristics of SARS, the main targets and drugs that have achieved excellent results in clinical trials.

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Propolis and its Key Chemical Constituents: A Promising Natural Product in Therapeutic Applications

Propolis is a natural resinous and waxy product obtained from honey bee

combs. Although propolis has been now explored globally for its wide range of

chemical constituents and its therapeutic value, the detailed investigation of

pharmacological activities of its key chemical constituents and its analogues is in its

infancy. In this study, a detailed review of the therapeutic potential of propolis and its

isolated key chemical constituents was carried out to provide basic literature data

required for further detailed investigation and discover new therapeutic potential

molecules from propolis. Till now, more than 300 isolated chemical compounds are

reported from worldwide propolis samples that include the presence of various

polyphenols, flavonoids, esters, beta-steroids, aromatic aldehydes, alcohols, etc. Some

specific chemical constituents of propolis, such as pinocembrin, are reported for its

potential neuroprotective action with reduced neurodegeneration in the cerebral cortex

and enhanced cognitive function in Aβ25-35-treated mice. Galangin is also well proven

for acetylcholinesterase enzyme inhibition and AβPP-Selective BACE inhibitor

(ASBI), which may be developed as a new therapeutic agent for Alzheimer's disease.

Caffeic acid phenethyl ester is reported as a moiety isolated from European propolis; it

is present even in the form of a mixture of caffeic acid esters and phenethyl ester for

antibacterial and antifungal properties. In vitro and in vivo evidence suggested that

caffeic acid phenethyl ester has cytotoxic mechanisms, including the activation of

p21protein, p38 MAPK, p53, and JNK kinase activity, inhibition of NF-B, and

increased caspase-3 or 7 activity. Various pharmacological activities are reported for

different propolis extracts, as well as for its constituents that include antioxidant, antiulcer,

anti-cancer, antiviral, anti-microbial, anti-inflammatory, anti-fungal, etc. Propolis

possesses tremendous therapeutic potential, and it is also reported worldwide in various

traditional systems of medicine. In this study, the key chemical constituents,
pharmacological activities, various critical issues in its application in drug delivery, and

detailed investigation on approaches for formulation development to enhance

biopharmaceutical aspects of propolis have been reviewed.

Development of Recombinant Therapeutic Proteins in Animal Cells: Challenges and Solutions

Recombinant therapeutic proteins, also referred to as biotherapeutics or

biologics, are widely used for the treatment of numerous diseases such as cancer,

diabetes and other non-communicable diseases. In addition, they also provide a

solution to several chronic and emerging viral diseases.

Most biologics are produced in animal host cells as they provide relevant protein

features, such as folding and post-translational modifications, similar to those produced

by humans.

However, these products usually face great challenges mainly related to high

manufacturing costs that may limit their use. To circumvent these issues, numerous

strategies have been proposed. While some approaches focus on improving protein

yield by introducing regulatory elements into the gene sequence, others specifically

aim to optimize cell protein expression performance through cell engineering. Here, we

will review the state of the art in the field of protein expression, focusing on the most

promising strategies to improve protein yield in animal cells.
Product safety constitutes another concern that may restrict the use of biotherapeutics.

Indeed, the development of unwanted immune responses against these drugs has been

extensively reported. These immunogenicity events are triggered as a consequence of a

breakdown in immune tolerance to the product. When a given biologic is administered

to a patient, it encounters a variety of innate and adaptive immune cells that ultimately

may orchestrate pro-inflammatory responses. Consequently, different scenarios may

take place ranging from the development of anti-drug neutralizing antibodies to tissue

damage. Hence, product immunogenicity is the main concern and should be closely

monitored during product manufacturing and also in the clinic. In this respect,

numerous in vitro and in vivo strategies are currently available, and more are still in

development. These experimental platforms include the use of specific human immune

cells, transgenic animals and even lymphatic micro-organoids. In this chapter, we will

comprehensively describe these experimental strategies and their use in pre-clinical

studies and clinical trials.

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Recent Updates in the Animal Models of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory, autoimmune disease characterized by neuronal demyelination of the Central Nervous System (CNS). It affects more than 2 million people worldwide. Animal models are of great importance in elucidating immune-pathological mechanisms of MS. The three most commonly studied categories of MS animal models are (1) the Experimental Autoimmune Encephalomyelitis (EAE); (2) chronic demyelinating disease models through virus inoculation known as Theiler's Murine Encephalomyelitis Virus (TMEV) infection and (3) toxin-induced models of demyelination, comprising the focal toxin-induced demyelination by lysolecithin (lysophosphatidylcholine), ethidium bromide, antigalactocerebroside (GaIC) antibody) and systemic toxin-induced demyelination by cuprizone. EAE is a widely accepted animal model that reflects the pathological mechanisms of MS, making it highly useful to analyze new therapeutic approaches. However, TMEV infection and toxin-induced models are most suitable for studying the role of de and remyelination processes and axonal injury or repair in MS. Furthermore, Zebrafish models have also emerged in recent years as novel animal models for MS because of their swift development and controllable genetic manipulations. In a nutshell, despite their limitations, animal models remain the most useful research tools to answer specific research questions related to pathological mechanisms and to validate potential experimental therapies for MS.

Black Cumin Seeds: From Ancient Medicine to Current Clinical Trials

Black cumin seeds are the seeds from Nigella sativa (Ranunculaceae), an annual flowering plant native to southwest Asia. Traditionally, the seeds or the oil from them have been used for a range of health problems, particularly diabetes, digestive diseases, arthritis, and asthma, as well as a food additive and spice. Laboratory studies have shown that the seeds of N. sativa have anti-diabetic, anti-hyperlipidemic, anticonvulsant, anti-microbial, anti-hypertensive, anti-asthmatic and anti-cancer activities. It has also been proven to possess analgesic and wound healing properties. These seeds are also of clinical interest, especially for metabolic disorders, as they have the ability to reduce fat body contents and have beneficial effects on hypertension and diabetes. In addition, many clinical trials are ongoing to investigate the effects of black cumin seeds for the treatment of infertility, cancer, asthma, non-alcoholic fatty liver disease (NAFLD), and arthritis rheumatoid. The mode of action of black cumin seeds is mostly mediated via anti-oxidant, immunomodulatory, cytoprotective and antiinflammatory mechanisms. The most important bioactive constituents of black cumin seeds are essential oils, including thymoquinone and alkaloids, including pyrazole alkaloids such as nigellidine and nigellicine, and isoquinoline alkaloids such as nigellimine-N-oxide. The aim of the current chapter is to review the chemical, botanical, and pharmacological studies as well as the clinical potential of black cumin seeds.

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.

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.

Pharmacotherapy of Multiple Sclerosis and Treatment Strategies

Multiple sclerosis (MS) is a well-known chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). It is considered the most common autoimmune demyelinating disease of the CNS. It affects mainly young adult females between 20-40 years of age. MS was previously considered a Tlymphocyte- disease, but now B lymphocytes appeared to have a critical role in MS's pathogenesis. Affected patients showed lower quality of life with an increased death rate than the general population. The treatment of MS is challenging, and many drugs have evolved primarily for the last 20-30 years. Since the introduction of interferons in 1993, there are more than sixteen disease-modifying therapies (DMTs) approved. These drugs have different pharmacologic forms like injections, oral forms, and intravenous infusion drugs. Each one has its benefits and drawbacks. Moreover, like any other patient, MS patient has other symptoms that are not covered by DMT and need symptomatic treatment. In this chapter, we attempt to present medications used to treat acute relapse, different DMTs, symptomatic treatment for different MS symptoms. Besides, we give attention to drugs under clinical trials.

The Beneficial Effects of Turmeric and its Active Constituent in Cancer Treatment: Current and Future Trends

‘Turmeric’ (Curcuma longa L.) is an important spice found almost in every culinary preparation of Asian cooking, especially in India. This yellow rhizome is known for its medicinal and nutritional properties for many centuries and hence in Chinese and Indian traditional medicine it has been used for treating internal diseases and common ailments. It has various pharmacological properties including anticancer activity, which is mainly centered on its orange colored curcuminoid polyphenol called “curcumin”. Cancer is a deadly multifactorial disease originating from cells affecting many parts of the body in later stages. New cancer drugs and treatment methods become an everyday search due to the genetic complexity of the disease. Nowadays, natural products like turmeric are gaining importance as cancer therapeutics since their dietary intake reduces the cancer risk. In this chapter, the background, importance and pharmacological activities of turmeric and its chemical constituent curcumin were discussed with reference to the recent anticancer studies. Numerous reports are available on the anticancer potential of turmeric and curcumin. As reflected from these study results, curcumin was observed to inhibit the proliferation of cells, invasion, angiogenesis and metastasis in tumor cells. It increases the accumulation of free radicals through the reactive oxygen species resulting in apoptosis. It also sensitizes cancer cells for other cancer therapies. Due to its antioxidant and pharmacological activities, it can even reverse the cancer progression in the early stages. In contrast, the poor absorption limits its clinical use but the conversion into nanoforms improves its solubility. Curcumin is nongenotoxic and nonmutagenic and hence it is approved as a safe substance in various clinical trials.

Nigella Sativa (Prophetic Medicine): The Miracle Herb

Nigella sativa Linn. belongs to the family Ranunculaceae and is recognized as a prophetic medicine because of its mention in Prophetic Hadith, as a natural remedy for all diseases except death. It is known as Habat-ul-Barakah/Habat-ul-Sauda in Arabian countries and as Kalonji in India. As per Tibb-e-Nabwi (Prophetic Medicine), its daily consumption has been highly suggested. Considering its potential, ancient herbalists have termed it as ‘the Herb from Heaven.’ Ibni Sina, famous as Avicenna in the West, also referred to N. sativa as the seed “that stimulates the body’s energy and helps recovery from fatigue” in his great book “The Canon of Medicine.” Seeds and oil of N. sativa have a long history of folklore usage in various systems of medicines and food like Unani and Tibb, Ayurveda and Siddha. Numerous studies support that the seed of N. sativa and specifically its main active constituent, thymoquinone, has significant potential and possesses a broad range of biological activities like antihypertensive, diuretics, digestive, hepatoprotective, anti-cancer, appetite stimulant, anti-diarrheal, nephroprotective, neuroprotective, analgesics, anti-bacterial, and in treating skin disorders. In this chapter, we intend to present a comprehensive review of traditional and ethnomedicinal uses of Nigella seeds in different systems of traditional medicines. Then, the present chapter is directed towards highlighting the beneficial contribution of researchers to explore the pharmacological actions with the therapeutic potential of this miraculous herb and its bioactive compounds in modern medicine as in vitro, in vivo, and clinical studies to reveal its potential for the treatment of various diseases.

Postbiotics: A Solution to Leave Problems of the Production and Consumption of Probiotics

The process of producing and distributing probiotics in the matrices of a wide variety of foods in the form of living cells has often been associate with difficulties. Several investigations have been doing to develop or optimize various approaches to maintain the viability of probiotic microbes. On the other hand, in recent years (mainly since 2010), a great deal of attention has been paid to using non-viable forms (postbiotics) bacteria as substitutes for probiotics. The term “postbiotic” refers to modified inactivated microbial cells, cell fractions, or cell metabolites that are naturally or synthetically generated by live probiotic cells and exert biological health-promoting effects to the host when administered in sufficient amounts. This chapter provides an overview of key concepts and main constituents of postbiotics, with emphasis on their biological activities.

History of Pandemics

Pandemic is the term coined for the widespread of a disease or infection on a very large scale and across borders. COVID-19, an outcome of the spread of coronavirus, reportedly started from China and spread to almost all the countries of the world. Though it is not for the first time that there was an outbreak of a disease at such a high magnitude but the duration for which it has continued to grapple the world with its virulence and contagious nature, it has become important to take a peek into the history of other pandemics of the world too. Before COVID -19, about 20 major outbreaks of infectious diseases took place and claimed millions of lives in a sweep. The awareness of government bodies, WHO, and non-government organizations grew better with every pandemic. Understanding the role of basic hygiene, self-immunity, social distancing, living in coherence with other living and non-living components of the planet are some positive outcomes of these pandemics. These pandemics also necessitated the need for discovering new drugs and vaccines.

This chapter describes the major pandemics in the history of mankind, the origin and types of coronaviruses, the association of different types of coronaviruses with the ranges and severity of infections, and the origin of COVID-19.

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Scale-up, Preclinical and Clinical Status of Poly (Lactide-Co-Glycolide) and its Copolymers based Drug Delivery Systems

Poly(lactide-co-glycolide) or PLGA is a kind of a synthetic polymer that has been approved by USFDA for its use in humans. PLGA nano/microparticles have proved to offer controlled as well as the sustained release of several medicinal moieties. PLGA is chemically synthesized by direct polycondensation of glycolic acid (GA) with lactic acid (LA) and different factors like LA: GA ratio, storage temperature, the initial molecular weight of the monomers, and exposure time to water influences the physical properties of PLGA. Similarly, various factors like morphology, crystallinity, molecular weight, shape, size molecular, hydrophobicity, chemical structure, physicochemical properties, glass transition temperature are some of the crucial factors responsible for the biodegradation of PLGA. PLGA based micro/nanoparticles are generally prepared by the oil-in-water emulsification process. On the other hand, spray drying is one of the industrial methods for the production of PLGA particles. In this chapter, we have summarized the extensive applications, laboratory, and industrial-scale methods for the production of PLGA nano/microparticles, preclinical, and clinical status PLGA based drug delivery systems.

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.

Current Status and Future Outlook of Deep Learning Techniques For Nodule Detection

This chapter reports that Artificial Intelligence (AI) in clinical oncology includes deep learning for detecting the lung nodules and other algorithms for analyzing the nodules to acquire an early diagnosis of nodules and tumors. Therefore, the early diagnosis is of great significance in the treatment of lung cancer or precancerous disease. Also, the early detection of nodules can improve the treatment effects and reduce the chance of misdiagnosis.

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.

Cloud/edge Computing and Big Data System with 6G

This chapter gives a systematic introduction to cloud/edge computing and big data system. Cloud computing provides the ability to use flexible and telescopic services for cloud users and could implement through various hosted services provided by the Internet. Edge computing refers to the open platform which uses the network, computing, storage, and application core capabilities on the side of the object or data source and provides the nearest end service to avoid the relatively long delay to reach the data cloud center. Big data technology refers to the analysis of potentially useful information from a large number of data. Analysis of big data can get hidden patterns, unknown relevance, customer trends, and other messages to ensure comprehensive data management. In addition, the speed of 6G is faster, and its service field becomes more extensive compared with the previous generation communication technologies, which makes 6G play a more important or extensive role in the future of the technology field and society. In this regard, the authors also analyze the effect of 6G on cloud/edge computing and big data system. According to the future users' demand for 6G and the characteristics of 6G itself, cloud/edge computing and big data system will play an irreplaceable role in achieving high efficiency and benefits.

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.

Subject Index

Advances in Experimental Animal Models Provide Insights into Different Etiology and Mechanism of Multiple Sclerosis to Design Therapeutics

Myelin covering of axons in the central and peripheral nervous system helps in faster propagation of neuronal action potentials. Demyelination is a neurodegenerative process in which the axons lose their myelin coverings, exposing the axons to surroundings and leading to a reduction in neuron-to-neuron communication. Several demyelinating diseases exist in humans, and one of the most frequently occurring demyelinating disease of the CNS is multiple sclerosis (MS). Although more than 2.3 million people suffer from MS globally, the disease etiology is still unknown, impeding the development of effective therapeutics. The available treatments are based on disease-modifying therapy to reduce or moderate the symptoms and slow the disease progression; however, none can cure the disease. One key to better design therapeutics is to understand the cellular and molecular mechanisms of MS by developing reliable model systems. Human studies have their own limitations, such as limited access to patient tissues. Moreover, genetic variability makes it difficult to identify the triggers of MS. This calls for the development of reliable experimental animal models to understand MS pathogenesis better. There is no exclusive experimental model that covers the entire gamut of the disease. In this chapter, we will discuss experiment autoimmune encephalomyelitis (EAE), Theiler’s murine encephalomyelitis virus (TMEV), and mouse hepatitis virus (MHV)-induced models of demyelination that mimic specific histopathological and neurobiological aspects of multiple sclerosis. The present understanding of MS as an autoimmune disease mediated by self-reactive T-cells comes mainly from studies on the EAE model. Further, viral-induced demyelination models have provided valuable insights into a better understanding of MS. Studies in the TMEV model have demonstrated molecular mimicry and epitope spreading as major mechanisms of virus-induced neuroinflammation. Our knowledge of immune-mediated CNS damage has been further enhanced by studies on MHV-induced neuroinflammatory demyelination, suggesting macrophage-mediated myelin stripping in neurodegeneration. While the limitations of these models of MS are obvious, appropriate use of this model has led to the development of clinically useful drugs for the treatment of this devastating disease.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China, affecting millions of peoples worldwide, and was declared as a global health emergency by the World Health Organization (WHO). This infection is extremely transmittable from humans to humans due to its long incubation period (as compared to other viruses of the same category), which results in asymptomatic carriers. The complete knowledge regarding this virus is still unclear and various studies are being conducted worldwide. Till now, no vaccines or specific drugs are available for its prevention and treatment. However, various classes of drugs are repurposed for their treatment and many new drugs and vaccines are under development. This chapter provides brief information related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) along with its diagnosis, prevention, and treatment strategies.

Helminth Therapy: A New Tool for Treatment of Allergic Diseases

The reduced prevalence of allergic disorders in patients infected with helminths and in experimental animal models has prompted the concept of helminth therapy (HT). It was the successful outcome of cooperation between parasitologists, immunologists and epidemiologists, based on the host-parasite immune regulatory interactions. This new approach aims at helping allergic patients especially those with unmet medical needs such as treating severe steroid-resistant asthmatic patients. Although HT is successful in regulating the proinflammatory responses in the host, it may predispose to possible risk of side effects of live worm infections. Thus, it would be more practical to isolate and characterize specific helminth-derived products. Epidemiological and experimental studies of HT in allergic diseases were very promising. However, there are some considerations that should be taken in account for further clinical trials. This chapter highlights the interaction between helminth infection and allergic diseases, the current status of HT, its challenges and future perspectives.

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Fatty Acid Amides as a New Potential Therapeutic Agent in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) frequently starting in young adulthood. However, the pathogenesis of the progressive disease phase is still not well-understood, and the inflammation as well as the mechanisms of demyelination and tissue damage is currently being discussed. The available drugs approved in the treatment of different clinical forms of MS prevent the relapses, alleviate the symptoms only partially and slow progression of the disease; however, none of these treatments is capable in stopping the MS clinical course. Moreover, approved MS treatments lead to unpredictable adverse effects associated with a range from mild (such as flu-like symptoms, fatigue, liver transaminase elevation, stomach pain or irritation at an injection site) to serious (such as bradycardia or progressive multifocal leukoencephalopathy). It is time to revise the MS drug development strategy by relying on our endogenous defense mechanisms. Endogenous fatty acid amides (FAAs) are a family of structurally different molecules found in mammalian systems. These compounds include anandamide, oleoylethanolamide and palmitoylethanolamide; research preclinical and clinical reported anti-inflammatory and neuroprotective activity of FAAs making them an alternative therapeutic approach in neurological disorders. In consideration that an endogenous compound able in the control of endogenous defense mechanisms can assume extraordinary importance, this chapter includes a discussion on current approved drugs in MS, and on pharmacological properties of FAAs that may play a promising role in complementing of medication approved for use in MS.

Pathogens

Pathogens live inside other organisms called hosts, exploiting them and causing disease. Viruses and other mobile genetic elements such as transposons are pathogens that parasite on all life forms. They are obligate pathogens since they replicate only inside their hosts. Many bacterial pathogens are facultative since they can live outside their host. Viruses recognize host cells by specific molecules that serve as viral receptors. Only cells expressing them can be infected. Multicellular organisms host pathogenic bacteria and eukaryotic pathogens such as fungi, protozoa, and helminths in addition to viruses. Infection depends on pathogen’s ability to survive inside the host. Some pathogens quickly kill their host with large numbers of new pathogens released, whereas others establish long-lasting infection. Lytic viruses replicate and then lyse their host to get released. Other viruses do not lyse their host; instead, they establish chronic infection by replicating slowly and exiting the host cells by extrusion. Temperate viruses integrate into host DNA and stay silent for many cell divisions until the cell experiences stress. Then, the lytic program is activated, and the virus replicates and kills the cell. Similar to viruses, some intracellular bacterial pathogens are obligate and can only replicate inside their host. Pathogens differ in their host range; some can infect only a single species, while others are generalists. Hosts constantly evolve mechanisms preventing infection and destroying pathogens. In turn, pathogens evolve to overcome host defenses.

Molecular Targets of Angiogenesis and Future Potential of Anti-angiogensis Therapy in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory, gray and white matter demyelinating disease of the central nervous system characterized by axon degeneration, oligodendrocytes damage and astrogliosis. As per epidemiological data obtained from national multiple sclerosis society, 2.3 million people are suffering from MS worldwide. In America and Europe, it is a leading cause of mortality in young adults. The MS international federation reports showed that the prevalence of MS has been increased up to 33/10000 in 2013 from 30/10000 in 2008. Along with degerative processes, such as axon damage and myelin sheaths destruction, inflammatory components, such as lymphocytes and macrophages also play pivotal role in the pathogenesis of MS. There is an infiltration of immune cells, macrophages and microglia, increased expression of cytokines and chemokines. The structural and functional changes in Blood Brain Barrier occur very commonly in MS.

Angiogenesis is a process of development of new blood vessels from the existing blood vessels. It is commonly involved in various CNS disorders, such as stroke, epilepsy and tumors, indicating that it might have a role in the progression of MS lesions. The inflammatory components involved in pathogenesis of MS have been observed to play significant role to support angiogenesis. Inter cellular cell adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), vascular cell adhesion molecule (VCAM) -1, matrix metalloproteinase -1, -2, -3, -7 and 9 (MMP-1,-2,-3,-7,-9), TNF-α /-β, Interferon – γ (IFN– γ) and many other components are involved in angiogenesis processes of MS. Moreover, MMPs and VEGF play significant role in vascular basement membrane degradation and breakdown of BBB in MS. This indicates that there is a firm link between angiogenesis and chronic inflammation for neovascularization in the progression of MS. Since the inflammation and angiogenic processes are very complex and involve multiple biochemical processes, there are several molecular targets associated with angiogenesis for therapeutic intervention in MS.

Thus, the aim of the present chapter will be to show the link between angiogenesis and inflammatory processes in the progression of multiple sclerosis. Furthermore, the chapter is also focused on the role of molecular targets of angiogenesis process in MS along with their inhibitors or activators from various sources.

Pro-Apoptotic and Anti-Telomerase Activity of Naturally Occurring Compounds

A common hallmark of human cancers is the over expression of telomerase, a ribonucleoprotein complex that is responsible for maintaining the length and integrity of chromosome ends and often directly correlated with the uncontrolled growth of cancer cells. Telomerase activity is present in 85-90% of all cancers, but absent in normal cells, which makes telomerase a good marker for cancer diagnosis and prognosis. Also, telomerase inhibition can be used as a novel anticancer therapy with reduced probability of toxicity than present antimalignancy drugs. However, current treatments used for cancer such as radiation, anti-hormonal therapy, surgery and chemotherapy using synthetic drugs, have been reported to produce various side effects. Therefore, it is crucial to reveal the beneficial effects of natural compounds with lesser side effects on normal cells and potential anticancer activity. In recent years, several natural molecules have been discovered so far that arrest proliferation of cancer cells by inhibiting telomerase. In this book chapter, we highlighted the effect of natural compounds on cancer cell proliferation, telomerase activity and their mechanism of action.

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.

Subject Index

Ribavirin Against Viral, Neoplastic and Inflammatory Diseases: Focus on Mechanisms of Action

Discovered 45 years ago, ribavirin still proves useful as a broad-spectrum anti-viral drug against different RNA and DNA viruses. Although many cellular and molecular mechanisms of ribavirin action have been proposed during several decades of the extensive research, the complete spectrum of its actions is still not fully known. The direct mechanisms of ribavirin anti-viral action involve RNA polymerase inhibition and lethal mutagenesis. The main intracellular target of ribavirin action is inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in a de novo synthesis of guanine nucleotides. The inhibition of IMPDH activity leads to depletion of the guanine nucleotide pool and the consequent attenuation of GTPdependent cellular processes, inducing cell cycle arrest, and the interruption of DNA and RNA synthesis. Since these processes are essential for the normal as well as mitogenic functions of all cells, the inhibition of IMPDH probably represents the central mechanism of ribavirin action, including its cytotoxic effect. Recent data suggest that ribavirin may also be effective as an anti-cancer drug. By inhibiting the eukaryotic translation initiation factor e4E (eIF4E), ribavirin impedes eIF4E-mediated oncogenic transformation. Additionally, immunomodulatory and immunosuppressive actions of ribavirin have been shown in different in vivo and in vitro models of neuroinflammation. Accumulating evidence points to important cell type-specific differences in response to ribavirin that may arise from cell specific variations in ribavirin metabolism, as well as the functional status of targeted cells. This chapter reviews the antiviral, anticancer and anti-inflammatory activities of ribavirin and its metabolites, and discusses the possible mechanisms of action.

Endosomal Toll-like Receptors: Rheostats of Inflammation and Diseases

Toll-like receptors (TLRs) are major components of the innate immune system playing an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs).Till date, thirteen mammalian TLR members (TLR1-13) have been identified, ten in human and thirteen in mice. The human TLRs are further divided into two subgroups: six surface bound (TLR 1, 2, 4, 5, 6 and 10) and four within the intracellular endosomal compartment (TLR 3, 7, 8, and 9) of TLR-expressing cells. Extracellular TLRs identify structural components of pathogens like lipopolysaccharides, peptidoglycan, βglucan etc. Whereas endosomal TLRs are specific to pathogenic nucleic acids viz. double-stranded RNA (dsRNA), single-stranded RNA (ssRNA) CpG ODN etc. These sensors are expressed in a number of cell types including conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), macrophages, and B cells. Interaction with specific pathogenic antigens incites TLRs to trigger the transcription followed by synthesis of pro-inflammatory cytokines. Both the groups of TLRs have been particularly implicated in the pathogenesis of cancer, allergy and autoimmune disorders. However the present chapter is focused on endosomal TLRs and their crucial role in inflammation and related diseases. The initial part is focused on structural features of TLRs, specific ligands and thereafter intracellular signaling arbitrating the release of inflammatory mediators. In addition the role of endosomal TLRs in disease aggravation is also discussed. Moreover, the inhibition of activation or ability of modulation of these endosomal TLRs with specific ligands has also been illustrated as complementary therapeutic agents to combat various human ailments.

Uses in Spine Surgery

The use of autogenous bone marrow aspirate concentrate (BMAC) may offer a nonsurgical treatment of lumbar degenerative disc disease. It can also be used to enhance the cervical spine fusion. This chapter focuses on: the feasibility for using BMAC in spine surgery, host factors that may affect the outcome, the local morbidity of aspiration, and outcome after application of BMAC.

Agent-based Modelling of Tourists Destination Decision-Making Process

Agent-Based Models (ABM) are becoming more relevant in computational social science (CSS) due to the potential to model complex phenomena that emerge from individual-based interactions. Most tourism theoretical models recognize the complex nature of the tourism system, and complexity is a subject of growing interest among researchers. Geosimulation models (GM) are presented as potential tools to address tourism in a complex systems lens. Particularly ABM, has a GM tool, as captured growing interest by tourism researchers, however there is little empirical application as a tool to explore and predict tourism patterns. The purpose of the chapter is to frame ABM in GM following a complex systems theoretical approach, in order to increase knowledge by (i) considering the complex nature of tourism, (ii) providing tools to explore the interactions between system components, (iii) discussing the potential for coupling ABM and Geographical Information Systems (GIS) in tourism research, and (iv) giving insights on the functioning of the tourist behaviours and decision-making process through an ABM approach. Also a theoretical ABM is developed to improve knowledge on tourist decision-making in the selection of a destination to vacation. Tourists’ behaviour, such as individual motivation and social network influence in the vacation decision-making process are presented. On-going work on loose coupling of ABM and GIS is discussed.

Dental Radiographic Techniques

Dental radiographic techniques include intra- and extraoral techniques. Among the intraoral techniques, the most used are the bisector technique and the interproximal technique. These are the radiographic techniques that produce greater sharpness or details of the image of the dental structures, with the exception of CTBC. The extraoral radiographic technique most commonly used in the dental routine is the panoramic radiograph, since it encompasses the entire maxillo-mandibular complex, the teeth naturally, and neighboring structures.

A Survey on the Recent Results Regarding Maximum Principles for the Time-Fractional Diffusion Equations

In this chapter, a survey on the recent results regarding the maximum principles for the time-fractional diffusion equations is presented. We formulate the maximum principles for the time-fractional partial differential equations with both the Caputo fractional derivative and the Riemann-Liouville fractional derivative. Along with the single-term time-fractional differential equations, the multi-term equations and the equations of the distributed order are considered. We also discuss some important applications of the maximum principles for the time-fractional diffusion equations including a priori estimates for solutions of the initial-boundaryvalue problems for these equations and uniqueness of their solutions.

Einstein’s 1905 ‘Annus Mirabilis’: Unification of Statistical Mechanics, Maxwellian Electrodynamics and Classical Thermodynamics

To figure out in what way Einstein’s 1905 ‘annus mirabilis’ (wonder year) writings hang together one has to take into account Einstein’s strive for unity evinced in his vigorous efforts to unify maxwellian electrodynamics, statistical mechanics and classical thermodynamics. It is exposed that Einstein’s ingenious approach to special theory of relativity creation, substantially distinguishing him from Lorentz’s and Poincaré’s impacts, turns out to be a mere milestone of implementation of maxwellian electrodynamics, statistical mechanics and thermodynamics unification programme. Since the ether conception was a substantial snag for Einstein’s statistical thermodynamics design, the leading part in the programme was played by Einstein’s 1905 audacious light quanta hypothesis. Though apparently influenced in his critical stand against the classical physics research tradition by David Hume and Ernst Mach, Einstein hold an overall eclectic philosophical position. Yet when it related to creative momenta, Einstein’s actual 1905 standpoint was closer to Kantian epistemology. It is contended that the most important Kantian concept apt to comprehend the special theory of relativity creation and all Einstein’s 1905 writings as a whole, as well as the order of their arrangement is Kant’s regulative idea of the systematic Unity of Nature. Maxwellian unification of electricity, magnetism and optics as a presentiment of the Einsteinian one is comprehended.

Natural Product Derived Drugs for Immunological and Inflammatory Diseases

Natural products derived drugs are usually associated with secondary metabolites, produced by different natural sources including plants, microorganisms, insects, animals, marine sources, etc, which can be used as a drug for the treatment of various diseases including, cancer, infectious disease, cardiovascular diseases, carbohydrate and cholesterol mediated diseases, inflammatory, neurological and immunological diseases. In this chapter, we describe the natural products derived drugs that are under clinical trials (Phase studies) for the treatment of inflammatory and immunological diseases. These diseases are named as immune-mediated inflammatory disorders (autoimmune disorders), which are associated with many other disorders. Voclosporin is under Phase IIb trials for the prevention and treatment of kidney graft rejection. KRP-203 is a fingolimod analogue undergoing Phase study for transplantation, autoimmune diseases and inflammatory bowel diseases. PG490-88 (14-succinyl triptolide sodium salt) is a semisynthetic analogue of triptolide, isolated from Tripterygium wilfordii, which exhibits anti-autoimmune and anti-inflammatory properties. Didemnin B (first compound obtained from the sea that directly entered into human clinical trials against cancer) feasibly modulates the activity of FK-506 binding proteins as part of its immunomodulatory process and thus leads to cell death via apoptosis. Didemnin B has been withdrawn subsequently due to its toxic and immunosuppressive effects. Some natural compounds such as manoalide and luffariellolide (with anti-inflammatory effects) are in clinical studies. Inflazyme Pharmaceuticals Ltd, Canada and Avantis Pharma Inc, Germany has reported some derivatives of the IPL576 series for asthma and other diseases. The derivative (IPL550,260) possessed anti-inflammatory activity and is currently in clinical studies. This chapter provides knowledge to the readers on the recent development on the clinical trials drugs derived from natural products for these diseases.

Hepatitis A Virus

Hepatitis A virus (HAV) infection is the most frequent cause of viral hepatitis worldwide. HAV belongs to the Picornaviridae family in the genus Hepatovirus. The genome of HAV is a positive-sense single-stranded RNA that is approximately 7.5 kb in length. In fact, HAV is classified into six genotypes: three isolated from humans (I–III) and three of simian origin (IV–VI). Worldwide, genotype I is the most prevalent, particularly subgenotype IA. A diagnosis of hepatitis A can be performed by detection of anti-HAV IgM and IgG antibodies by enzyme immunoassay or HAV RNA detection by nested-PCR. Hepatitis A is transmitted principally via the fecal-oral route, including person-to-person contact and the ingestion of water or food that is contaminated by the feces of infected individuals. HAV infection is usually selflimited and benign, with no symptoms, but a severe form of the disease, fulminant hepatitis, affects approximately 1% of the patients who are hospitalized for hepatitis A. In Latin America, several seroprevalence studies have demonstrated an epidemiological shift in HAV infection from high towards intermediate endemicity levels. In Brazil, a large number of children under five years of age (74.1-90%) have been found to be susceptible to HAV infection in 3 capitals of the North, Midwest and Southeast region of Brazil. There is no specific treatment for hepatitis A. Therapy should be supportive and aimed at maintaining an adequate nutritional balance.

Immunity of Geohelminthiasis and the Effect on Modulation of Autoimmunity and Allergy

Geohelminths infections are a group of nematodes worms that are transmitted to human by ingestion of eggs or larvae penetration after contact with contaminated soil. The main species that infect people are the Ascaris lumbricoides, Trichuris trichiura, Necator americanus and Ancylostoma duodenale. Geohelminth infection has been shown to have a significant impact in modulates others pathologies. These parasites might enhance the survival modulating the immune response of their host inducing a regulatory response. This chapter is a review of the recent literature about the host immune response against geohelminths and the potential effect of these infections on non-parasite immune response.

Neuroimmune Regulation of Pain and Inflammation: Targeting Glial Cells and Nociceptor Sensory Neurons Interaction

Chronic pain, differently from nociceptive pain, results from a maladaptive response of the body. Accumulating evidence shows that the mechanism of persistent pathological pain is mediated by complex interactions between sensory neurons and glial cells, namely astrocytes, microglia, and oligodendrocytes. In this chapter, we focus on the current understanding of the neuroimmune contribution to pathological pain and the mechanisms by which glial cells interact with sensory neurons to modulate pain and inflammation. The glial cells biology and how sensory neurons can modulate inflammatory response are also highlighted topics in this chapter. Given the heterogeneous immune functions of different cells in the spinal cord and the sex differential role of glial cells in chronic pain, we also explore how this could be harnessed to develop new therapeutic approaches for pain relief.

Calpain Inhibition: A Potential Therapeutic Target for Neurodegenerative and Neuromuscular Disorders

Proteases are involved in different neurodegenerative and neuromuscular disorders. The role of protease inhibitors as therapeutic agents has been the matter of intense research. Given the role of proteases in these diseases, it is appealing to develop a single agent as a “magic bullet” that would target all the disease states. Calpain inhibitors have been tested with success in animal models of human diseases. In this review, we summarize the role of calpain in selected neurodegenerative and neuromuscular diseases. We describe the various instances in which calpain has been implicated and discuss the results of calpain inhibition in each disease entity as well as how targeted calpain inhibition could be beneficial. The focus of this review is to highlight the potential role of targeted inhibition as a therapeutic option and to introduce three newer calpain inhibitors with unique characteristics.

Current Therapeutic Situation

Craniopharyngiomas are benign midline tumors that have a propensity for local recurrence and are ideally curable via total surgical resection. Many survivors suffer from behavioral, cognitive, endocrine, hypothalamic, and visual disturbances. Optimal management remains highly controversial. In this chapter, we reviewed the therapy strategies for Craniopharyngiomas including surgery, radiotherapy and chemotherapy. Complete resection is even more important in children, especially those younger than 3 years, because of the additional morbidity associated with radiotherapy during early childhood. The aim of radiotherapy is to achieve long-term disease control in patients lacking complete removal or with recurrent tumors. Systemic chemotherapy has rarely been reported in terms of craniopharyngioma management. Local intratumoral chemotherapy for craniopharyngioma was used to treat difficult, recurrent cystic tumors and has subsequently been employed as a strategy to avoid late-term effects of surgery or radiotherapy. The roles of all therapies should be balanced according to factors such as the patient’s age, the tumor size and location, and prior treatment.

NMR Spectroscopy in Medical Diagnosis – Recent Developments

In the field of diagnostic medicine, Nuclear Magnetic Resonance (NMR) spectroscopy has found wide applications. Simplicity of sample preparation, biological safety, non-invasiveness, and non-destructiveness are the advantages of NMR based metabolomic studies. One of the main drawbacks is lower sensitivity. This review summarises the current achievements of NMR spectroscopy in the diagnosis of human disorders. NMR spectroscopy has been useful in metabolomics-based diagnosis. NMRbased screening for inborn errors of metabolism is practised as more metabolites can be detected. Fast, simple and cost-effective screening is possible. Neuropsychiatric disorders like schizophrenia, panic disorders, major depression, bipolar disorders and autism-spectrum disorders have been investigated systematically using NMR spectroscopy. NMR metabolomics is used in the search for biomarkers of infectious diseases like tuberculosis, malaria and pneumonia, neurological disorders and Parkinson’s disease. NMR metabolomics has been used in the identification of biomarker for cardiovascular diseases and risk stratification. It has also been used in cancer diagnosis and therapy. NMR metabolomics has been used to investigate processes like transformation, progression, proliferation and metastasis in cancer cell lines. Other examples for applications of NMR metabolomics include gastro-intestinal disorders, endocrine and nutritional disorders, disorders of the nervous system and respiratory system disorders. In the coming years, it is expected that further developments to overcome the technical limitations will take place, making it one of the key diagnostic modalities of the future.

Chinese Herbal Formula Naoxintong and Cardiovascular Protection

Cardiovascular disease (CVD) is a major health problem worldwide with high morbidity and mortality. A lot of effective treatments with various classes of pharmaceutical synthetic drugs have shown significant benefits for controlling and preventing CVD on individuals with high CVD risks. Apart from these pharmacological agents, herbal medicines also are gaining their roles in the clinical practice in terms of CVD therapy and prevention. Herbal medicines represent the main therapeutic approaches of evidence-based complementary and alternative medicine for CVD and can be tracked back thousands of years ago in ancient China. Although more systematic, well-designed experimental and randomized clinical studies with sufficient sample sizes are essential to further explore the exact pharmacological mechanisms of herbal medicines and to validate their safety and pharmacokinetics, promising therapeutic effects against CVD are already evidenced from a number of herbs and herbal formulas containing potent ingredients. In this chapter, we focus on the significant effects and potential underlying mechanisms of some key herbal medicines, especially Chinese herbal formula Naoxintong, in the treatment of CVD, based on clinical and basic science reports, which might help to shed light on further exploration and clinical application of herbal medicines with cardiovascular protective effects.

Subject Index

Neuro-protective Properties of the Fungus Isaria japonica: Evidence from a Mouse Model of Agedrelated Degeneration

Isaria japonica (IJ), is an entomopathogenic fungus that is grown on pupae of the silkworm Bombyx mori for its medicinal properties. Its extracts have potential neuro-protective effects. An extract reversed astrogliosis in the CA3 area of the hippocampus of aged mice. The CA3 area is responsible for spatial pattern association and completion, detection of novel situations, and short-term memory. This finding led us to the development of treatments to improve age-related impairment of patients with Alzheimer’s disease (AD). Acute and subchronic toxicity and chemical profiling of the extract were conducted for the assessments of medical use. We are now evaluating preclinical trials with AD patients. For the diagnosis of AD, magnetic resonance imaging (MRI) enabled the detection of the previously invisible pathological alterations in a mouse sclerosis model with autoimmune encephalomyelitis. Magnetic resonance spectroscopy (MRS) showed that demyelination regions in some multiple screlosis (MS) patients had increased lactic acid content, suggesting the presence of ischemic events. These results show that products derived from IJ may prevent or reduce the impact of dementia, especially AD, and MRI and MRS could lead widely to the diagnosis of neurological diseases.

Iatrogenic Lesions in Neurosurgery

Complications in neurosurgery can occur during diagnostic procedures, such as lumbar puncture, lumbar drainage, suboccipital cisternal tap or cerebral/spinal angiography, or during neurosurgical procedures. Severe complications during or subsequent to lumbar puncture are extremely rare and include brainstem herniation, infection, subdural hematoma and subarachnoid hemorrhage. Insertion of a catheter into the lumbar subarachnoid space to drain the cerebrospinal fluid (CSF) can also be followed by infection or overdrainage. The complications of cisternal tap include hemorrhage in the cisterna magna and piercing of the medulla oblongata that can cause cardiac or respiratory arrest. The iodine-based contrast agents used for cerebral angiography can cause allergic reactions and epileptic seizures. Iatrogenic complications during surgical procedures can occur at any stage pre-, intra- or immediately postoperative. Complications occur during patient positioning, rendering this step of paramount importance to the success of surgery. Infectious and cosmetic complications can occur during skin disinfection, incision of the skin of the scalp and surgical incision of the skull. Dural lesions can lead to cerebrospinal fluid leak or fistulae. Corticotomy or corticectomy should be realized cautiously and external to functional areas. Ligation or coagulation of brain vessels can lead to cerebral infarction (arterial or venous) with loss of cerebral function. Iatrogenic lesions in different regions of the brain lead to specific neurological manifestations. Lesions in the anterior fossa can lead to anosmia, abulia or behavioral alterations. Lesions in the middle fossa can lead to aphasia and motor deficits, while lesion in the posterior fossa can lead to cranial nerve deficits or coma.

Essential Oils, Polyphenols and Glycosides: Secondary Plant Metabolites against Human Pathogenic Microbes

Higher plants produce secondary metabolites involved in defense mechanisms against herbivores, pests and pathogens. These phytochemicals have also potential healthy properties on human organism, including antioxidant, antiinflammatory and anti-microbial. The pressure to discover and develop new and effective anti-infectious substances has grown due to the intensification of new and reemerging infectious diseases as well as the increasing resistance to the antibiotics in current clinical use. There are several approaches to control diseases caused by microorganisms, and one of them is the use of natural bioactive chemicals that can combat the infection. The essential oils, polyphenols and glycosidic glucosinolates extracted from various species (e.g. medicinal and aromatic plants) have shown promising anti-microbial activity against several pathogens responsible for human diseases. Some of these diseases include mouth diseases as periodontitis, urinary infections, acne, stomach cancer and ulcers associated with Helicobacter pylori, wound infections and gastric infections. Beyond the in vitro and in vivo studies, several compounds from the plant secondary metabolites have been subjected to clinical trials in order to validate their efficacy as anti-infectives (e.g. proanthocyanidins, a polyphenol, that have been tested against periodontitis or tea tree oil 4% against methicillin-resistant Staphylococcus aureus – MRSA) for future prescription. As most of these compounds have poor water solubility and are easily oxidized a chemical transformation which may alter their anti-infective properties, new strategies are being considered both to protect these phytochemicals against oxidation and to enhance their bioavailability and delivery to the desired organs. This chapter summarizes and discuss the most promising phytochemicals that are being used to treat human diseases, antimicrobial mechanisms, the results of clinical trials and the new approaches based on nanoencapsulation strategies to deliver and target these compounds in vivo.

Neuroregeneration after Stroke

Promoting tissue plasticity is a very important therapeutic approach to reduce post-stroke disability. The neurological damage occurring after stroke indeed is a consequence of disrupted brain connectivity circuits due to cellular degeneration and impairment of plasticity processes. Axonal degeneration is also invariably seen in remote brain structures that have neuroanatomical links to the ischemic area. Recovery from stroke is thus very much depending on the possibility to develop treatments able to halt the neurodegenerative process and to foster adaptive tissue plasticity. Due to the intricacy of the systems involved, therapies that foster endogenous repair processes in a spatially and time targeted manner are required. We here discuss the physiology of recovery processes occurring after stroke and the main strategies to foster compensatory neuronal networks aiming to reduce stroke-related disability.

Stroke and the Immune System: Therapeutic Targeting of Toll-Like Receptors

Local and systemic inflammatory responses have been shown to play an important role in post-stroke damage. Recent studies suggest that the innate immune cells contribute to stroke-induced brain injury by activating an inflammatory response that further increases local ischemic damage. Innate immune signaling, via Toll-like receptors (TLRs), has been shown to be involved in several neuropathological processes. This chapter summarizes the current knowledge concerning the involvement of TLRs in acute ischemic brain injury. In particular, the therapeutic role of TLR2 and TLR4 antagonists will be discussed. Moreover, since TLR3 stimulation could play a beneficial role through the production of anti-inflammatory molecules, including I type interferons (IFNs), the potential benefits of TLR3 agonist administration to counteract stroke-related inflammation will be also focused.

Students Coping with Chronic Physical Conditions

Students with chronic physical conditions may experience substantial risk of undesirable outcomes in school. The experience of physical challenges may synergistically affect mental health and school performance. School personnel and families may experience additional stress meeting the needs of students for whom the expertise or resources necessary for care provision is insufficient. Information, support, and effective programming can result in a more desirable outcome for everyone. While often considered synonymous with disability, these are distinct issues.

Uncommon Cause of Stroke: Diagnosis and Treatment (Part I)

This chapter contains detailed, up-to-date information about the nature, diagnosis, and treatment of those relatively uncommon types of cerebrovascular disease that cause strokes. Although many of the conditions discussed are rare, the chapter covers the causes of up to 10% to 15% of all strokes and of up to 40% of strokes in young adults. This chapter may be an essential resource to help physicians diagnose and treat stroke patients who do not fit well into the usual clinical categories.

Discussed within are the dissection of carotid and vertebral arteries, the more relevant cause of stroke in the young. The collagen vascular disorders causing stroke as a consequence of dissection , occlusion and, more rarely, rupture of extracranial and intracranial arteries are reported in detail. Various forms of cerebral angiitis, with focus on the primary central system vasculitis and reversible cerebral vasoconstriction syndrome are discussed.

Stem Cells and Neurodegenerative Diseases

Neurodegenerative diseases are a major concern of our present time and which underpin the ageing era that invades the world. The Neurodegenerative diseases are caused by certain neuronal loss in specific regions of the brain. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are some of the examples of the neurodegenerative diseases that have no fundamental cure available. Some drug treatments can alleviate the symptoms associated with the neurodegenerative diseases. However, they do not tackle the main pathological factors and cannot be clinically suitable for all patients. Moreover, they are not affordable by all patients as a long term medicine. Therefore, developing new and effective medications for AD and PD is deemed necessary. Recent research has aimed at developing therapies that modify the disease. These therapies perform their actions by interacting with the pathophysiologic cascade in order to postpone the disease onset or prevents the progression from occurring on a fast pace. Embryonic and Adult stem cells have demonstrated high therapeutic potential for tissue regeneration. As well, cell replacement therapy would introduce cure for these neurological disorders. Treatment of neurodegenerative diseases using stem cell transplantation has attracted a great deal of attention lately. This is owing to the fact that stem cells are readily available, can be easily expanded in culture, and can have sustainability when transplanted for relatively long periods of time. Moreover, the growth factors and cytokines released by stem cells facilitate neo-vascularization of damaged tissue leading to neurogenesis, as well as affording anti-inflammatory, antiapoptotic, and anti-oxidative effects among other reparative responses. From this point of view, stem cell therapy will provide a powerful and effective cure for most of neurodeteriorative diseases in the near future.

References

Multiple Sclerosis Drug Therapy: From the Classical Pharmaceutical Down to Cellular and Molecular Approach

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting over 2.000.000 individuals around the world. Although MS etiopathogenesis is still not completely defined environmental factor exposure and genetic background are relevant in disease development. Moreover, MS shows heterogeneous onset and course so that different disease forms can be described which are all characterized by motor and/or sensory and even cognitive impairment.

Two steps in the disease progression can be described. First MS lesions are originated by the activated immune system which recognizes CNS myelin as a foreign element thus leading to the formation of demyelinated plaques that evolve into axonal damage and subsequent neurodegeneration over the time.

Since the beginning MS therapy has been focused on counteracting immune system action. Nevertheless, besides the immunosuppressive/immunomodulating drugs such as Glatiramer acetate, Beta-interferons and steroids, the advance in the comprehension of the immune-mediated mechanisms has sustained the development and use of molecular and cellular-focused approaches, e.g. monoclonal antibodies and stem cells.

At the same time very few weapons are specifically available for fighting MS neurodegenerative progression.

We report an overview on MS and both old and new therapeutic approaches to the disease.

Neuroinflammation

Neuroinflammation is a ubiquitous component of central nervous system (CNS) response to injury. In addition to the disorders traditionally considered inflammatory in nature, neuroinflammation contributes to CNS response in ischemic, traumatic and neurodegenerative disorders. Depending on the particular disorder, both innate and adaptive immune responses may contribute to neuroinflammation. This chapter outlines the basic mechanisms relevant to CNS inflammation. The cells of the CNS innate immune response, including microglia, astrocytes, their mechanisms of activation and innate effector mechanisms such as the production of reactive oxygen and nitrogen species and cytokines are discussed. Features unique to the CNS such as the blood-brain barrier and other mechanisms of CNS immune privilege are outlined. Cells and mechanisms of CNS adaptive immune response such as T lymphocytes, B lymphocytes, activation and effector mechanisms are discussed.

Session Lectures

Pharmaceutical and Nutritional Benefits in Alzheimer's Disease via Convergence on the Melatoninergic Pathways

As reviewed in the previous chapter above, tryptophan utilization for serotonin synthesis increases the necessary precursor for the melatoninergic pathways. The changes and susceptibility factors associated with Alzheimer's disease (AD) regulate, and can be regulated by, the melatoninergic pathways. In this chapter we look at the role of the melatoninergic pathways in more detail in relation to changes and interventions relevant to AD.

Many pharmaceutical and dietary factors, with efficacy in AD and/or AD models, regulate the melatoninergic pathways, either directly or indirectly. As such, much of the experimental data pertaining to regulators of the etiology, course and treatment of AD, such as zinc, selenium, acetylcholinesterase inhibitors and valproate, may be intimately intertwined with the melatoninergic pathways.

In this chapter, we review the role of the melatoninergic pathways in AD, highlighting its previously little recognised involvement in a host of susceptibility factors and treatment approaches. More insight as to the relevant changes occurring in AD should allow treatments to better target relevant biochemical targets, thereby improving the management of this poorly conceptualized, and therefore poorly treated, disease.

Targeted Cancer Therapy: The Roles Played by Antibody-Drug and Antibody-Toxin Conjugates

In recent years, antibody therapeutics have been widely and successfully used in treating cancer. Antibodies that specifically bind tumor surface antigens can also be used as therapeutics, and over 35 of them are in clinical use (e.g. trastuzumab, bevacizumab and cetuximab). However, some unmodified antibodies against tumorspecific antigens lack therapeutic activity. Conjugation to cytotoxic agents can increase the antibodies’ activity and, at the same time, enable extremely cytotoxic drugs to be used.

Antibody-delivered drugs and toxins are poised to become important classes of cancer therapeutics. These biopharmaceuticals have potential in this field, as they can selectively direct highly potent cytotoxic agents to cancer cells that present tumorassociated surface markers, thereby minimizing systemic toxicity. The activity of some conjugates is of particular interest receiving increasing attention, thanks to very promising clinical trial results in hematologic cancers. Over forty antibody-drug conjugates and six immunotoxins now in clinical trials, as well as some recently approved drugs, support the maturity of this approach.

This chapter focuses on recent advances in the development of these two classes of biopharmaceuticals: conventional toxins and anticancer drugs are described, together with their mechanisms of action. The processes of conjugation and purification, as reported in the literature and in several patents, are discussed and the most relevant results in clinical trials are listed. Innovative technologies and preliminary results on novel drugs and toxins, as reported in the literature and in recently-published patents (up to January 2015) are lastly examined.

Parasites-Based Immunotherapy to Treat Allergies and Autoimmune Diseases

It is postulated that helminth infections are able to protect their hosts from immune mediated diseases such as allergies and autoimmune diseases, due to strong parasite-driven immune regulatory processes. The development of helminth-based therapies is very attractive to treat those pathologies. In this chapter, we will be reviewing some epidemiological and experimental evidences whereby helminth infection could protects from immune-mediated diseases, the mechanisms that are behind this phenomenon as well as the main strategies that have been used by research groups to develop biological products for treatment and prophylaxis of these immunopathologies based in mild infection by worms or, more importantly, their molecules.

Immunomodulation by Parasitic Helminths and its Therapeutic Exploitation

Parasitic worms are able to survive in their mammalian hosts for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. These products differ between species of helminths, but they share common mechanisms of action such as modulation of Toll-like receptor pathways and induction of regulatory immune responses along with pro-inflammatory Th2 responses, what is often termed as a ‘modified Th2 response’. Interestingly, it is increasingly clear that, reflecting the anti-inflammatory actions of such worm-derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialised countries, this \"Hygiene Hypothesis\" has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of allergic and autoimmune disorders. We summarize here, the current understanding of helminth-derived molecules with immunomodulatory activity and their associated cellular and molecular mechanisms that act in the host to modulate the immune response. In addition, we reveal how these findings have been applied in the clinic and in research to develop novel therapies for allergy and autoimmune diseases, like asthma, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis.

Index

Part F: Pathways for Activating Implantation Tolerance in Early Pregnancy

Immune attack of the conceptus at implantation is suppressed predominantly by the actions of T regulatory (Treg) cells and deficiency in these cells is linked with unexplained infertility, miscarriage, and preeclampsia. The pathways by which Treg cells originate and the factors that control their ontogeny and recruitment into the implantation site are now being explored. Experiments in mice show that male seminal fluid plays a pivotal role in expanding the size of the inducible Treg cell pool after every coital event, in readiness for potential pregnancy. The cytokine TGFβ which induces Treg cells, as well as male alloantigens, are abundant in seminal fluid and exposure of female tissues to seminal fluid initiates a sequence of events causing Treg cells to be recruited into the endometrial tissue. This pathway depends on female dendritic cells that take up seminal fluid antigens and traffic to local lymph nodes to cross-present antigens to both CD8+ and CD4+ T cells, which in turn circulate via the blood to be sequestered back into the endometrium. Thus, agents of both male and female origin in the peri-conceptional environment are important determinants of maternal immune tolerance and ultimately the progression and success of pregnancy. Components of this pathway are present in the human genital tract, and recent studies show seminal fluid activates immune cells in the cervix and seminal fluid TGFβ together with E-series prostaglandins play an important role in triggering this response. Defining how mechanisms of tolerance induction occur in women will be important for informing development of new therapies for pathologies of pregnancy that have an immune aetiology.

Part D: Role of Regulatory T Cells in Human Reproduction

Regulatory T cells emerged in the last years as key players in allowing fetal survival within the maternal uterus. They were shown to be a unique subpopulation of T cells expanding during human and mice pregnancy. However, there is now consensus that surface phenotypes of human and mouse Treg cells are not exactly the same. While mice Treg cells seem to be homogenous and exhibit regulatory function; human FOXP3⁺ Treg cells show more heterogeneity, containing suppressor and non suppressor subsets.

Regulatory T cells accumulate in the uterus not only during pregnancy, but also every time the female becomes fertile. Their periodic accumulation is accompanied by matching fluctuations in uterine expression of several chemokines, and the participation of immunological factors which play a role in the recruitment and retention of regulatory T cells.

This process also requires the adequate role of additional factors, like galectin-1, responsible of an adequate induced tolerance during pregnancy. Similarly, CTLA-4 expressed on Treg cells was shown to up-regulate IDO expression on decidual and peripheral blood dendritic cells and monocytes by the induction of IFN-gamma production.

While in normal decidua a functionally unique regulatory lymphocyte subset exists, decidual tissues from women suffering from recurrent spontaneous abortions (RSA) show a decreased regulatory activity, associated with a harmful role of Th17⁺ cells in rejecting conceptus antigens, and a decreased expression of IDO.

We also discussed the classical and the trans-signaling pathway of IL-6 signaling in modulating the induction of FOXP3 in women suffering from RSA.

Part C: Immunological Tolerance / Acceptance of the Semi-Allogeneic Embryo: Decidual Transforming Growth Factors and Tolerance Signaling Molecules

In a within-species mating of two histoincompatible individuals, the semiallogenic embryo may be ‘rejected’ by maternal defense mechanisms. In a danger environment, the more histoincompatible embryos survive due to activation of maternal immunoregulatory cells, particularly Foxp3⁺ Treg cells, which are present at the implantation site. The CD200 tolerance signaling molecule that is expressed by fetal trophoblast cells and by cells in decidua appears to play an important role in activating a variety of regulatory T cells, and in suppressing macrophage pro-inflammatory mediator production. CD200 may be present in a membrane bound and soluble form. Whilst αβ TCR⁺ CD4⁺ Treg cells may be generated and activated in situ via maternal antigen-presenting cells in decidua, at and shortly after the time of implantation, CD8⁺ Ts appear important and these may infiltrate to the surface of the implanting embryo and produce soluble FGL2 (fibroleukin) in response to direct recognition of embryonic Class I MHC + peptide molecules; soluble FGL2 may act via FcγRII to suppress inflammation and immune cell activation. Although cytokines such as fibroleukin may arise.

Part J: Placental Interferons, Implantation and Pregnancy

Interferons have antiviral, antiproliferative and immunomodulatory effects on immune responses to defend the body against viral infections and malignant cells. The type I interferon family includes interferons alpha (IFNA1-IFNA10, IFNA13, IFNA14, IFNA16, IFNA17 and IFNA21), interferon beta (IFNB), interferon delta (IFND), interferon epsilon (IFNE), interferon kappa (IFNK), interferon tau (IFNT) and interferon omega (IFNW1-IFNW3). Interferon gamma (IFNG) is the only known type II interferon. Of the type I interferons, IFNT is expressed by mononuclear trophectoderm cells of ruminant conceptuses and IFND is expressed by equine and porcine conceptuses to affect pregnancy recognition and the uterine environment at the peri-implantation stage.

The pig conceptus also secretes IFNG during the peri-implantation period, but its role is not known. It is clear that interferons secreted by conceptus trophectoderm and/or immune cells recruited to the site of implantation of blastocysts during early pregnancy affect mechanisms for establishing the window of implantation as well as uterine acceptance of the conceptus, and placentation in many, if not all, species of mammals. This conserved trait of the mammalian peri-implantation period involves secretion of type I and/or a type II IFNs by trophectoderm cells which induces and/or enhances the expression of interferon stimulated genes in a cell-specific (spatial) fashion. Ruminant IFNT is the sole interferon so far identified as a signal of early pregnancy. But interferons produced by the conceptus or uterine immune cells of other species likely affect the peri-implantation uterus as well as endometrial decidualisation, and placental growth and development critical to successful outcomes of pregnancy. This review will highlight current knowledge of interferons that may affect pregnancy outcomes in humans, domestic animals and rodents.

The Classic Basic Protein of Myelin–Conserved Structural Motifs and the Dynamic Molecular Barcode Involved in Membrane Adhesion, Protein-Protein Interactions, and Pathogenesis in Multiple Sclerosis

The myelin basic protein (MBP) family comprises a variety of developmentally-regulated members arising from different transcription start sites, differential splicing, and post-translational modifications. The “classic” isoforms of MBP include the 18.5-kDa form, which predominates in adult human myelin and facilitates compaction of the mature myelin sheath in the central nervous system, thereby maintaining its structural integrity. In addition to membrane-association, the 18.5-kDa and all other classic isoforms are able to interact with a multitude of proteins, including Ca²⁺-calmodulin, actin, tubulin, and SH3-domain-containing proteins, and thus may be signalling linkers during myelin development and remodelling. All proteins in this family are intrinsically disordered, creating a large effective surface to facilitate multiple protein associations, and are post-translationally modified to various degrees by methylation, phosphorylation, and deimination. We have used spectroscopic (fluorescence, circular dichroism, electron paramagnetic resonance, and nuclear magnetic resonance) and computational (molecular dynamics) approaches to study MBP’s conformational adaptability. A highly-conserved central domain consists of an amphipathic α-helix that associates with a phospholipid membrane. In multiple sclerosis, this segment represents a primary immunodominant epitope. This α-helical structure is adjacent to a proline-rich region that contains a classic SH3-ligand along with two threonyl MAP-kinase phosphorylation sites, and forms a poly-proline type II (PPII) structure. This α-helical segment of the protein is thus essential to proper positioning of the PPII protein-interaction motif, with the local conformation and accessibility being modulated by MAP-kinases, and may represent an important molecular switch. Aberrant post-translational or other modifications in this segment of the protein may participate in the onset and pathogenesis of the human demyelinating disease multiple sclerosis.