Biological Macromolecules: Bioactivity and Biomedical Applications

Biological Macromolecules: Bioactivity and Biomedical Applications presents a comprehensive study of biomacromolecules and their potential use in various biomedical applications. Consisting of four sections, the book begins with an overview of the key sources, properties and functions of biomacromolecules, covering the foundational knowledge required for study on the topic. It then progresses to a discussion of the various bioactive components of biomacromolecules. Individual chapters explore a range of potential bioactivities, considering the use of biomacromolecules as nutraceuticals, antioxidants, antimicrobials, anticancer agents, and antidiabetics, among others. The third section of the book focuses on specific applications of biomacromolecules, ranging from drug delivery and wound management to tissue engineering and enzyme immobilization. This focus on the various practical uses of biological macromolecules provide an interdisciplinary assessment of their function in practice. The final section explores the key challenges and future perspectives on biological macromolecules in biomedicine.

• Covers a variety of different biomacromolecules, including carbohydrates, lipids, proteins, and nucleic acids in plants, fungi, animals, and microbiological resources
• Discusses a range of applicable areas where biomacromolecules play a significant role, such as drug delivery, wound management, and regenerative medicine
• Includes a detailed overview of biomacromolecule bioactivity and properties
• Features chapters on research challenges, evolving applications, and future perspectives

• Language: English
• Publisher: Academic Press
• Release date: Nov 23, 2021
• ISBN: 9780323856386

Book preview

Preface

Amit Kumar Nayak¹, Amal Kumar Dhara² and Dilipkumar Pal³, ¹Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, India, ²Department of Pharmacy, Contai Polytechnic, Govt. of West Bengal, Contai, India, ³Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India

The scope of this book, entitled Biological Macromolecules: Bioactivity and Biomedical Applications, is the coverage and review of recent trends and applications of biological macromolecules, such as carbohydrates, lipids, proteins, peptides, and nucleic acids in biomedicines, drug delivery, growth factors delivery, nutrients and nucleic acids delivery, cell encapsulation, enzyme mobilization, and tissue engineering.

The mysteries of life lie in biological macromolecules. A large volume of biological macromolecules is obtained from different biological origins such as plants, algae, fungi, animals, and microbial sources. Biological macromolecules exhibit some significant and favorable advantages over synthetic macromolecules, such as sustainable and economic production, biocompatibility, biodegradability, and improved bioavailability. In recent years, a plethora of biological macromolecules (carbohydrates, lipids, proteins, peptides, and nucleic acids) has been used in the biomedical and healthcare fields. They showed varieties of bioactivities such as antioxidant, anticancer, antidiabetic, antimicrobial, immunomodulatory activities on the central nervous system, and gastrointestinal activity. The other biomedical applications include drug delivery, growth factors delivery, nutrients and nucleic acids delivery, cell encapsulation, enzyme mobilization, and tissue engineering. The structure–property relationship is also an important aspect for a thorough understanding of the bioactivity of biological macromolecules.

This book, containing 4 sections and 26 chapters, provides a systematic insight into the inclusive discussions on bioactivity and biomedical applications of different biological macromolecules. We are glad to see that many authors across the globe accepted our invitation and contributed valued chapters for this book, covering a wide spectrum of fields. A concise account of the contents of each chapter has been described to provide a glimpse of the book to the potential readers of various fields.

The topics in the book (in order of preference) include the following: Biological Macromolecules: Sources, Properties, and functions (Chapter 1)—this chapter describes sources physicochemical properties, bioactivity and biomedical applications of different biological macromolecules concisely; Structure–Activity Relationship of Biological Macromolecules (Chapter 2)—this chapter aims to provide an overview of the structural features influencing the bioactivities of biological macromolecules, namely L-amino acid oxidases, lysostaphin, and metallo-β-lactamase-such as lactonase and chitosan; The Importance of Biological Macromolecules in Biomedicine (Chapter 3)—this chapter highlights the therapeutic aspects of macromolecules and the medicinal use of biological macromolecules against various diseases and ailments; Modification Techniques for Carbohydrate Macromolecules (Chapter 4)—this chapter characteristically abridges the significant developments of the last five to ten years and discusses critically in the area of modification of carbohydrates macromolecules; Biological Macromolecules as Nutraceuticals (Chapter 5)—this chapter aims to demonstrate some recent knowledge regarding the nutraceutical and biological activities of the macromolecules of biological origin, as well as some frontier applications of these in healthcare; Biological Macromolecules as Antioxidants (Chapter 6)—this chapter highlights the potential applications of biological macromolecules as antioxidants to scavenge reactive oxygen species and control oxidative stress, which leads to various pathogenesis; Biological Macromolecules as Antimicrobial Agents (Chapter 7)—the chapter describes the antimicrobial activity of biological macromolecules (chitosan, cellulose, alginate, gelatin, collagen, and keratin) and also, comprehensively elucidates their applications in addressing challenges associated with drug delivery, wound dressing, food packaging, and so on Biological Macromolecules From Algae and Their Antimicrobial Applications (Chapter 8) –this chapter provides an overview of bioactive macromolecules and their antimicrobial activities with particular reference to algal sources; Biological Macromolecules Acting on Central Nervous System (Chapter 9)—in this chapter, the role of biological macromolecules on central nervous system and their critical role in downregulation after the various neurological disorders have been discussed; Biological Macromolecules as Antidiabetic Agents (Chapter 10)—this chapter is an overview of different types of biological macromolecules and their applications as potential antidiabetic agents and also, highlights the advantages, limitations and future perspectives of biological macromolecules as antidiabetic agents; Biological Macromolecules as Anticancer Agents (Chapter 11)—this chapter presents the extraction of macromolecules such as carbohydrate, proteins, lipids, and nucleic acid (miRNAs) from different biological sources, such as plants, animal, algae and fungi. The various mechanisms by which the macromolecules exhibit their anticancer activity have been discussed briefly along with several assays done to evaluate cytotoxicity of the macromolecules against various cancers such as lung cancer, breast cancer, cervical cancer, and colon cancer. Biological Macromolecules as Immunomodulators (Chapter 12)—this topic focuses on the potential modulations of immune response of biomacromolecules (three major classes of compounds: lipids, proteins and polysaccharides); Biological Macromolecules Acting on Gastrointestinal Systems (Chapter 13)—this chapter describes the role of biological macromolecules for the management of gastrointestinal system and related disorders; Synthetic Macromolecules With Biological Activity (Chapter 14)—this chapter describes some classes of synthetic macromolecules with biological activity that have a great importance on the human comfort and health, including antimicrobial polymers, antioxidant polymers, and polymeric sequestrants; Biological Macromolecules in Drug Delivery (Chapter 15)—this chapter focuses on the advancements in the uses of various biological macromolecules in drug delivery applications; Biological macromolecules in tissue engineering (Chapter 16)—this chapter provides an overview on the important role of natural-derived biomaterials (alginate, chitosan, carrageenan, fucoidan, ulvan, collagen, and gelatin) combining with ceramic biomaterials for bone tissue construction; Biological Macromolecules for Drug Delivery in Tissue Engineering (Chapter 17)—This chapter is focused on the preparation and physicochemical characterization of engineered biomaterials, based on biological macromolecules (polysaccharides and proteins), as scaffolds which are capable of supporting physiological activities of cells, but also can act as drug delivery systems for tissue engineering and wound healing; Biological Macromolecules for Growth Factor Delivery (Chapter 18)—this chapter discusses the fabrication of synthetic and natural macromolecules, sometimes combined with other mineral or metallic compounds for growth factor delivery; Biological Macromolecules for Growth Factor Delivery in Bone Regeneration (Chapter 19)—this chapter describes the process of bone tissue regeneration in healing injuries and arthritic conditions, introduces the main ideas through the scope of allogenous and autogenous transplantation and demonstrates the role of growth factors in these processes; Biological Macromolecules for Nutrients Delivery (Chapter 20)—This chapter focuses on the types of nutrients that need to be delivered, the biological macromolecules that can be used to construct edible delivery systems, the most common delivery systems currently used for this purpose, and some of the major challenges that must be addressed in the future; Biological Macromolecules for Nucleic Acid Delivery (Chapter 21)—this chapter describes the nonviral nucleic acid delivery systems made up of biological macromolecules, such as peptides, lipids, and carbohydrates and also gives an introduction on the history and structure of nucleic acids; Biological Macromolecules in Cell Encapsulation (Chapter 22)—this chapter aims to review the most examined, most promising and recently proposed biopolymers that are used in tissue engineering scaffolds, and to highlight their main properties, drawbacks, fields of applications and fabrication technologies in order to provide readers with important guidelines for selecting appropriate scaffold biomaterials; Biological Macromolecules for Enzyme Immobilization (Chapter 23)—this chapter provides a broad overview of properties and the applications of various naturally occurring biopolymers, that is, chitosan, chitin, agarose, alginates, cellulose, gelatin, dextran, carrageenan, pectin and xanthan gum for their applications in enzyme immobilization with recent literature studies indicating biopolymer-based support material development and their utilization to make biocatalysts with desired stability and catalytic functionalities; Carbohydrates for Enzyme Inhibition and Their Use as Target Molecules for the Interference of Diseases (Chapter 24)—this chapter describes the study of a widespread group of enzymes and the inhibition of these enzymes constitutes an interesting and novel strategy to approach new therapies against numerous diseases; Current Challenging Issues of Biological Macromolecules in Biomedicine (Chapter 25)—this chapter provides information on recent innovations in various biomaterials, engineered from macromolecules ranging from drug delivery, cancer therapies, tissue engineering, bioprinting and wound healing; Future Perspectives of Biological Macromolecules in Biomedicine (Chapter 26)—this chapter discusses the impact of the combination of nanotechnology and chronobiology in personalized cancer treatment.

We sincerely acknowledge the valuable contribution of the distinguished authors and convey our sincere thanks. This book could not have been published without the cooperation of Barbara Makinster, Editorial Project Manager. We wish to express our cordial gratitude to Elsevier Inc., Michelle Fisher (Acquisition Editor), and other editorial staff for their invaluable supports in organizing the intelligent editing of the book. We also gratefully acknowledge all the permissions we received for reproducing the copyright materials from different sources. Finally, we cannot overlook the sacrifices and supports from our family members during the preparation of the current book. All our friends, colleagues, and students who have helped in the process of editing this book deserve our great appreciation. Contributing authors, the publishers, and we, the editors, will be extremely happy if our endeavor fulfills the needs of the academicians, researchers, students, pharmaceutical experts, biomedicine experts, and formulators.

Part I

Background

Outline

Chapter 1 Biological macromolecules: sources, properties, and functions

Chapter 2 Structure–activity relationship of biological macromolecules

Chapter 3 The importance of biological macromolecules in biomedicine

Chapter 4 Modification techniques for carbohydrate macromolecules

Chapter 1

Biological macromolecules: sources, properties, and functions

Amal Kumar Dhara¹ and Amit Kumar Nayak²,    ¹Department of Pharmacy, Contai Polytechnic, Contai, India,    ²Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, India

Abstract

Biological macromolecules are large cellular components abundantly obtained naturally and are responsible for varieties of essential functions for the growth and survival of living organisms. There are four important classes of biological macromolecules, viz., carbohydrates, lipids, proteins, and nucleic acids. These possess some favorable characteristics, such as good biocompatibility, excellent biodegradability, desired mechanical strength, better bioavailability, etc., and these characteristics are directing the uses of these biological macromolecules in the biomedical and related fields. Biological macromolecules can also modulate the pathophysiology of neurodegenerative disorders/diseases. The current chapter deals with a brief discussion about the sources, properties, and valued applications of various biological macromolecules.

Keywords

Macromolecules; carbohydrates; lipids; proteins; nucleic acids

1.1 Introduction

The mystery of life is in biological macromolecules. There are four important classes of biological macromolecules, viz., carbohydrates, lipids, proteins, and nucleic acids (Luo, Zhang, Wu, Liang, & Li, 2020; Zhang, Sun, & Jiang, 2018). Carbohydrates, proteins, and nucleic acids naturally exist as long chain polymers, while lipids are smaller and in true sense, these are all considered as biopolymers (Albertsson, 2019; Teramoto, 2020; Zhang et al., 2018). Carbohydrates are the storage form of energy and meet the demand as and when required (Slavin & Carlson, 2014). Lipids are also storage form of energy and are the important structural components of the cell membrane (van Meer, Voelker, & Feigenson, 2008; Zheng, Fleith, Giuffrida, O'Neill, & Schneider, 2019). Proteins serve several functions including structural support, catalyzing important metabolic reactions, signals receiving and transmission, etc. (Watford & Wu, 2018; Zaretsky & Wreschner, 2008). Nucleic acids, that is, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are responsible for carrying genetic blueprint and information for protein synthesis (Minchin & Lodge, 2019; Schwartz, Schwartz, Mieszerski, McNally, & Kobilinsky, 1991).

Biological macromolecules are abundantly available in nature and also possess properties like biocompatibility, environmental friendly, biodegradability, etc., because of their natural sources (Chandika et al., 2020; Teramoto, 2020). Various species of algae have been mentioned to be used as bioactive compounds and are also employed as antibacterial agents (Shannon & Abu-Ghannam, 2016). Various disorders related to central nervous system, such as Alzheimer’s disease, Parkinson’s disease, convulsive disorders, etc., are being treated with the biological macromolecules (Acosta & Cramer, 2020; Soderquist & Mahoney, 2010; Zhang et al., 2018). All the biological macromolecules, viz., carbohydrates, lipids, proteins and nucleic acids, have shown their significant role in the management of cancer therapy and have been advocated to be used against various cancers like lung cancer, colon cancer, breast cancer, cervical cancer, etc. (Corn, Windham, & Rafat, 2020; Oana, Adriana, Mircea, Dragos, & Monica, 2018; Rodrigues Mantuano, Natoli, Zippelius, & Läubli, 2020; Sun, Jing, Ma, Feng, & Hu, 2020). Another important area of research is immunomodulators with respect to present SARS-CoV-2 perspective, where the biological macromolecules, mainly proteins, play significant role (Ji et al., 2020). Proteins are associated with the development process of immune system (Daly, Reynolds, Sigal, Shou, & Liberman, 1990). Lipids are also responsible to play key role as adjuvants for the development of vaccines (Martinez-Gil, Goff, & Tan, 2018; Schwendener, 2014). Day by day, the incidence of lifestyle diseases more specifically diabetes, hypertension, etc., are increasing vertically, where the roles of biological macromolecules have been studied and were found to be utilized widely as antidiabetic agents (Alam, Shafique, Amjad, & Bin Asad, 2019; Hu, Nie, & Xie, 2018; Ríos, Francini, & Schinella, 2015; Yu, Shen, Song, & Xie, 2018). They cause increase in insulin secretion and thus, reduce the blood glucose level (Ríos et al., 2015). Chitosan is a well-known polysaccharide, which is reported to exhibit antimicrobial and antidiabetic activities (Hasnain & Nayak, 2018; Karadeniz & Kim, 2014; Rabea, Badawy, Stevens, Smagghe, & Steurbaut, 2003). Extensive research is going on in the area of tissue engineering for the development of artificial tissue to repair and replace defective or diseased tissue or organs (Hasnain, Ahmad, Chaudhary, Hoda, & Nayak, 2019; Nayak, Ahmed, Tabish, & Hasnain, 2019; Pal, Saha, Nayak, & Hasnain, 2019). Naturally derived biological macromolecules like chitosan, alginate, carrageenan, ulvan, gelatin, etc., have been used for bone tissue regeneration (Hasnain, Nayak, Singh, & Ahmad, 2010; Maity, Hasnain, Nayak, & Aminabavi, 2021; Nayak, Ahmed, Tabish, & Hasnain, 2019). Numbers of polysaccharide have long been used in different types of drug delivery systems as biopolymeric excipients (Hasnain et al., 2020; Kandar, Hasnain, & Nayak, 2021; Maity et al., 2021; Nayak & Hasnain, 2019a, 2019b; Nayak, Hasnain, Dhara, & Pal, 2021; Pal, Saha, Nayak et al., 2019). Polysaccharide and proteins are used extensively for the preparation of hydrogels for drug delivery, tissue regeneration, wound dressings, etc. (Del Valle, Díaz, & Puiggalí, 2017; Nayak & Pal, 2016b; Nayak, Hasnain, Pal, Banerjee, & Pal, 2020; Pal, Nayak, & Saha, 2019a, 2019b; Ray et al., 2020). Beside drug delivery, the biological macromolecules have continuously been used to formulate delivery carrier-systems for growth factors (Rao, Rekha, Anil, Lowe, & Venkatesan, 2019; Shariatinia, 2019). Polysaccharides are also employed for the encapsulation of various bioactive substances like vitamins and nutraceuticals (Bala, Singha, & Patra, 2019; Lauro, Amato, Sansone, Carbone, & Puglisi, 2019). The current chapter deals with a brief discussion about the sources, properties, and valuable applications of various biological macromolecules like carbohydrates, lipids, proteins and nucleic acids.

1.2 Carbohydrates

The most widely found organic compounds in nature are carbohydrates. These are well-known as very essential source of life or sustaining life itself (Slavin & Carlson, 2014). Carbohydrates are commonly found in plants, microorganisms and animal tissues (Werz & Seeberger, 2005). These are also present in blood, tissue fluids, etc. (Kilcoyne & Joshi, 2007). Carbon, hydrogen and oxygen are the three primary elements of molecular structure of carbohydrates (Luo et al., 2020; Werz & Seeberger, 2005). These are optically active polyhydroxy aldehydes or ketones. There are three major classes of carbohydrates, broadly, monosaccharides, oligosaccharides and polysaccharides (Slavin & Carlson, 2014).

1.2.1 Monosaccharides

These are generally called simple sugars, and the most common monosaccharide is glucose. Most of the monosaccharides comprise of the general formula CnH2nOn (Pigman & Horton, 1972). The different classes of monosaccharides include aldoses (functional group is aldehyde), and ketoses (functional group is keto) (Slavin & Carlson, 2014; Werz & Seeberger, 2005). On the basis of number of carbon in the sugar, they are also subcategorized into (Shin & Kim, 2013; Slavin & Carlson, 2014):

1. Trioses (containing three carbon atoms in the sugar), for example, glyceraldehydes and dihydroacetone,

2. Tetroses (containing four carbon atoms in the sugar), for example, erythrose and erythrulose,

3. Pentoses (containing five carbon atoms in the sugar), for example, ribose and xylulose,

4. Hexoses (containing six carbon atoms in the sugar), for example, glucose, glactose, fructose and mannose, and

5. Heptoses (containing seven carbon atoms in the sugar), for example, sedoheptulose.

Physicochemical properties of monosaccharides: These are soluble in water, sweet in taste and permeable through plasma membrane. Monosaccharides react with hydrazine to form osazones (Pigman & Horton, 1972). They undergo reduction and form sugar alcohols (e.g., glucose-sorbitol; fructose-mannitol; galactose-dulcitol; glyceraldehyde-glycerol, etc.). On oxidation, these produce sugar acids like gluconic acid. Monosaccharides play varieties of important physiological functions (Pigman & Horton, 1972). These are used for energy production in living organisms. The vital components of cells are RNA and DNA, which are composed of ribose and deoxyribose and are well-recognized as the building blocks of life (Minchin & Lodge, 2019).

1.2.2 Oligosaccharides

These yield 2–10 monosachharides on hydrolysis. On the basis of number of monosaccharide units present, these are further subclassified into (Shin & Kim, 2013; Slavin & Carlson, 2014): disaccharides (e.g., sucrose, maltose, lactose and trehalose), trisaccharides (e.g., raffinose and maltotriose), etc. These can exhibit reducing property, when these contain free aldehyde and/or ketone group, which is/are not participated in the formation of linkage.

1.2.3 Polysaccharides

These are formed by uniting monosaccharide or there derivatives. These are joined together by glycosidic linkage (Maity et al., 2021). Unlike proteins and nucleic acids, polysaccharides exist as both linear as well as branched polymers. These are colloidal in nature. Polysaccharides are grouped into two categories (Shin & Kim, 2013; Slavin & Carlson, 2014):

1. Homopolysaccharides: These yield one type of monosaccharides on hydrolysis, for example, starch, cellulose, glycogen, etc.

2. Heteropolysaccharides: These yield two or more different type of monosaccharides on hydrolysis, for example, hyaluronic acid, heparin, chondriotin sulfate, etc.

Some important homopolysaccharides are described here:

1. Starches—These contain several units of glucose joined in α-1, 4-linkages and are well-known as examples of homopolysaccharides (Nayak & Pal, 2017). In plants, it is the storage form of carbohydrates. Different parts of the plants are rich in starches like tubers, roots, vegetables, cereals, etc. (Nayak & Pal, 2017; Nayak, Bera, & Hasnain, 2020). In higher animals, starches are the most important source of food. These consist of two types of molecules (Fig. 1.1): (A) linear and water soluble component, e.g., amylose and (B) branched water insoluble, e.g., amylopectin. Commercially, starch is produced mostly from corn, but wheat starch, potato starch, and tapioca starch are also used (Nayak et al., 2020).

2. Cellulose—It is the chief constituent of fibrous parts of the plants and consequently, is the most abundant organic material occurring in nature (Pal et al., 2019b). It is made up of long chains of β D-glucose molecules linked by 1, 4-linkages (Fig. 1.2). It serves as bulk forming agent of the food. Undigested cellulose increases the bulk of feces and helps in the evacuation of bowels. Cellulose exhibits some of important properties like low density, flexibility, high strength, biocompatibility, biodegradability, etc., which suggest for biomedical applications (Hasnain et al., 2020; Kandar et al., 2021). In traditional healthcare, cellulosic biomaterials play an important role and recently, some significant areas of application are being explored with the uses of cellulose like drug delivery (Hasnain et al., 2020; Kandar et al., 2021; Pal et al., 2019b), tissue engineering (Hasnain, Nayak, Singh, & Ahmad, 2010; Murizan, Mustafa, Ngadiman, Mohd Yusof, & Idris, 2020), management of wound (Alven & Aderibigbe, 2020), etc. By using quaternary ammonium salt the surface of cellulose nanocrystals (CNC) is modified, which can inhibit the growth of Staphylococcus aureus and Escherichia coli (Tavakolian, Jafari, & van de Ven, 2020).

Figure 1.1 Molecular structure of starch: (A) linear and water soluble component: amylose and (B) branched water insoluble: amylopectin.

Figure 1.2 Molecular structure of cellulose.

3. Dextran—It is a highly branched polymer of glucose, produced by yeast or bacteria (Chen, Huang, & Huang, 2020; Huang & Huang, 2018). The linear chain dextran molecular structure are formed by 1, 6-α glycosidic linkages (Fig. 1.3). Dextran occurs in honey, maple syrup, etc. It is used as plasma substitutes as it retains water in circulation for longer period, when administered intravenously (i.v.). Dextran and its derivatives are being used to formulate nanocarriers for advanced drug delivery applications (Huang & Huang, 2018).

4. Pectins—These form gel with sugar solutions. In nature, pectins are usually found in pulps and peels of citrus fruits, apple pomaces, beet roots, etc. (Nayak & Pal, 2016a). Chemically pectins are polysaccharide of galacturonic acid, galactose, and arabinose (Hasnain et al., 2020; Kandar et al., 2021). Molecular structure of pectin is presented in Fig. 1.4. Pectins have been found to possess beneficial biological activities, like antioxidant, antiinflammatory, antibacterial, immune regulation, and anticoagulation activities (Rascoń-Chu, Gomez-Rodriguez, Carvajal-Millan, & Campa-Mada, 2019). Biomedical applications of pectins include tissue engineering, drug delivery, wound healing and gene delivery (Hasnain et al., 2020; Kandar et al., 2021; Maity et al., 2021; Nayak et al., 2019, 2021; Rascoń-Chu et al., 2019).

5. Gum acacia or Gum Arabic—It is a plant-derived gum containing hexoses or pentoses or both. It is extensively used in pharmaceutical, food and cosmetic industries (Nayak, Das, & Maji, 2012). It is an effective and useful excipient for the preparation of nanomaterials for drug delivery (De, Nayak, Kundu, Das, & Samanta, 2021).

6. Alginates—These consist of linear polymer of β (1→4)-linked D-mannuronic acid (M-unit) and α (1→4)-linked L-guluronic acid (G-unit) (Hasnain et al., 2020; Kandar et al., 2021; Nayak et al., 2021). Molecular structure of pectin is presented in Fig. 1.5. It is processed from marine algae and giant kelp as raw materials. These are widely used as thickener, emulsifier, stabilizer, etc. (Kandar et al., 2021). Alginate based drugs are effectively used for antimicrobial as well as antiviral therapy (Szekalska, Pucilowska, Szymańska, Ciosek, & Winnicka, 2016). The alginate film with EDTA exhibited stronger antimicrobial effects against Gram-negative bacteria, especially, in case of processed food packaging (Senturk Parreidt, Müller, & Schmid, 2018). Structural modifications of alginates can easily be made by using crosslinkers, improvise the mechanical strength and cell affinity and was widely used in the biomedical applications mainly in drug delivery and tissue regeneration (Malakar, Nayak, Jana, & Pal, 2013; Malakar, Nayak, & Das, 2013).

7. Chitosan—It is a cationic natured carbohydrate polysaccharide, extracted by deacetylation of chitin (Hasnain & Nayak, 2018). It is reported to show various biological properties including antidiabetic, antioxidant, immune-enhancing, antimicrobial as well as anticancer activities (Hasnain & Nayak, 2018; Rabea et al., 2003; Ríos et al., 2015). Chitosan is very much effective in the formulation of insulin with controlled delivery functionality at the target site (Barbosa et al., 2020). Carboxymethyl-hexanoyl derivative and polyethylene glycol-trimethyl complexes of chitosan have been found to possess fat-lowering and fat-preventing properties. Chitosan-based collagen complex sponges showed effectiveness in the healing of diabetic wounds (Wang et al., 2008). Chitosan and its derivatives are being extremely used in many biomedical applications, such as drug delivery, tissue engineering, wound dressing, orthopedics, etc. (Hasnain et al., 2020; Hasnain, Ahmad, Chaudhary, Hoda, & Nayak, 2019; Hasnain, Nayak, Singh, & Ahmad, 2010; Kandar, Hasnain, & Nayak, 2021; Maity, Hasnain, Nayak, & Aminabavi, 2021; Nayak, Ahmed, Tabish, & Hasnain, 2019; Pal, Saha, Nayak, & Hasnain, 2019).

8. Agar—It is a natural polysaccharide obtained from seaweeds. It is a sulfuric acid ester of a complex galactose polysaccharide (Kandar et al., 2021). It is nondigestible material and is used as a bulk laxative. Recent years, a number of biocompatible agar-based composite has been formulated for their potential applications in biomedical fields including drug delivery and tissue engineering applications (Kandar et al., 2021; Nayak, Alkahtani, & Hasnain, 2021; Shah et al., 2019).

9. Glycogen—This is also known as animal starch, as it is a principal polysaccharide occurring in animal tissues, specifically in liver and muscle (Roach, Depaoli-Roach, Hurley, & Tagliabracci, 2012). Glycogen is the storage form of energy release, quickly, when needed (Kreitzman, Coxon, & Szaz, 1992). Similar to starch, this is also composed of glucose units united by 1, 4-linkages and branches arising by 1, 6-linkages.

Figure 1.3 Molecular structure of dextran.

Figure 1.4 Molecular structure of pectin.

Figure 1.5 Molecular structure of alginate.

Sources and functions of various polysaccharides are listed in Table 1.1.

Table 1.1

1.3 Lipids

Lipids are heterogeneous group of organic compounds, related either actually or potentially, to the fatty acids (Pandey & Kohli, 2018). They are poorly soluble in water and soluble in nonpolar solvents like chloroform, benzene, petroleum ether, etc. In our body, lipids are an integral part of the cell membrane structure, metabolic fuel and storage form of energy (van Meer et al., 2008; Zheng et al., 2019). Lipids act as mechanical, thermal and electrical insulators (Pandey & Kohli, 2018). Lipids are usually classified as follows:

1.3.1 Simple lipids

These are esters of fatty acids with certain alcohols, generally glycerol. According to nature of alcohols, these are (Vance & Vance, 2002):

1. Fats and oils: Ester of fatty acids with glycerol. These are also known as natural fat or triglyceride or triacylglycerol. At room temperature when these are solid known as fat and when liquid these are known as oil.

2. Waxes: These are esters of fatty acid with higher molecular weight monohydric alcohol.

1.3.2 Compound or conjugate lipids

These are ester of fatty acids containing groups, in addition to an alcohol and the fatty acids. These are further classified as (Vance & Vance, 2002):

1. Phospholipids: These contain fatty acids, glycerol, a phosphoric acid residue and sometimes a nitrogenous base. They are subdivided as:

a. Phosphotidic acids—on hydrolysis, these produce one molecule each of glycerol and phosphoric acid with two molecules of fatty acids.

b. Lecithins—contain glycerol, fatty acid, phosphoric acid and the nitrogen base choline. These are widely distributed in different animal tissues including brain, liver, blood, cardiac muscles, etc., and also found in plant seeds. Lecithins are used as emulsifying and smoothing agents in food industry (Robert, Couëdelo, Vaysse, & Michalski, 2020). Lecithins have been mentioned to be used for the development of nanocarriers for drug delivery (Das, Sen, Maji, Nayak, & Sen, 2017; Malakar, Sen, Nayak, & Sen, 2012).

c. Cephalins—similar in structure with lecithin but the base is ethanolamine. These are found in brain, liver, cardiac muscles, erythrocytes, etc.

d. Plasmalogens—found in brain, cardiac muscles, erythrocytes, etc.

e. Sphingomyelins—on hydrolysis, these give a single fatty acid, a nitrogen base sphingosine, phosphoric acid and choline but no glycerol. These participate in different signaling pathways.

2. Glycolipids: These contain sphingol, a carbohydrate (galactose), and fatty acid. Large amount of glycolipids are present in the white matter of brain and in the myelin sheath of nerves (Willison, 2018).

3. Sulpholipids: Lipid material containing sulfur has long been known to be present in the different tissues like liver, kidneys, brain, etc. It is found in the white matter of the brain.

4. Lipoproteins: These are composed of lipid material bound to the protein. The lipid of lipoproteins mainly consists of cholesterol esters and phospholipids (such as stearic, palmitic, and oleic acids) (Schumaker & Adams, 1969). These are found in plasma and the four important lipoproteins are chylomicrons, pre-β-lipoprotein, β-lipoprotein and α-lipoprotein. Hyperlipoproteinemia is clinically significant, nowadays, as lipoproteins are directly related with atherosclerotic cardiovascular disease (Arnao, Tuttolomondo, Daidone, & Pinto, 2019).

1.3.3 Derived lipids

These are substances derived by hydrolysis of simple or compound lipids.

1. Steroids: These are abundantly found in nature. Steroids are derivative of complex ring system named as cyclopentano perhydro phenantherene (Fig. 1.6A). The important classes of steroids include sterols, bile acids, sex hormones, adrenal cortical hormones, Vitamin D, saponins and cardiac glycosides (Cole, Short, & Hooper, 2019).

2. Sterols: Cholesterol is a well-known sterol (Fig. 1.6B). It is a white and waxy substance, widely distributed in all cells of the body, particularly in nervous tissue. Cholesterol is the precursor of bile salts, adrenocorticoids, sex hormones, Vitamin D and cardiac glycosides (Schade, Shey, & Eaton, 2020). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) play important roles with respect to immune functions, neurological and cardiovascular disorders (Ochi & Tsuchiya, 2018).

Figure 1.6 (A) Cyclopentano perhydro phenantherene ring system in steroids, and (B) molecular structure of cholesterol.

Basic functions of different lipids are listed in Table 1.2. Recent studies have showed the efficacy of various lipid-based drug delivery carrier systems, such as liposomes, transferosomes, solid lipid nanoparticles, lipid nanostructures, etc.

Table 1.2

1.4 Proteins

Proteins constitute a diverse, heterogeneous class of macromolecules and these may be said as the essence of life processes (Zaretsky & Wreschner, 2008; Zhang et al., 2018). These are high molecular weight extremely complex polymers of amino acids (Watford & Wu, 2018). In addition to carbon, hydrogen, oxygen atoms, the molecular structure of proteins contains nitrogen and sometimes sulfur, phosphorus, iron, copper, manganese, iodine, zinc, and other elements. The amino acids of proteins are joined together with the help of peptide bonds (–CO–NH–). The common structure of protein is presented in Fig. 1.7. These exhibit varieties of functions in cells by acting as structural materials, carrier molecules, enzymes, lubricants, etc. (Zaretsky & Wreschner, 2008). Proteins derived from different sources (animals and plants) have been used for the isolation of peptides, and exhibited different biological activities for humans (Daly et al., 1990; Nayak, 2010). Proteins are classified in three groups, namely simple proteins, conjugated proteins and derived proteins (Watford & Wu, 2018).

Figure 1.7 Common structure of protein.

1.4.1 Simple proteins

Upon hydrolysis, these types of proteins yield only amino acids or their derivatives (Murray, Harper, Granner, Mayes, & Rodwell, 2006; Watford & Wu, 2018). Simple proteins are further classified into albumins, globulins, glutelins, prolamins, albuminoids (scleroproteins), histones and protamines.

1. Albumin: These are soluble in water, coagulated by heat, and precipitated by saturated salt solution. Examples are lactalbumin, serum albumin, egg albumin, myogen of muscle, etc.

2. Globulin: These are soluble in dilute solution of strong acids and bases and get coagulated by heat. Examples are serum globulin, ovoglobulin, myosin of muscle, etc.

3. Glutelin: These are soluble in dilute acids and alkalis and get coagulated by heat. Examples are glutenin from wheat and oryzenin from rice, etc.

4. Prolamines: These are soluble in 70%–80% alcohol and insoluble in water, absolute alcohol and other neutral solvents. Examples are zein (corn), hordein (barley), gliadin (wheat), etc.

5. Albuminoids (Screlroproteins): Albuminoids are insoluble proteins and form supportive tissues. These are animal proteins found in hair, nails, horns and hooves. Examples are keratin, collagen, gelatin, etc.

6. Histones: These are soluble in water, very dilute acids and salt solutions. These are not conjugated by heat and contain basic amino acids. Examples include nucleic acids.

7. Protamines: These are the simplest of proteins and are basic polypeptides, soluble in water and ammonium hydroxides. These are not conjugated by heat. Examples include salmine (salmon sperm), clupeine (herring sperm), etc.

1.4.2 Conjugated proteins

These contain simple protein combined with nonprotein prosthetic group (Murray et al., 2006). These include: (1) nucleoproteins (2) proteoglycans and glycoproteins (3) chromoproteins (4) phosphoproteins (5) lipoproteins and (6) metalloproteins (Murray et al., 2006; Watford & Wu, 2018).

1. Nucleoproteins: These proteins are composed of simple proteins with nucleic acids as prosthetic group. In nucleoproteins, protein moiety is usually a basic protein like protamine and histone. Examples include chromosomal proteins and some glandular proteins.

2. Proteoglycans and glycoproteins: These proteins contain carbohydrates as prosthetic group like hyaluronic acid and chondroitin sulpahte. These are mainly found in blood plasma, gastric and salivary mucine, immunoglobulins, human chorionic gonadotropins, etc.

3. Chromoproteins: These are composed of simple proteins with chromotropic group as prosthetic group. Examples include hemoglobin (prosthetic group is heme), flavoproteins (prosthetic group is riboflavin), cytochrome (prosthetic group is heme), etc.

4. Phosphoproteins: These are composed of proteins and phosphoric acid as the prosthetic group. Caesin (milk protein) and vitelline (egg yolk protein) are the important examples of this group.

5. Lipoproteins: These proteins are the combination of proteins and lipids (fatty acid, lecithin, cephalin, etc.) as prothetic group. Lipoproteins occur in blood, cell nuclei, milk, cell membranes, egg yolk, etc.

6. Metalloproteins: These are compounds of proteins and some metals (such as iron, cobalt, zinc, manganese, copper and magnesium). Examples are ferritin, ceruloplastin, carbonic anhydrase, etc.

1.4.3 Derived proteins

These are formed from simple and conjugate proteins by denaturation or partial hydrolysis (Murray et al., 2006). They are of two types (1) denatured or primary derived proteins and (2) secondary derived proteins (Murray et al., 2006; Watford & Wu, 2018).

1. Denatured or primary derived proteins: These proteins may be of different types.

a. Proteans—derived in the early stages of protein hydrolysis by water, dilute acids or alkalis or enzymes. Examples include fibrin from fibrinogen, myosan from myosin and edestan from edestin.

b. Metaproteins—derived by further hydrolysis by stronger acids or alkalies, which are insoluble in very dilute acids and alkalis. Examples of such proteins include acid metaproteins and alkali metaproteins.

c. Coagulated proteins—derived by the action of heat, ultraviolet (UV)-rays, X-rays, very high pressure, mechanical shaking, etc. Examples are coagulated albumin, cooked meat, etc.

2. Secondary derived proteins: Progressive hydrolysis of peptide bond caused breakdown of proteins into smaller molecules, which include (Murray et al., 2006):

a. Proteoses—formed by the action of pepsin and trypsin,

b. Peptones—produced by further hydrolytic decomposition and

c. Peptides—composed of two or more amino acids (such as dipeptides, and polypeptides).

Plethora of proteins and peptides with varieties of biological activities has already been identified (Nayak, 2010). Some of the proteins and peptides exhibit bioactivities like antioxidant, antihypertensive, antibiotics, immunomodulatory, anticancer activities, etc. (Giromini, Cheli, Rebucci, & Baldi, 2019). Bioactive proteins obtained from legumes have been found beneficial in the prevention of obesity and type-II diabetes (Moreno-Valdespino, Luna-Vital, Camacho-Ruiz, & Mojica, 2020). Anticancer activities are also demonstrated by some important biological proteins like lectins, glycoproteins, etc. (Laaf, Bojarová, Pelantová, Křen, & Elling, 2017; Rodrigues Mantuano et al., 2020; Singh, Kaur, & Kanwar, 2016). Gelatin obtained from animal collagen, either acid or alkali treated, is used in bone tissue engineering as it is biocompatible, low immunogenic and biodegradable (Hasnain et al., 2019). Pharmacological effects of bioactive proteins/peptides along with their sources are listed in Table 1.3.

Table 1.3

1.5 Nucleic acids

Nucleic acids are nonprotein nitrogenous macromolecules, in which the nucleotides remain linked to each other by phosphodiester bonds in-between the 3′ and 5′ position of the sugars (Minchin & Lodge, 2019; Nelson & Cox, 2005). A nucleotide is composed of a pentose, a phosphate and a nitrogen base. The nitrogen base may be a purine or a pyrimidine. In case of RNA and DNA, the pentose is ribose and deoxyribose, respectively (Brosius & Raabe, 2016; Schwartz et al., 1991). Adenine and guanine are the major purine bases (others are methyladenine, methylguanine, hypoxanthine, etc.) whereas cytosine, uracil and thymine are the major pyrimidine bases (others include 5-methylcytosine, 5, 6-dihydrouracil, etc.) of nucleic acids (Brosius & Raabe, 2016; Schwartz et al., 1991). Various functions of nucleic acids are (Minchin & Lodge, 2019; Nelson & Cox, 2005):

1. Nucleic acids direct the metabolism process of the cell throughout the life

2. Synthesis of protein is directed by nucleic acids

3. They regulate the synthesis of enzymes

4. They play important role in the transfer of genetic information from one offspring to another

5. Nucleic acids contribute essential substances of the genes and the apparatus by which the genes act

6. Nucleic acids are intimately involved with the varieties of disease like cancers, etc. and are major areas for research

1.5.1 Nucleotides

When the phosphate diester bond gets hydrolyzed, the monomeric nucleic acids are separated which consist of nitrogenous base, a sugar and a phosphate, and that unit is called nucleotide (Nelson & Cox, 2005; Zaharevitz et al., 1992). According to the presence of ribose or deoxyribose, these may be ribonucleotides or deoxyribonucleotides, respectively. Nucleotides carrying more than one phosphate group are called higher nucleotides, for example, adenosine triphosphate (ATP), adenosine diphosphate (ADP), guanosine triphosphate (GTP), guanosine diphosphate (GDP), cytidine triphosphate (CTP), cytidine diphosphate (CDP), uridine triphosphate (UTP), etc. (Murray et al., 2006).

1.5.2 Nucleosides

It is a structural subunit of nucleic acids. In living cell, nucleoside is the heredity controlling component (Murray et al., 2006; Nelson & Cox, 2005). When the ester bond between the sugar and the phosphate group in a nucleotide is hydrolyzed, a fragment consists of nitrogenous base and a sugar moiety is obtained which is called as nucleoside. Sugar moiety in nucleoside is either ribose or deoxyribose, whereas nitrogenous bases consist of either a pyridine, that is, cytosine, thymine, or uracil or a purine, that is, adenine or guanine (Nelson & Cox, 2005).

1.5.3 DNA

DNA is a biological macromolecule where genetic information of cell is confined, which is known as genome of the cell (Nelson & Cox, 2005; Watson & Crick, 1953). It is a polymer of deoxyribonucleotides. It occurs in chromosomes, mitochondria and chloroplasts. The chemical nature of monomeric units of DNA is deoxyadenylate, deoxyguanylate, deoxycytidylate and thymidylate (Watson & Crick, 1953). The monomeric units are held in polymeric form by 3′, 5′-phophodiester bridges constituting a single strand (Murray et al., 2006). The genetic information resides in the sequence of the monomeric unit. The polymer possesses a polarity, that is, one end has a 5′-hydroxyl or phosphate terminus while other has a 3′-phosphate or hydroxyl moiety. In DNA, the concentration of adenosine nucleotide equals to thymidine and the concentration of guanosine nucleotide equals to cytosine nucleotide (Nelson & Cox, 2005; Watson & Crick, 1953). The secondary structure of DNA consists of a double stranded helix (Watson & Crick, 1953). The two strands of right handed DNA molecules are held by hydrogen bonds. Each strand is again compactly held by hydrophobic forces between the rings of its consecutive bases. The pairing between the purine and pyrimidine nucleotides on opposite strands is (Chang, 2017) specific and dependent upon hydrogen bonding of adenine (A) residue with thymine (T) residue and guanine (G) with cytosine (C) residue (Malhotra & Ali, 2018; Watson & Crick, 1953). Schematic representation of the structure of DNA with its nitrogenous bases is presented in Fig. 1.8 (right-hand side).

Figure 1.8 Schematic representation of the structure of RNA (left-hand side) and DNA (right-hand side) with its nitrogenous bases (Malhotra & Ali, 2018). Source: With permission, Copyright © 2018 Elsevier Inc.

Important biological roles of DNA are (Nelson & Cox, 2005; Pisetsky, 2017; Watson & Crick, 1953):

1. The function of DNA is to act as a storage house of genetic information and to control the synthesis of protein in the cell.

2. Cell replication—Hereditary characteristics are passed on to daughter cells through replication of DNA.

3. Control protein synthesis.

4. Transcription and translation.

1.5.4 RNA

There are three types of RNA known to exist (Brosius & Raabe, 2016):

1. Messenger RNA (mRNA)

2. Transfer RNA (tRNA)

3. Ribosomal RNA (rRNA)

These are polymer of purine and pyrimidine ribonucleotides linked together by phophodiester bonds (Nelson & Cox, 2005). Schematic representation of the structure of RNA with its nitrogenous bases is presented in Fig. 1.8 (left-hand side). Major nucleotides in RNA are adenylic, guanylic, cytidylic and uridylic acids. However, thymine is absent except in tRNA. RNA is distributed throughout the cell, most of which remains present in cytoplasm as soluble and rRNA, but about 10% is found in nucleus with very small quantities being also present in the mitochondria (Higgs & Lehman, 2015; Nissen et al., 2000).

1. Messenger RNA (mRNA): These are homogenous in size and stability. Amongst all RNAs, mRNAs exhibit highest molecular weight (Sergeeva, Koteliansky, & Zatsepin, 2016). An mRNA carries adenine, guanine, cytosine and uracil as the major bases along with some minor bases, such as methylpurines and methylpyrimidines (Guan & Rosenecker, 2017). mRNAs give signal for the synthesis of very important substances like the enzymes, the proteins, a variety of polypeptide hormones, etc. (Guan & Rosenecker, 2017; Sergeeva et al., 2016).

2. Transfer RNA (tRNA): This consists of approximately 75 nucleotides and generated by nuclear processing of precursor molecule (Balatti, Pekarsky, & Croce, 2017; Phizicky & Hopper, 2010). It serves as an adapter molecule for the translation of information in sequence of nucleotides of mRNA into specific amino acids. tRNA is participated in protein synthesis (Phizicky & Hopper, 2010). Beside the presence of regular bases, that is, adenine, guanine, uracil and cytosine, tRNA has been found to contain some very unusual bases like ribothymidine, dihydrouracil, inosine, dihydrouridine (DHU), pseudouridine, etc., which possess an unusual linkage in-between the sugar ribose and the base (Higgs & Lehman, 2015; Nelson & Cox, 2005). All tRNA molecules consist of an ACC sequence at the 3′ termini. It is through an ester bond to the 3′-hydroxyl group of the adenosyl moiety that the carboxyl groups of amino acids are attached (Phizicky & Hopper, 2010). The anticodon group at the end of base paired stem recognizes the triplet nucleotide or codon of the template mRNA. The DHU loop helps to recognize the specific enzyme which activates the specific amino acids. The Thymidine-pseudouridine cytidine binds the tRNA in ribosomes for protein synthesis (Phizicky & Hopper, 2010).

3. Ribosomal RNA (rRNA): It constitutes nearly 50%–60% of the total RNA of the cell and is single stranded fibrous molecules which are highly elongated (Nelson & Cox, 2005; Urlaub, Kruft, Bischof, Müller, & Wittmann-Liebold, 1995). An mRNA carries adenine, guanine, cytosine and uracil as the major bases along with some minor bases such as methylpurines and methylpyrimidines. One or more segments of mRNA strand carry the genetic code or message, which is translated into the primary structure of a protein. Each genetic code consists of many consecutive nucleotide triplets called codons, each of which helps to incorporate specific amino acids in the peptide being synthesized (Higgs & Lehman, 2015).

Nucleic Acids, that is, DNA and RNA are significantly employed as biomedicine for the management of varieties of physiological conditions (Minchin & Lodge, 2019). In a study, it was observed that chitosan nanoparticles loaded with probiotic DNA showed hypoglycemic activity (Kaur, Bhatia, Sethi, Kaur, & Vig, 2017). Antidiabetic activity has been reported by some other researchers by combining of berberine and noncoding RNA (Chang, 2017). Floxuridine, a cytotoxic nucleoside analog, is a very good anticancer drug and it can be incorporated into DNA strands by synthesis or incorporated into RNA by transcription (Ma et al., 2018). This can be used as a real nucleoside. DNases II of tumor cells hydrolyze the nucleotide strands and cytotoxic drug is released.

1.6 Conclusion

Biological macromolecules are large cellular components abundantly obtained naturally and are responsible for varieties of essential functions for the growth and survival of living organisms. Biological macromolecules play an important role in the biomedical and related fields. These possess some favorable characteristics, such as good biocompatibility, excellent biodegradability, desired mechanical strength, better bioavailability, etc. These exhibit various bioactivities like anticancer, antidiabetic, antimicrobial, antioxidant, immunomodulatory, etc. Important carbohydrates like alginate, chitosan, pectin, starches, carrageenan, fucoidan, etc., are used commercially. Proteins (polymer of amino acids) and lipids are being extensively used in materials sciences as well as in biomedical field. Carbohydrates, lipids, proteins, and/or nucleic acids can modulate the pathophysiology of neurodegenerative disorders/diseases.

References

Acosta and Cramer, 2020 Acosta W, Cramer CL. Targeting macromolecules to CNS and other hard-to-treat organs using lectin-mediated delivery. International Journal of Molecular Sciences. 2020;21(3):971.

Alam et al., 2019 Alam F, Shafique Z, Amjad ST, Bin Asad MHH. Enzymes inhibitors from natural sources with antidiabetic activity: A review. Phytotherapy Research: PTR. 2019;33(1):41–54.

Albertsson, 2019 Albertsson AC. Celebrating 20 years of Biomacromolecules!. Biomacromolecules. 2019;20(2):767–768.

Alven and Aderibigbe, 2020 Alven S, Aderibigbe BA. Chitosan and cellulose-based hydrogels for wound management. International Journal of Molecular Sciences. 2020;21(24):9656.

Arnao et al., 2019 Arnao V, Tuttolomondo A, Daidone M, Pinto A. Lipoproteins in atherosclerosis process. Current Medicinal Chemistry. 2019;26(9):1525–1543.

Bala et al., 2019 Bala E, Singha S, Patra S. Polysaccharides from leafy vegetables: chemical, nutritional and medicinal properties. In: Hasnain MS, Nayak AK, eds. Natural polysaccharides in drug delivery and biomedical applications. Academic Press, Elsevier Inc. 2019;569–588.

Balatti et al., 2017 Balatti V, Pekarsky Y, Croce CM. Role of the tRNA-derived small RNAs in cancer: New potential biomarkers and target for therapy. Advances in Cancer Research. 2017;135:173–187.

Barbosa et al., 2020 Barbosa FC, Silva MCD, Silva HND, et al. Progress in the development of chitosan based insulin delivery systems: A systematic literature review. Polymers (Basel). 2020;12(11):2499.

Brosius and Raabe, 2016 Brosius J, Raabe CA. What is an RNA? A top layer for RNA classification. RNA Biology. 2016;13(2):140–144.

Chandika et al., 2020 Chandika P, Heo SY, Kim TH, et al. Recent advances in biological macromolecule based tissue-engineered composite scaffolds for cardiac tissue regeneration applications. International Journal of Biological Macromolecules. 2020;164:2329–2357.

Chang, 2017 Chang W. Non-coding RNAs and Berberine: A new mechanism of its anti-diabetic activities. European Journal of Pharmacology. 2017;795:8–12.

Chen et al., 2020 Chen F, Huang G, Huang H. Preparation and application of dextran and its derivatives as carriers. International Journal of Biological Macromolecules. 2020;145:827–834.

Chen et al., 2007 Chen H, Takahashi S, Imamura M, et al. Earthworm fibrinolytic enzyme: Anti-tumor activity on human hepatoma cells in vitro and in vivo. Chinese Medical Journal. 2007;120(10):898–904.

Cole et al., 2019 Cole TJ, Short KL, Hooper SB. The science of steroids. Seminars in Fetal and Neonatal Medicine. 2019;24(3):170–175.

Corn et al., 2020 Corn KC, Windham MA, Rafat M. Lipids in the tumor microenvironment: From cancer progression to treatment. Progress in Lipid Research. 2020;80:101055.

Daly et al., 1990 Daly JM, Reynolds J, Sigal RK, Shou J, Liberman MD. Effect of dietary protein and amino acids on immune function. Critical Care Medicine. 1990;18(2 Suppl):S86–S93.

Das et al., 2017 Das B, Sen SO, Maji R, Nayak AK, Sen KK. Transferosomal gel for transdermal delivery of risperidone: Formulation optimization and ex vivo permeation. Journal of Drug Delivery Science and Technology. 2017;38:59–71.

De et al., 2021 De A, Nayak AK, Kundu A, Das B, Samanta A. Gum arabic-based nanomaterials in drug delivery and biomedical applications. In: Bera H, Hossain CM, Saha S, eds. Biopolymer-based nanomaterials in drug delivery and biomedical applications. Academic Press, Elsevier Inc. 2021;165–177.

Del Valle et al., 2017 Del Valle LJ, Díaz A, Puiggalí J. Hydrogels for biomedical applications: Cellulose, chitosan, and protein/peptide derivatives. Gels. 2017;3(3):27.

Giromini et al., 2019 Giromini C, Cheli F, Rebucci R, Baldi A. Invited review: Dairy proteins and bioactive peptides: Modeling digestion and the intestinal barrier. Journal of Dairy Science. 2019;102(2):929–942.

Guan and Rosenecker, 2017 Guan S, Rosenecker J. Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Therapy. 2017;24(3):133–143.

Hasnain et al., 2019 Hasnain MS, Ahmad SA, Chaudhary N, Hoda MN, Nayak AK. Biodegradable polymer matrix nanocomposites for bone tissue engineering. Woodhead Publishing Series in Biomaterials In: Inamuddin, Asiri AM, Mohammad A, eds. Applications of nanocomposite materials in orthopedics. Elsevier Inc. 2019;1–37.

Hasnain et al., 2020 Hasnain MS, Ahmed SA, Alkahtani S, et al. Biopolymers for drug delivery. In: Nayak AK, Hasnain MS, eds. Advanced biopolymeric systems for drug delivery. Springer 2020;1–29.

Hasnain and Nayak, 2018 Hasnain MS, Nayak AK. Chitosan as responsive polymer for drug delivery applications. Woodhead Publishing Series in Biomaterials In: Makhlouf ASH, Abu-Thabit NY, eds. Stimuli responsive polymeric nanocarriers for drug delivery applications, Volume 1, Types and Triggers. Elsevier Ltd. 2018;581–605.

Hasnain, Nayak, Singh, & Ahmad, 2010 Hasnain MS, Nayak AK, Singh R, Ahmad F. Emerging trends of natural-based polymeric systems for drug delivery in tissue engineering applications. Science Journal Ubon Ratchathani University. 2010;1(2):1–13.

Higgs and Lehman, 2015 Higgs PG, Lehman N. The RNA World: Molecular cooperation at the origins of life. Nature Reviews Genetics. 2015;16(1):7–17.

Hou et al., 1999 Hou WC, Liu JS, Chen HJ, Chen TE, Chang CF, Lin YH. Dioscorin, the major tuber storage protein of yam (Dioscorea batatas decne) with carbonic anhydrase and trypsin inhibitor activities. Journal of Agricultural and Food Chemistry. 1999;47(5):2168–2172.

Hu et al., 2018 Hu JL, Nie SP, Xie MY. Antidiabetic mechanism of dietary polysaccharides based on their gastrointestinal functions. Journal of Agricultural and Food Chemistry. 2018;66(19):4781–4786.

Huang and Huang, 2018 Huang G, Huang H. Application of dextran as nanoscale drug carriers. Nanomedicine (Lond). 2018;13(24):3149–3158.

Ji et al., 2020 Ji P, Chen J, Golding A, et al. Immunomodulatory therapeutic proteins in COVID-19: Current clinical development and clinical pharmacology considerations. Journal of Clinical Pharmacology. 2020;60(10):1275–1293.

Kandar et al., 2021 Kandar CC, Hasnain MS, Nayak AK. Natural polymers as useful pharmaceutical excipients. In: Nayak AK, Pal K, Banerjee I, Maji S, Nanda U, eds. Advances and challenges in pharmaceutical technology: Materials, process development and drug delivery strategies. Academic Press, Elsevier Inc. 2021;1–44.

Karadeniz and Kim, 2014 Karadeniz F, Kim SK. Antidiabetic activities of chitosan and its derivatives: A mini review. Advances in Food and Nutrition Research. 2014;73:33–44.

Kaur et al., 2017 Kaur M, Bhatia A, Sethi D, Kaur G, Vig K. Hypoglycemic potential of probiotic DNA loaded chitosan nanoparticles: An in vivo study. Journal of Drug Delivery and Therapeutics. 2017;7:70–76.

Kilcoyne and Joshi, 2007 Kilcoyne M, Joshi L. Carbohydrates in therapeutics. Cardiovascular and Hematological Agents in Medicinal Chemistry. 2007;5(3):186–197.

Kreitzman et al., 1992 Kreitzman SN, Coxon AY, Szaz KF. Glycogen storage: Illusions of easy weight loss, excessive weight regain, and distortions in estimates of body composition. The American Journal of Clinical Nutrition. 1992;56(Suppl. 1):292S–293S.

Laaf et al., 2017 Laaf D, Bojarová P, Pelantová H, Křen V, Elling L. Tailored multivalent neo-glycoproteins: Synthesis, evaluation, and application of a library of galectin-3-binding glycan ligands. Bioconjugate Chemistry. 2017;28(11):2832–2840.

Lauro et al., 2019 Lauro MR, Amato G, Sansone F, Carbone C, Puglisi G. Alginate carriers for bioactive substances: Herbal natural compounds and nucleic acid materials. In: Hasnain MS, Nayak AK, eds. Alginate: Versatile Polymer in Biomedical Applications and Therapeutics. Apple Academic Press 2019;559–604.

Luo et al., 2020 Luo Y, Zhang Y, Wu JY, Liang L, Li Y. Nanotechnology with biological macromolecules. International Journal of Biological Macromolecules. 2020;155:834.

Ma et al., 2018 Ma Y, Liu H, Mou Q, Yan D, Zhu X, Zhang C. Floxuridine-containing nucleic acid nanogels for anticancer drug delivery. Nanoscale. 2018;10(18):8367–8371.

Maity et al., 2021 Maity M, Hasnain MS, Nayak AK, Aminabavi TM. Biomedical applications of polysaccharides. In: Nayak AK, Hasnain MS, Aminabhavi TM, eds. Tailor-made polysaccharides in biomedical applications. Academic Press, Elsevier Inc. 2021;1–34.

Malakar et al., 2013 Malakar J, Nayak AK, Das A. Modified starch (cationized)-alginate beads containing aceclofenac: Formulation optimization using central composite design. Starch – Stärke. 2013;65:603–612.

Malakar et al., 2013 Malakar J, Nayak AK, Jana P, Pal D. Potato starch-blended alginate beads for prolonged release of tolbutamide: Development by statistical optimization and in vitro characterization. Asian Journal of Pharmaceutics. 2013;7:43–51.

Malakar et al., 2012 Malakar J, Sen SO, Nayak AK, Sen KK. Preparation, optimization and evaluation of transferosomal gel for transdermal insulin delivery. Saudi Pharmaceutical Journal: SPJ. 2012;20:355–363.

Malhotra and Ali, 2018 Malhotra BD, Ali MA. Nanostructured materials for DNA biochip. In: Malhotra BD, Ali MA, eds. Nanomaterials for biosensors, fundamentals and applications. Elsevier Inc. 2018;221–262.

Markwardt, 2002 Markwardt F. Hirudin as alternative anticoagulant–a historical review. Seminars in Thrombosis and Hemostasis. 2002;28(5):405–414.

Martinez-Gil et al., 2018 Martinez-Gil L, Goff PH, Tan GS. The role of self-assembling lipid molecules in vaccination. Advances in Biomembranes and Lipid Self-Assembly. 2018;27:1–37.

Minchin and Lodge, 2019 Minchin S, Lodge J. Understanding biochemistry: Structure and function of nucleic acids. Essays in Biochemistry. 2019;63(4):433–456.

Moreno-Valdespino et al., 2020 Moreno-Valdespino CA, Luna-Vital D, Camacho-Ruiz RM, Mojica L. Bioactive proteins and phytochemicals from legumes: Mechanisms of action preventing obesity and type-2 diabetes. Food Research International. 2020;130:108905.

Murizan et al., 2020 Murizan NIS, Mustafa NS, Ngadiman NHA, Mohd Yusof N, Idris A. Review on nanocrystalline cellulose in bone tissue engineering applications. Polymers (Basel). 2020;12(12):2818.

Murray et al., 2006 Murray RF, Harper HW, Granner DK, Mayes PA, Rodwell VW. Harper's illustrated biochemistry New York: Lange Medical Books, McGraw-Hill; 2006.

Nayak, 2010 Nayak AK. Advances in therapeutic protein production and delivery. International Journal of Pharmacy and Pharmaceutical Science. 2010;2(2):1–5.

Nayak et al., 2019 Nayak AK, Ahmed SA, Tabish M, Hasnain MS. Natural polysaccharides in tissue engineering application. In: Hasnain MS, Nayak AK, eds. Natural polysaccharides in drug delivery and biomedical applications. Academic Press, Elsevier Inc. 2019;531–548.

Nayak et al., 2021 Nayak AK, Alkahtani S, Hasnain MS. Biomedical nanocomposites. In: Nayak AK, Hasnain MH, eds. Biomedical composites-perspectives and applications. Springer International Publishing, Springer Nature 2021;35–69.

Nayak et al., 2020 Nayak AK, Bera H, Hasnain MS. Particulate matrices of ionotropically gelled alginate- and plant-derived starches for sustained drug release. In: Nayak AK, Hasnain MS, eds. Alginates in drug delivery. Academic Press, Elsevier Inc. 2020;257–295.

Nayak et al., 2012 Nayak AK, Das B, Maji R. Calcium alginate/gum Arabic beads containing glibenclamide: Development and in vitro characterization. International Journal of Biological Macromolecules. 2012;51:1070–1078.

Nayak and Hasnain, 2019a Nayak AK, Hasnain MS. Plant polysaccharides in drug delivery applications. In: Nayak AK, Hasnain MS, eds. Plant polysaccharides-based multiple-unit systems for oral drug delivery. Springer 2019a;19–23.

Nayak and Hasnain, 2019b Nayak AK, Hasnain MS. Some other plant polysaccharide based multiple units for oral drug delivery. In: Nayak AK, Hasnain MS, eds. Plant polysaccharides-based multiple-unit systems for oral drug delivery. Springer 2019b;123–1128.

Nayak et al., 2021 Nayak AK, Hasnain MS, Dhara AK, Pal D. Plant polysaccharides in pharmaceutical applications. Advanced Structured Materials In: Cham: Springer; 2021;93–125. Pal D, Nayak AK, eds. Bioactive natural products for pharmaceutical applications. vol 140.

Nayak et al., 2020 Nayak AK, Hasnain MS, Pal K, Banerjee I, Pal D. Gum-based hydrogels in drug delivery. In: Pal K, Banerjee I, Sarkar P, Kim D, Deng W-P, Dubey NK, Majumder K, eds. Biopolymer-based formulations, biomedical and food applications. Elsevier Inc. 2020;605–645.

Nayak and Pal, 2016a Nayak AK, Pal D. Plant-derived polymers: Ionically gelled sustained drug release systems. In: New York: Taylor and Francis; 2016a;6002–6017. Mishra M, ed. Encyclopedia of biomedical polymers and polymeric biomaterials. Vol. VIII.

Nayak and Pal, 2016b Nayak AK, Pal D. Sterculia gum-based hydrogels for drug delivery applications. In: Kalia S, ed. Polymeric hydrogels as smart biomaterials, springer series on polymer and composite materials. Springer International Publishing 2016b;105–151.

Nayak and Pal, 2017 Nayak AK, Pal D. Natural starches-blended ionotropically-gelled micrparticles/beads for sustained drug release. In: Thakur VK, Thakur MK, Kessler MR, eds. Handbook of composites from renewable materials, Volume 8, nanocomposites: Advanced applications. WILEY-Scrivener 2017;527–560.

Nelson and Cox, 2005 Nelson DL, Cox MM. Principles of biochemistry 4th ed. New York: W. H. Freeman; 2005.

Nissen et al., 2000 Nissen P, Hansen J, Ban N, Moore PB, Steitz TA. The structural basis of ribosome activity in peptide bond synthesis. Science (New York, N.Y.). 2000;289(5481):920–930.

Oana et al., 2018 Oana C, Adriana T, Mircea C, Dragos S, Monica H. Natural macromolecules with protective and antitumor activity. Anti-cancer Agents in Medicinal Chemistry. 2018;18(5):675–683.

Ochi and Tsuchiya, 2018 Ochi E, Tsuchiya Y. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in muscle damage and function. Nutrients. 2018;10(5):552.

Pal et al., 2019a Pal D, Nayak AK, Saha S. Interpenetrating polymer network hydrogels of chitosan: Applications in controlling drug release. In: Mondal MIH, ed. Cellulose-based superabsorbent hydrogels. Springer Nature 2019a;1727–1768.

Pal et al., 2019b Pal D, Nayak AK, Saha S. Cellulose-based hydrogels: Present and future. In: Akhtar MS, Swamy MK, Sinniah UR, eds. Natural bio-active compounds. Springer 2019b;285–332.

Pal et al., 2019 Pal D, Saha S, Nayak AK, Hasnain MS. Marine-derived polysaccharides: Pharmaceutical applications. In: Nayak AK, Hasnain MS, Pal D, eds. Natural polymers for pharmaceutical applications, Vol II: Marine and microbiologically derived polymers. Apple Academic Press 2019;1–36.

Pandey and Kohli, 2018 Pandey V, Kohli S. Lipids and surfactants: The inside story of lipid-based drug delivery systems. Critical Reviews in Therapeutic Drug Carrier Systems. 2018;35(2):99–155.

Phizicky and Hopper, 2010 Phizicky EM, Hopper AK. tRNA biology charges to the front. Genes and Development. 2010;24(17):1832–1860.

Pigman and Horton, 1972 Pigman W, Horton D. Stereochemistry of the monosaccharides. In: 2nd ed. San Diego, CA: Academic Press; 1972;1–67. Pigman W, Horton D, eds. The carbohydrates: Chemistry and biochemistry. Vol. 1A.

Pisetsky, 2017 Pisetsky DS. The biological functions of DNA: From the sublime to the slime. Arthritis Research and Therapy. 2017;19(1):275.

Qian et al., 2012 Qian GM, Pan GF, Guo JY. Anti-inflammatory and antinociceptive effects of cordymin, a peptide purified from the medicinal mushroom Cordyceps sinensis. Natural Product Research. 2012;26(24):2358–2362.

Rabea et al., 2003 Rabea EI, Badawy ME, Stevens CV, Smagghe G, Steurbaut W. Chitosan as antimicrobial agent: Applications and mode of action. Biomacromolecules. 2003;4(6):1457–1465.

Rao et al., 2019 Rao SS, Rekha PD, Anil S, Lowe B, Venkatesan J. Natural polysaccharides for growth factors delivery. In: Hasnain MS, Nayak AK, eds. Natural polysaccharides in drug delivery and biomedical applications. Academic Press, Elsevier Inc. 2019;495–512.

Rascoń-Chu et al., 2019 Rascoń-Chu A, Gomez-Rodriguez GH, Carvajal-Millan E, Campa-Mada AC. Pectin in drug delivery applications. In: Hasnain MS, Nayak AK, eds. Natural polysaccharides in drug delivery and biomedical applications. Academic Press, Elsevier Inc. 2019;249–262.

Ray et al., 2020 Ray P, Maity M, Barik H, et al. Alginate-based hydrogels for drug delivery applications. In: Nayak AK, Hasnain MS, eds. Alginates in drug delivery. Academic Press, Elsevier Inc. 2020;41–70.

Ríos et al., 2015 Ríos JL, Francini F, Schinella GR. Natural products for the treatment of Type 2 diabetes mellitus. Planta Medica. 2015;81(12–13):975–994.

Roach et al., 2012 Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: Some new developments and old themes. The Biochemical Journal. 2012;441(3):763–787.

Robert et al., 2020 Robert C, Couëdelo L, Vaysse C, Michalski MC. Vegetable lecithins: A review of their compositional diversity, impact on lipid metabolism and potential in cardiometabolic disease prevention. Biochimie. 2020;169:121–132.

Rodrigues Mantuano et al., 2020 Rodrigues Mantuano N, Natoli M, Zippelius A, Läubli H. Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy. Journal for Immunotherapy of Cancer. 2020;8(2):e001222.

Schade et al., 2020 Schade DS, Shey L, Eaton RP. Cholesterol review: A metabolically important molecule. Endocrine Practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2020;26(12):1514–1523.

Schumaker and Adams, 1969 Schumaker VN, Adams GH. Circulating lipoproteins. Annual Review of Biochemistry. 1969;38:113–136.

Schwartz et al., 1991 Schwartz TR, Schwartz EA, Mieszerski L, McNally L, Kobilinsky L. Characterization of deoxyribonucleic acid (DNA) obtained from teeth subjected to various environmental conditions. Journal of Forensic Sciences. 1991;36(4):979–990.

Schwendener, 2014 Schwendener RA. Liposomes as vaccine delivery systems: A review of the recent advances. Therapeutic Advances in Vaccines. 2014;2(6):159–182.

Senturk Parreidt et al., 2018 Senturk Parreidt T, Müller K, Schmid M. Alginate-based edible films and coatings for food packaging applications. Foods. 2018;7(10):170.

Sergeeva et al., 2016 Sergeeva OV, Koteliansky VE, Zatsepin TS. mRNA-based therapeutics – Advances and perspectives. Biochemistry. 2016;81(7):709–722.

Shah et al., 2019 Shah N, Zaman T, Rehan T, et al. Preparation and characterization of agar based magnetic nanocomposite for potential biomedical applications. Current Pharmaceutical Design. 2019;25(34):3672–3680.

Shannon and Abu-Ghannam, 2016 Shannon E, Abu-Ghannam N. Antibacterial derivatives of marine algae: An overview of pharmacological mechanisms and applications. Marine Drugs. 2016;14(4):81.

Shariatinia, 2019 Shariatinia Z. Pharmaceutical applications of natural polysaccharides. In: Hasnain MS, Nayak AK, eds. Natural polysaccharides in drug delivery