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Fermentative Nutraceuticals, the latest volume in the series Bioprocessing in Food Science, presents recent advances and breakthroughs in bioactive peptides derived from fermented foods, highlighting their applications as nutraceuticals. This volume explores opportunities for product design and innovation in food processing.

Bioprocessing in Food Science is a series of volumes that comprehensively covers unit operations in food processing. This latest installment addresses the advances, breakthroughs, and challenges associated with fermentative nutraceuticals.

The demand for food nutraceuticals and functional foods is growing among consumers worldwide. Academia, researchers, and the food industry are working in a fragmented manner, with technologies developed at each level often not compiled in a unified resource for stakeholders. Typically, the foods we consume are enriched with certain nutrients but deficient in others. Microbial fermentation can enhance the nutritional properties of food. Bioactive peptides produced through fermentation exhibit antioxidative, anticancer, and antidiabetic properties. Increased efforts from the food industry are needed to focus research on peptides and their applications as food-grade preservatives and functional food ingredients.

This groundbreaking volume provides a comprehensive compilation of existing research, practical applications, and future research prospects. The editors and contributing experts have made an earnest effort to include every possible detail, presenting an up-to-date repository of scientific literature and their own research findings. This volume is an invaluable resource for students, researchers, product developers, and industry professionals.

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Table of Contents

Cover

Table of Contents

Series Page

Title Page

Copyright Page

Preface

1 Bioactive Compounds and Their Benefits

1.1 Introduction

1.2 Bioactive Compounds of Microbial Origin

1.3 Bioactive Compounds of Animal Origin

1.4 Bioactive Compounds Derived from Mammals

1.5 Bioactive Compounds of Endophytic Origin

1.6 Conclusion

References

2 Solid-State Fermentation of Plant-Based Food to Enhance Bioactive Components

Introduction

2.1 Terpenes/Terpinoids

2.2 Alkaloids

2.3 Phenolic/Ployphenolics

2.4 Solid-State Fermentation

2.5 Important Aspects of SSF

2.6 Microorganisms Involved in SSF

2.7 Solid-State Fermentation for the Enhancement of Bioactive Components

Conclusions

References

3 Biopreservative Agents for Food Applications

Abbreviations

3.1 Introduction

3.2 Need of Biopreservation

3.3 Fermentation: A Crucial Aspect of Biopreservation

3.4 Biopreservative Agents

3.5 Natural Antimicrobials: Their Classification

3.6 Antimicrobial Agents in Plants and Animals

3.7 Bacteriophages and Endolysins: Applications in Food Industry

3.8 Conclusion

References

4 Bioactive Peptides From Fermented Pulses

4.1 Introduction

4.2 Methods of Bioactive Peptide Production

4.3 Pharmacological Properties of Bioactive Peptides

References

5 Physiological Activities of Bioactive Peptides Against Diabetes and Obesity

5.1 Introduction

5.2 Bioactive Peptides on Human Health

5.3 Diversity in Production of Bioactive Peptides

5.4 Purification and Characterization of Bioactive Peptides

5.5 Conclusion

References

6 Biosurfactant Production From Economical Sources

6.1 Introduction

6.2 Classification of Biosurfactants

6.3 Biosurfactant Production

6.4 Factors Influencing Biosurfactant Production

6.5 Conventional Substrates for Biosurfactant Production

6.6 Food Industry Byproducts for Biosurfactant Production

6.7 Agro-Industrial Waste Utilization in Biosurfactant Production

6.8 Economic Feasibility

6.9 Applications of Biosurfactants

6.10 Conclusion

References

7 Biofortification of Food Using Fermentation

7.1 Introduction

7.2 The Need for Biofortification

7.3 Why Biofortification via Fermentation?

7.4 Nutrients that Have Been Fortified Using Fermentation Approaches

7.5 Application of Biofortification

7.6 Comparative Advantages

7.7 Bioavailability and Efficacy of Micronutrients Provided by Fermented Biofortified Foods

7.8 Conclusion

References

8 Consumers and Health Claims of Nutraceuticals

8.1 Introduction

8.2 Consumers for Nutraceuticals

8.3 Factors Influencing Consumer’s Food Preferences

8.4 Health Claims and Their Substantiation

8.5 International Regulatory Framework for Nutraceuticals’ Health Claims

8.6 Clinical and

In Vitro

Studies Validating Nutraceuticals’ Health Claims

8.7 Conclusion

References

9 Application of Bacteriocin in Wine

9.1 Introduction

9.2 Bacteriocin

9.3 Immobilized Cells Against Free Cell of LAB-Producing Bacteriocin

9.4 Potential Application of Bacteriocin in Food Industry

9.5 Bacteriocin in Wine

9.6 Factor Affecting Activity of Bacteriocin

9.7 Safety and Regulatory Consideration of Bacteriocin

9.8 Conclusion

References

10 Current Trends in Fermentative Nutraceuticals

10.1 Introduction

10.2 Phytochemicals

10.3 Polyphenolic Compounds

10.4 Alkaloids

10.5 Terpenoids

10.6 Prebiotics

10.7 Polysaccharides

10.8 Poly Amino Acids

10.9 Polyunsaturated Fatty Acids

10.10 Conclusions

References

11 Bioactive Compounds in Fermented Seafood and Their Health Benefits

11.1 Introduction

11.2 Marine-Based Bioactive Compounds From Fermentation Process and Their Health Benefits

11.3 Challenges and Future Aspects

References

Index

Also of Interest

End User License Agreement

List of Tables

Chapter 2

Table 2.1 Classification of terpenoids with bioactive properties and number of...

Table 2.2 Classification of alkaloids.

Table 2.3 Classification of phenolic bioactive components.

Table 2.4 List of substrates and microorganism used by researchers to improve ...

Chapter 3

Table 3.1 Advantages and limitations of biopreservative cultures.

Table 3.2 LAB and their biopreservative effect.

Table 3.3 Applications of bacteriocins in food industry.

Table 3.4 Lysozyme and its source

Table 3.5 Prohibitins and associated compounds.

Table 3.6 Phage and their biopreservative action.

Chapter 4

Table 4.1 Peptide sequences from common bean protein isolate hydrolysate and t...

Chapter 5

Table 5.1 Examples of food proteins derived bioactive peptides and their mecha...

Table 5.2 Cholesterol-lowering peptides.

Table 5.3 Antidiabetic peptides for T2DM.

Chapter 6

Table 6.1 Main classes of biosurfactants and respective producing microorganis...

Table 6.2 Substrates used for biosurfactant production.

Table 6.3 Advantages and disadvantages of cheaper substrates in biosurfactant ...

Table 6.4 Applications of biosurfactants in various sectors.

Chapter 8

Table 8.1 Major components of nutraceutical regulatory system in Japan.

Table 8.2 Clinical and

in vitro

studies for health effects of different nutrac...

Chapter 9

Table 9.1 List of various factors affecting the activity of bacteriocin.

Chapter 10

Table 10.1 Fermentative production of polyphenolic compounds (nutraceuticals) ...

Table 10.2 Fermentative production of flavonoid through metabolic engineering ...

Table 10.3 Fermentative synthesis of alkaloids through metabolic engineering i...

Table 10.4 Fermentative production of prebiotics through metabolic engineering...

Table 10.5 Fermentative production of polysaccharides through metabolic engine...

Table 10.6 Fermentative production of poly amino acids (nutraceuticals) throug...

Table 10.7 Fermentative production of polyunsaturated fatty acids through meta...

Chapter 11

Table 11.1 Bioactive peptide generated or transformed during fermentation.

Table 11.2 Biological methods for the chitin extraction.

List of Illustrations

Chapter 1

Figure 1.1 Various bioactive compounds produced by several microbes having ant...

Figure 1.2 Several bioactive compounds released by various species of the

Spir

...

Figure 1.3 Several bioactive compounds are released by various species of the

Figure 1.4 Several bioactive compounds released by various species of the

Chlo

...

Figure 1.5 Several bioactive compounds released by various species of the

Duna

...

Figure 1.6 Chemical structure of chitin and chitosan.

Figure 1.7 Chemical structure of glucosamine.

Figure 1.8 Chemical structure of chondroitin sulfate.

Figure 1.9 Structure of collagen.

Figure 1.10 Chemical structure of sterol.

Figure 1.11 Chemical structure of melatonin.

Chapter 3

Figure 3.1 Features of biopreservative cultures.

Figure 3.2 LAB biopreservative actions.

Figure 3.3 Bacteriocins mechanism of action.

Figure 3.4 Classes of bacteriocins.

Figure 3.5 Mode of action of various antimicrobial peptides (AMPs).

Figure 3.6 Chitosan features in food.

Figure 3.7 Antimicrobial from plant extracts.

Chapter 4

Figure 4.1 Bioactive peptides from pulses.

Figure 4.2 Mechanism of anti-cancerous activity of peptides.

Figure 4.3 Antimicrobial activity of bioactive peptide.

Chapter 5

Figure 5.1 Bioactive peptides, known for their diverse physiological activitie...

Figure 5.2 The interaction between peroxisome proliferator-activated receptors...

Figure 5.3 On Type 2 diabetes mellitus, bioactive peptides demonstrate antidia...

Figure 5.4 The production of bioactive peptides involves several methods. Enzy...

Figure 5.5 Structural characterization of fish-based bioactive peptides begins...

Chapter 6

Figure 6.1 Formation of micelles due to surfactants.

Figure 6.2 Representation for one stage and two stage fermentation process for...

Figure 6.3 Factors affecting production of biosurfactants.

Figure 6.4 Production of bio-surfactants using various substrates (a process o...

Figure 6.5 Schematic representation of conventional whey processing into vario...

Figure 6.6 Distribution of operating costs (item and percent of total operatin...

Chapter 8

Figure 8.1 Determinants of consumers’ preferences for nutraceuticals.

Figure 8.2 Classification of foods with health claims in Japan.

Figure 8.3 FOSHU system for foods in Japan.

Figure 8.4 Approval processes for FOSHU and FFC in Japan.

Figure 8.5 Nutraceuticals’ health claim types and approval process in Europe.

Figure 8.6 Evolution of Chinese health food function claims.

Figure 8.7 Outline of regulatory requirements for nutraceuticals in India.

Figure 8.8 Licensing process for nutraceuticals in India.

Chapter 9

Figure 9.1 Application of bacteriocin in different food industries.

Chapter 10

Figure 10.1 Microorganism-based production of plant-derived bioactive compound...

Figure 10.2 Diagrammatic representatives of microorganism-based generation of ...

Chapter 11

Figure 11.1 The main types of fatty acids.

Figure 11.2 Various bioactivities of marine bioactive peptides in fermented pr...

Figure 11.3 The major polysaccharides used in the current pharmaceutical indus...

Figure 11.4 Carotenoids have a wide range of bioactivity and health benefits.

Guide

Cover Page

Table of Contents

Series Page

Title Page

Copyright Page

Preface

Begin Reading

Index

Also of Interest

WILEY END USER LICENSE AGREEMENT

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Scrivener Publishing100 Cummings Center, Suite 541JBeverly, MA 01915-6106

Bioprocessing in Food Science

Series Editor: Anil Panghal, PhD

Scope: Bioprocessing in Food Science will comprise a series of volumes covering the entirety of food science, unit operations in food processing, nutrition, food chemistry, microbiology, biotechnology, physics and engineering during harvesting, processing, packaging, food safety, and storage and supply chain of food. The main objectives of this series are to disseminate knowledge pertaining to recent technologies developed in the field of food science and food process engineering to students, researchers and industry people. This will enable them to make crucial decisions regarding adoption, implementation, economics and constraints of the different technologies. Bioprocessing has revolutionised the food industry by allowing for more efficient and sustainable production methods. This comprehensive series will be focused on microbial fermentation, enzyme technology, genetic engineering, microbial transformations, and bioreactor design. As we continue to face challenges such as population growth and climate change, bioprocessing will play an increasingly important role in ensuring a sustainable food supply for future generations.

Manufacturers are looking for new opportunities to take a significant position in a food market that is continually changing as demand for healthy food rises in the current global environment. In the current scenario, academia, researchers and food industries are working in a scattered manner and different technologies developed at each level are not implemented for the benefits of different stake holders. Compiled reports and knowledge on bioprocessing and food products is a must for industry people. However, the advancements in bioprocesses are required at all levels for betterment of food industries and consumers.

The volumes in this series will be comprehensive compilations of all the research that has been carried out so far, their practical applications and the future scope of research and development in the food bioprocessing industry. The novel technologies employed for processing different types of foods, encompassing the background, principles, classification, applications, equipment, effect on foods, legislative issue, technology implementation, constraints, and food and human safety concerns will be covered in this series in an orderly fashion. These volumes will comprehensively meet the knowledge requirements for the curriculum of undergraduate, postgraduate and research students for learning the concepts of bioprocessing in food engineering. Undergraduate, post graduate students and academicians, researchers in academics and in the industry, large- and small-scale manufacturers, national research laboratories, all working in the field of food science, agri-processing and food biotechnology will benefit.

Publishers at ScrivenerMartin Scrivener ([email protected])Phillip Carmical ([email protected])

Fermentative Nutraceuticals

Edited by

Meena Sindhu

and

Anil Panghal

This edition first published 2025 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA© 2025 Scrivener Publishing LLCFor more information about Scrivener publications please visit www.scrivenerpublishing.com.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

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For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Limit of Liability/Disclaimer of WarrantyWhile the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchant-ability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials, or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read.

Library of Congress Cataloging-in-Publication Data

ISBN 978-1-119-77563-8

Front cover images supplied by Adobe FireflyCover design by Russell Richardson

Preface

The growing global interest in the health benefits of bioactive compounds has spurred significant research into their identification, extraction, and application across various industries. In particular, bioactive compounds derived from natural sources have garnered attention for their potential therapeutic properties, offering diverse solutions to modern-day health challenges. The intricate relationship between bioactive compounds and human health has led to their incorporation in fields as varied as food, medicine, and cosmetics, making them indispensable in the ongoing pursuit of improving human well-being.

This book, Fermentative Nutraceuticals, is a comprehensive compilation that explores the diverse array of bioactive compounds derived from various sources, including microorganisms, plants, animals, and marine organisms. Edited by a group of eminent international scholars, each chapter provides valuable insights into the latest research, technological advancements, and practical applications of bioactive compounds across different sectors.

The book delves into bioactive compounds of microbial origin, with chapters covering a range of sources such as bacteria, probiotics, prebiotics, and microalgae and expand the scope to include bioactive compounds of animal origin, including those derived from marine invertebrates, fishes, and mammals, which have been shown to provide anti-inflammatory, antioxidant, and immune-modulating effects. Additionally, bioactive compounds from endophytic plants and those produced through solid-state fermentation are covered in detail. This fermentation-based approach is increasingly recognized as an effective means to enhance the bioavailability and potency of bioactive components, with profound implications for both health and industry.

One of the key highlights of this book is the detailed discussion on the use of biopreservatives and natural antimicrobials. With the growing demand for natural and sustainable food preservation methods, this section highlights how bioactive agents from bacteria, plants, and animals can play a pivotal role in ensuring food safety while maintaining nutritional value. The book also touches upon the potential of bioactive peptides—small proteins with powerful bioactive effects—ranging from antihypertensive to antimicrobial properties, with a focus on their production from fermented pulses. Biofortification, a process of enhancing the nutrient profile of food through fermentation, is also thoroughly examined, with a particular focus on its ability to improve the bioavailability of essential micronutrients.

Finally, the evolving world of nutraceuticals is explored, with chapters discussing the health claims of various bioactive compounds and the regulatory frameworks governing their approval. International perspectives from regulatory systems in Japan, Europe, the United States, China, and other regions provide a comprehensive understanding of the global landscape surrounding nutraceutical products and their health benefits.

This book is a valuable resource for researchers, academics, and industry professionals interested in the diverse applications of bioactive compounds. It serves as a bridge between scientific research and real-world applications, offering an in-depth look at how bioactive compounds can be harnessed to address pressing health issues and promote well-being on a global scale.

We extend our sincere gratitude to the esteemed authors who have contributed their expertise and to Wiley-Scrivener for their continued support in publishing this important work. Their collaboration has made it possible to bring together the latest scientific advancements and practical knowledge into a single, accessible volume for the benefit of all readers interested in the future of bioactive compounds and their transformative potential.

We would like to express our sincere gratitude to our employer, Chaudhary Charan Singh Haryana Agricultural University, Hisar, for their unwavering support and encouragement throughout the course of this work.

Meena Sindhu

Anil Panghal

1Bioactive Compounds and Their Benefits

Love Singla1* and Smriti Batoye2

1Department of Microbiology, Maharaja Agrasen University, Baddi, Himachal Pradesh, India

2Department of Zoology, Maharaja Agrasen University, Baddi, Himachal Pradesh, India

Abstract

Bioactive compounds are one of human health's most critical and essential components. These are primarily released from various biological sources, including microorganisms (bacteria, fungi, and algae), animals, and endophytes. Their molecular diversity offers excellent support in possessing several therapeutic attributes and biological workings. Over the past few years, massive natural compounds have been extracted, identified, and applied as dietary or medicinal compounds. Because of this reason, various pharmaceutical and food industries have shown their interest in shifting to these kinds of bioactive compounds to uncover the secrets of disease treatments and enhancement of food nutritional components by these compounds of diverse biological origin. Several bacterial species help combat human diseases, including intestinal, liver, and kidney infections. In addition to bacteria, several algal and fungal species also help in the containment of these kinds of conditions. Moreover, some compounds are also procured from animals and endophytes. Let us detail the applications of these bioactive compounds in human health and disease protection.

Keywords: Bioactive compounds, bacterial origin, microalgal origin, animal origins, endophytic origins

1.1 Introduction

In this contemporary world, several reports have stated the dangerous effects of bad eating habits and the rapid pace of junk food intake compared to the past decade. Moreover, excess intake of antibiotics has increased the cases of antibiotic resistance, which has affected thousands of patients at present. This dissimilarity among the eating patterns has led to the enhancement of oxidative stress levels that, in turn, causes various chronic disorders like cardiovascular and neurodegenerative disorders and several types of cancer [1]. According to the WHO reports, most of the mortality rate has been because of cancer in the last decade globally [2]. Similar to cancer, diabetes mellitus is also one of the dangerous disorders in present times that are associated with several health problems like heart failure, kidney dysfunction, and blindness [3–5]. Due to the enhancement of antibiotic resistance, scientists look forward to newer approaches to combat this apocalypse. In addition, several other problems are also increasing with antibiotic resistance, like toxicity in cells and metabolic dysfunctioning [1]. Researchers use natural products/metabolites as alternative and safe options against pathogenic microbes [6]. Their presence in day-today diet or standardized formulation helps prevent the negative impact of oxidative stress on human health [7–10].

Natural compounds or metabolites are among the safest and eco-friendliest sources in various living entities like microorganisms, endophytes, plants, animals, and humans [11]. It comprises a large number of chemically diversified and is marked as one of the remarkable therapeutics capable of fighting against a wide variety of infectious entities. The first ever bioactive molecule beneficial for human health was found in ancient Mesopotamia near 2600 B.C. Over time, natural bioactive metabolites gain importance but at a slow rate compared to antibiotics growth in the pharmaceutical market. In today's world, more than 60% of pharmaceutical products are derived from compounds with bioactive properties, and around 50% of Food and Drug Administration (FDA)–approved drugs are related to bioactive metabolites [12, 13].

The application of natural metabolite for human benefit is seen from the discovery of the penicillin antibiotic. The accidental discovery of penicillin from a fungal species called Penicillium chrysogenum (earlier known as Penicillium notatum) in 1928 has led to the scientific interest shift from plants to microbes regarding the extraction of metabolites as a bioactive compound source [14]. From then, the secondary metabolites of microbes gain their application in various fields like pharmaceuticals, healthcare, the food industry, and scientific research [15]. With the advancement in technology, scientists gain the ability to discover newer beneficial effects of bioactive compounds on human health, including various discoveries of new methods that help in the development of novel therapies [16]. These bioactive compounds are further investigated for several properties that make them the best candidate for the fight against antibiotic resistance and attenuate the symptoms of several pathogenic infections, which are gaining power at an alarming rate [17].

Herein, we will summarize several bioactive compounds of various origins like plants, animals, endophytes, marine environment, and microorganisms and their biological applications in present-day pharmaceutical industries and discoveries of various newer therapies.

1.2 Bioactive Compounds of Microbial Origin

1.2.1 Bacterial Origin

The presence of dietary compounds in a contemporary diet provides an excellent way to enhance the nutritional value of public health [18]. The presence of various compounds having nutraceutical value and the addition of dietary compounds leads to the decrement of disease occurrence possibilities. This implies the importance of emerging innovative functional foods that help in providing physiological benefits and decreases the long-term risk of disease occurrence [19]. In these functional food groups, lactic acid is one of the most important examples that is further divided into three groups based on the availability in different formulations [20]:

1.2.1.1 Probiotics

These play a crucial role in enhancing the digesting mechanism in microbes, like most of the Lactobacillus and Bifidobacterium genera species. These benefit the host by maintaining the intestine–bacteria balance and growing in association with the intestinal mucosa by releasing several enzymes that help preserve osmoregulation and digestion. Due to so many benefits for human health, these are incorporated in various substances/products like yogurts, ice cream, and frozen dairy desserts [21, 22].

1.2.1.2 Prebiotics

These are a group of food supplements that are non-digestible and are extracted from the plants followed by the action of hydrolytic enzymes but have the ability to stimulate the multiplication/growth of specific natural microbiota/probiotic bacteria present in the colon region by providing various kinds of development promoting/enhancing derivatives or nutrients [23].

1.2.1.3 Biogenics

These are the bioactive compounds released by various bacterial species in favor of the host, i.e., they help the host in multiple types like its growth, immunostimulation, peroxidation, and intestinal putrefaction.

In addition to the growth enhancement of intestinal microbiota with the help of various growth-enhancing compounds produced by the different bacterial species, they also release various other biogenic compounds that function against other bacteria species, leading to the bactericidal effect and enhancing the immune system by acting as an immunostimulant [20]. Due to various health-beneficial effects (treatment of several human-associated intestinal dysfunctions) other than gut-specific (enhanced digestion) and immunological (cell-mediated immune response), it is believed that probiotics show beneficial effects at both levels (cellular and molecular levels) [24, 25]. Moreover, these probiotics can also act as a delivery system for different types of vaccines without being affected by intestinal microbiota. Recent reports also explain the beneficial properties of probiotics in cancer therapy and as a therapeutic agent in patients with high cholesterol levels [26]. Mainly, Lactobacillus and Bifidobacterium species are primarily associated with the functioning of probiotics due to their beneficial properties like non-pathogenic, safe to consume, metabolic stable, adherence to the walls of the intestine, and no antibiotic resistance.

In addition to benefits, there should be some properties that bacteria species should possess to be a part of the probiotic group. It includes the survival ability of bacilli along the upper digestive tract (resistance from hydrochloric acid, gastric juice including bile, various proteolytic enzymes, and several other reactive-oxidative radicles) and possesses the ability to aggregate along through the natural microbiota present in the lower digestive tract with the secretion of several beneficial compounds that have the capability to enhance the health status of the host after its adherence along the intestinal walls [20, 26]. However, during the delivery of probiotic bacteria to its site, we encounter various problems (biotic and abiotic) that resist its effect, leading to its loss of beneficial properties. Biotic conditions include a decrease in the viability of probiotic microbes in dairy food materials. Abiotic conditions include variations in pH, temperature, and the concentration of dissolved oxygen in the medium.

To overcome these conditions, several delivery systems/approaches are used to enhance probiotic resistance by selecting specific bacterial species that show resistance against the biotic and abiotic conditions, incorporating the bacilli with micronutrients, or got microencapsulated [27]. Scientists have discovered many delivery systems that are further categorized into two groups:

Use of non-conventional commercial-based formulations: It consists of food products (cheese, yogurts, creams, chocolates, meat, milk, and many more), in which probiotic bacteria might help their growth and formation.

Use of conventional pharmaceutical systems: It includes the use of capsules or tablets as a delivery system that can be promising and shows effectiveness in this scenario as they are well described and formulated concerning other carrier systems available commercially in the food industry.

It has been found that each formulation has its advantages in delivering probiotics, demonstrating its difference in how well it makes an appropriate number of bacteria available to the human gastrointestinal system and how much its effectiveness is in protecting the bacteria added to the body system [26]. Figure 1.1 presents microbial-derived natural products having antibacterial properties.

Figure 1.1 Various bioactive compounds produced by several microbes having antibacterial properties [28–31].

1.2.2 Microalgal Origin

Microalgae are a group of unicellular species that have the ability to grow in both (freshwater or saline water) water bodies with variation in length or diameter (ranges in 3–10 μm approximately). It includes organisms from both organisms group (prokaryotic and eukaryotic) [32]. Cyanobacteria are classified under this group and are named green algae due to the presence of chlorophyll α and other essential compounds for a photosynthetic process [33]. It accounts for about 40% of total photosynthesis by microorganisms in the aquatic environment globally [34]. Several studies have shown that these microalgae contain many bioactive compounds with commercial value [35]. Other reports stated the beneficial effects of these bioactive compounds on humans, their ability to degrade, and their applicability in the case of animals [35]. These compounds might possess several properties, like antibacterial, antiviral, antifungal, antioxidant, anticoagulant, anti-cancerous, and anti-inflammatory [36].

1.2.2.1 Spirulina

This is one of the best protein food supplements with approval from the FDA as GRAS (generally recognized as safe). These are groups of prokaryotic cyanobacteria of the Cyanophyta phylum. [37]. These are recalled as a former member of oxygen generation on this planet and plays a regulatory role in this planetary biosphere [38]. This group of microalgae has a high protein value with significant levels of essential polyunsaturated fatty acids (PUFAs) and other crucial phenolic compounds [39]. It is also rich in vitamins (B1, B2, B12, and E) and several pigments or oligo-elements, the primary source of calcium, iron, and several essential elements required for growth [37].

Additionally, several microalgae species have the property to produce several pigments with antioxidant properties [40–42] (Figure 1.2). Moreover, they can release several chemicals in intracellular and extracellular environments with various biological and therapeutic properties like antiviral, antimicrobial, antimalarial, treatment of hyperlipidemia, and cancer [39, 42–46]. Because of these abilities, this is one of the most studied microalgae on the global level [47].

1.2.2.2 Nostoc

Nostoc is a group of edible microalgae that possesses various bioactive compounds and biomass; both have efficient biological properties as they can be used in the medical sphere and can act as a dietary supplement due to the presence of several essential biomolecules like vitamins, minerals, and protein content. Practical applications of these microalgae are seen in treating fistula and some types of cancer. Their biomass can be used as an anti-inflammatory compound in addition to digestion, blood pressure, and boosting of the immune system, as well as being antiviral and antibacterial [51–53]. Several species of Nostoc released cyanovirin, a bioactive compound with proteinaceous nature, possess a constructive effect against viral infections [HIV and influenza virus (H1N1)] [54, 55]. Various precursors of biomolecules important for the pharmaceutical industry are also released by Nostoc sps. that includes several PUFAs, including essential fatty acids (e.g., linoleic acid and octadecatetraenoic acid) [56]. Figure 1.3 shows different bioactive compounds of microalgal origin.

Figure 1.2 Several bioactive compounds released by various species of the Spirulina genus [48, 50].

1.2.2.3 Chlorella

It is one of the members of the microalgal biomass market, with 4,000 tons of annual production as a significant source of protein. It has a eukaryotic genetic framework belonging to the Chlorophyta group [57]. This genus contains chlorophyll, proteins, and other biomolecules [37]. Their biomass is also enriched in vitamin B12 complex, and several other members are essential from a medical point of view. Biomass of Chlorella species is also certified as GRAS by FDA. Chlorella releases several bioactive molecules into the environment. Out of this, β-1,3-glucan is the most critical bioactive compound that has the ability to reduce the concentration of free radicals and cholesterol levels in the blood.

Figure 1.3 Several bioactive compounds are released by various species of the Nostoc genus [48].

Additionally, Chlorella produces many other compounds that are antitumor, anti-inflammatory, anticoagulant, etc. It was also reported that some of their molecules could act as a preventive measure against hypercholesterolemia and atherosclerosis [58]. Figure 1.4 presents various bioactive compounds released by different species of Chlorella.

Figure 1.4 Several bioactive compounds released by various species of the Chlorella genus [48, 50, 59].

Figure 1.5 Several bioactive compounds released by various species of the Dunaliella genus [48, 64, 65].

1.2.2.4 Dunaliella

This is one of the extensively studied microalgae because of its ability to multiply in extensive environmental conditions. It is green unicellular microalgae of the Chlorophyceae group with halotolerant properties and has many applications in biotechnological aspects [60, 61]. It contains β-carotene (14% of its dry weight), also rich in proteins and essential fatty acids with low growth conditions (high salinity, nutrients, light, and temperature deficiency) [37]. Research stated the antibiotic ability of cells’ extract. According to the researchers, a crude extract shows antimicrobial properties against a wide variety of bacterial species (Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Escherichia coli, Candida albicans, Aspergillus niger, and Enterobacter aerogenes) [60, 62, 63]. Figure 1.5 shows bioactive compounds secreted by different species. Out of these, some play a crucial role in the food industry as they contain several important enzyme production properties in the food and meat industry.

1.3 Bioactive Compounds of Animal Origin

Chemical compounds that have biological effects on living creatures are referred to as bioactive substances. The bioactivities include the potential for disease prevention and treatment; function as substrates for the production of biomolecules and biostructures, control of biosystem function; effects as preservatives against bacteria; and carriers for medications, enzymes, and nutrients. Animals are abundant sources of bioactive chemicals due to their extensive biodiversity, and humans can benefit from these compounds by eating animal food. Some animals have the capacity to release some bioactive compounds required for biological and protective activities from several kinds of stresses, like endogenous or exogenous stresses. Moreover, in some cases, these compounds are more critical for other unrelated organisms than their benefit [66].

1.3.1 Marine Invertebrates

Crabs, mollusks, and Echinodermata are edible marine invertebrates that can be utilized as organic-based biopolymers for many purposes. These biopolymers, composed of protein and polysaccharides, have been used by humans as food and nutraceutical ingredients for decades to cure various ailments. In the biomedical business, biopolymers like chitin, chitosan glycosaminoglycans, and fucosylated chondroitin sulfate have recently gained popularity for treating various illnesses. In addition to being utilized in animal feed, these substances have anticancer, antibacterial, anti-inflammatory, wound-healing, and antimicrobial properties [67].

1.3.1.1 Chitin and Chitosan

These compounds are made of amino-polysaccharides. Chitin is a polymer with β-(1→4)-N acetyl-D-glucosamine as a monomeric unit, whereas chitosan formation involves different deacetylation levels in the alkaline environment. It is made of two polymers β-(1→4)-2-acetamido-D-glucose and β-(1→4)-2-amino-D-glucose units are illustrated in Figure 1.6.

Because of their distinct structural characteristics, chitin and chitosan are highly insoluble substances with minimal chemical reactivity that support the external and internal organization, as seen in invertebrates.

Crab and shrimp shells are the primary commercial chitin sources, particularly those collected as industrial food waste for economic considerations. Chitin is industrially extracted from crustaceans by removing calcium carbonate with acid and then solubilizing proteins with alkali [68]. The extracted chitin may be further decolorized and treated to remove pigments and impurities due to the raw material sources and the purity and color requirements for later utilization. Chemical (acidic) hydrolysis and enzymatic hydrolysis are two ways to make chitin and chitosan oligomers of 10 units or less. To increase their strength, solubility, and tractability and create new features, functions, and applications, particularly in the biomedical field, chitin and chitosan can also be physically and chemically altered.

Figure 1.6 Chemical structure of chitin and chitosan.

1.3.1.2 Glucosamine

Glucosamine is an amino monosaccharide endogenously synthesized from glucose (Figure 1.7). Meat, chicken, and fish are food sources of glucosamine, while one of the most popular dietary supplements is glucosamine sulfate, which is the salt of D-glucosamine with sulfuric acid. Additionally offered as glucosamine nutritional supplements are glucosamine hydrochloride and N-acetylglucosamine. Oral administration, intravenous injections, intramuscular injections, and intra-articular injections are the methods for taking glucosamine supplements. Taking glucosamine via the oral route can significantly reduce osteoarthritis symptoms [69].

The fact that glucosamine accumulates in cartilage shows that glucosamine plays a significant role in the composition and structure of cartilage. Chondrocytes do their primary production with the help of glucose, which acts as the primary substrate for producing several critical biological chemicals like glycosaminoglycans and proteoglycans (which constitute the extracellular cartilage matrix). A lack of proteoglycans can cause articular cartilage to degenerate, and glucosamine is necessary to rebuild the proteoglycan-rich matrix, balance cartilage catabolism and anabolism, and safeguard damaged cartilage from metabolic impairment [66].

Figure 1.7 Chemical structure of glucosamine.

1.3.1.3 Chondroitin

The linear polysaccharide chondroitin (Figure 1.8) comprises D-glucuronic acid and D-N-acetyl-galactosamine disaccharide units. Although chondroitin sulfates share the same basic structural features as naturally isolated chondroitin, they contain additional sulfate ester groups, primarily at the C-4 and C-6 of N-acetylgalactosamine or the C-2 of glucuronic acid. Pig and ox cartilage contains up to 35%–40% chondroitin. It is also possible to isolate from sharks, squid, and crab cartilage. Like glucosamine, one of the critical functions of chondroitin sulfate in medicine is the management of osteoarthritis. Chondroitin interacts with a wide range of molecules, including growth factors, cytokines, chemokines, adhesion molecules, and lipoproteins, to perform various biological tasks. To target tumor cells with new medications or drug delivery systems and to interact with potent molecules in the extracellular matrix or on cell surfaces, chondroitin sulfate that has undergone chemical modification or undergone changes to its sulfation patterns has been developed [70]. As a result, chondroitin sulfate serves as a crucial precursor molecule for developing effective anticancer agents.

The broad group of marine invertebrates can be found throughout the environment, from the intertidal zone to the deep ocean. Some taxonomic groups are Annelida (marine worms), Porifera (sponges), cnidaria (corals, jellyfish), mollusks (oysters, prawns, and crayfish), and echinoderms (starfish, sea cucumbers, and sea urchin). Coastal communities have a long history of employing marine invertebrates in their diets and for medical purposes. Commercially significant compounds, called collagen, are obtained from edible marine animals. About 30% of the total protein in all animal skin and bones is collagen. Mammalian collagen can be replaced by marine-produced collagen, which is frequently employed in biomedical applications [67].

Figure 1.8 Chemical structure of chondroitin sulfate.

1.3.1.4 Collagen

The marine environment is an exciting source of collagen and bioactive substances utilized in different fields, including the pharmaceutical, cosmetic, and food industries. Depending on the source, marine collagen can be divided into two categories: Invertebrate sources of marine collagen include cuttlefish, sea anemones, prawns, starfish, jellyfish, sponges, sea urchins, octopuses, and squid. Collagen obtained from these creatures is known as marine invertebrate collagen. Fish and mammals are examples of marine vertebrate sources comprising another type of marine collagen. Figure 1.9 shows the basic structure of collagen in addition to its molecular size. In fishes, collagen is usually extracted from meat, skin, fins, scale, and fish wastes; fish collagen can be purified in cosmetics, medicine, sports, and nutrition [71].

It has long been recognized that sponges contain many bioactive substances. Marine sponges contain large amounts of unusual sterols (Figure 1.10), and these sterols have a variety of roles in biological membranes. Sulfated and alkaloid sterols have been demonstrated to be antibacterial [72].

Figure 1.9 Structure of collagen.

Figure 1.10 Chemical structure of sterol.

Cnidarians are the wealthiest natural producers of prostaglandins, recently discovered in the soft coral Plexaura hamomala of the Caribbean Sea. Bioactive chemicals have also been extracted from bryozoans. A marine polychaete (phylum Annelida) effectively treats various pathophysiological conditions, including osteoporosis, bone cancer, and arthritis. The marine annelid Arenicola marina was used to extract the bioactive chemical. Marine arthropods have produced several bioactive compounds like Limulus Amoebocyte, Tachypleus, and Lysate. The most famous bioactive substance synthesized from marine arthropods is called Amoebocyte lysate. It is an aqueous extract of blood cells from horseshoe crabs [73].

Shrimp is popular seafood worldwide, and its lipids have been investigated for biological activity in muscle and exoskeleton. This fraction comprises free fatty acids, triglycerides, carotenoids, and other lipids, and some of these substances have been connected to cancer chemoprevention. Carotenoids and PUFAs have been extensively studied for their chemopreventive properties in both in vivo and in vitro studies. The bioactive Spisulosine, derived from the Hawaiian mollusc Elysia rufescens, has antileukemic qualities. The synthetic analogs of Dolstatin, Synthadotin, and Soblidotin derived from the molluscan species Dolabella auricularia are presently being evaluated for medicinal potential. It has been discovered that the mollusc D. auricularia produces several dolastatins, which are cytotoxic and anticancer substances [74]. The most prevalent bioactive substances that can be located in echinoderm metabolites are saponins. These can be found in sea urchins, starfish, and sea cucumbers, among other things. Asterosaponins are sterol derivatives, but it has been asserted that sea cucumber saponins are terpenoid-derived [75].

1.3.2 Marine Fishes

Marine fish have long been regarded as a nutritious food. Still, recent developments in the field of nutraceuticals and functional foods have revealed that their value goes beyond nutritive value, as they contribute molecules to our diet that play a crucial therapeutic role in preventing human diseases. Recently, by-products from the fish industry have been considered a potential source of beneficial components, including enzymes, peptides, and collagen, that could improve human health or be used to create new pharmaceuticals [76]. Fish are the most frequently consumed marine species, essential to the world economy. The nutritional advantages of fish-eating are attributed to proteins, minerals (such as selenium, calcium, iron, and zinc), essential unsaturated fatty acids, and vitamins, such as vitamins A, D, E, B3, B6, and B12. Additionally, it has been discovered that peptides produced from fermented fish following enzymatic treatment are effective therapies for several types of hypertension, cancer, viral infections, and Alzheimer's disease [77].

1.3.2.1 Omega-3 Fatty Acids

Omega-3 fatty acids are PUFAs with two or more double bonds, and one double bond is located at the third carbon atom counting from the methyl end of the carbon chain. Several types of omega-3 fatty acids are present in foods and are essential, including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA).

Fish and seafood products are the principal dietary sources of omega-3 fatty acids, which include ALA, EPA, DPA, and DHA. Fish and seafood account for more than 70% of EPA, DPA, and DHA intake, whereas meat accounts for the remaining 20%. Several fish species having high EPA and DHA content include herring, salmon, sardines, tuna, and halibut. At first, phytoplankton and other marine plants, as well as algae, produce EPA and DHA. These compounds are then transmitted down the food chain and deposited in fish lipids. Fish residing in the Atlantic region seem to have exceptionally high stocks of these long-chain omega-3 fatty acids, probably due to the cold water's chilly temperature maintaining the fatty acids’ fluidity [78].

The biological importance of omega-3 fatty acid supplementation comprises two aspects:

Humans are inefficient in producing/synthesizing omega-3 fatty acids on their own. So, diet is the central area where it is readily available.

Various scientists have researched the health benefits of the consumption of omega-3 fatty acids

[84]

.

The biological benefits of omega-3 fatty acids for preventing and even treating several disorders have received extensive publication. Several reports have shown that people from various regions of the world (Japan, South India, Quebec, and several others) have lower risks of cardiovascular diseases when they consume fish as their daily diet, especially fish with fatty acids (like tuna, mackerel, trout, and salmon).

1.4 Bioactive Compounds Derived from Mammals

1.4.1 Conjugated Linoleic Acid

The concentration of CLA is much higher in meat and dairy products received from ruminants compared to the meat from monogastric animals (such as turkey, pork, and chicken) and fish, which has CLA in a lower concentration. PUFAs act as the substrate for the biosynthesis of CLA, which involves isomerization or hydrogenation as part of their lipid metabolism. CLA provides various bioactive properties, including anti-adipogenic and anticarcinogenic activities [66].

1.4.2 Milk Peptides

Milk is the best source of various bioactive peptides, out of which most of them remain inactive until activated by enzymatic proteolysis. In lactic acid bacteria, the milk fermentation process enhances the activity of various cell wall-bounded and intracellular enzymes, including proteinases and peptidases [80]. Enzymes released in the human digestive tract also play an essential role in activating bioactive peptides, leading to the breakdown of proteins and other long polypeptides. There are several peptides that are derived from milk proteins, including phosphopeptides, that can act as a carrier of different minerals, especially calcium. This activity is due to its mineral binding ability, which can act as an attribute to bind with negatively charged phosphate groups while influenced by adjacent amino acids around the binding site [66].

1.4.3 L-Carnitine

In 1905, Russian researchers extracted free carnitine for the first time from beef muscle. Foods derived from animals, such as milk and meat, are commonly found to contain this highly polar small amino acid derivative. Lysine and methionine, two essential amino acids, are used as precursors and cofactors for the production of carnitine, which primarily takes place in the liver. The kidney and brain can also produce carnitine [81]. L-carnitine provides several bioactive activities with critical biological origins (oxidation of long-chain fatty acids by the mitochondria, the export of acetyl and chain-shortened acyl products from peroxisomes, the maintenance of cellular CoA homeostasis, etc.) [82].

1.4.4 Choline

Choline molecules are mainly a component of phospholipid “lecithin” (phosphatidylcholine), primarily consumed via our daily diet, as humans cannot produce it by themselves. These are critically required to provoke liver and muscular dysfunction. The acceptable amount of choline is based on factors like sex, clinical status, and gene polymorphisms. Four enzymatic reactions occur in mammalian tissues (phosphorylation, oxidation, acetylation, and base exchange) [83].

1.4.5 Melatonin

The hormone melatonin, also known as N-acetyl-5-methoxy-tryptamine (Figure 1.11), is primarily produced and secreted by the pineal gland in animals. The metabolic synthesis utilizes plasma tryptophan as a precursor, which undergoes four intracellular enzymatic steps catalyzed by tryptophan hydroxylase, aromatic amino acid decarboxylase, arylalkylamine-N-acetyltransferase, and hydroxy indole-Omethyltransferase successively [84]. Both melatonin synthesis and release are rhythms controlled by a circadian clock in the hypothalamus. Specifically, the production of this pineal hormone is light-inhibited, so the level over nighttime far exceeds that of daytime. The gastrointestinal tract of vertebrates is a rich source of extrapineal melatonin, and the concentration in tissues and plasma cells is mainly associated with its concentration in food intake.

Figure 1.11 Chemical structure of melatonin.

In certain countries, melatonin is available in grocery stores as a “food supplement” without a prescription. It is believed that using melatonin in small amounts for its advantageous clinical effects is safe. Exogenous melatonin has been proposed as a treatment for psychiatric and sleep problems based on the physiological significance of melatonin in regulating circadian and seasonal rhythms [85].

1.5 Bioactive Compounds of Endophytic Origin

Several medicinal plants have the ability to excrete a wide variety of scavenging molecules that are bioactive and have antioxidant properties. These molecules involve quinones, lignins, alkaloids, terpenoids, etc., that can prevent the reactive oxygen species (ROS) and oxygen-derived free radicals from causing deterioration at the cellular and molecular level, carcinogenesis and DNA damage, etc. As a result, they hold great promise for preventing and treating diseases linked to ROS, including hypertension, cancer, cardiovascular diseases, atherosclerosis, neurode-generative diseases, diabetes mellitus, and aging. Scientists are mainly focused on the antioxidative properties of several endophytes of medicinal plants [86].

Endophytic microbial communities are a natural source of various bioactive substances, including metabolites from host plants. The endophytic Pestalotiopsis microspora from Papua New Guinea provided pestacin and isopestacin. The antioxidant activity of pestacin was discovered to have more antioxidant training than regular Trolox (a vitamin E derivative) [87]. Five endophytic fungal strains with high antioxidant capacity were found through research on the alpine plant Rhodiola rosea[88]. When antioxidant components of 112 Chinese medicinal plants were examined, phenolic compounds were found to be the predominant component, indicating positive linear relationships between the overall antioxidant capabilities and phenolic levels [89]. A recent phytochemical investigation of the endophytic fungi of Eugenia jambolana reported the presence of several antioxidant chemicals of several nature (alkaloids, phenols, flavonoids, saponins, and terpenes). The main chemical components that reduce lipid peroxidation are phenols and terpenes, which function as primary and secondary antioxidants. Endophytic extracts with more amazing phenolic content also displayed intense antioxidant action [90].

Azadirachtin is an oxygenated tetranortriterpenoid found in Azadirachta indica (Indian neem; used to cure fever, pain, leprosy, and malaria) [91]. Camptothecin is a pentacyclic quinoline alkaloid with antineoplastic (that prevents or halts tumor growth) properties obtained from Camptotheca acuminata and Nothapodytes nimmoniana[92]. The medicinal plant Hypericum perforatum (commonly known as St. John's Wort) produces hypericin (a naphthodianthrone derivative), which has several medicinal properties such as antimicrobial (bacteria, fungi, and viruses) antioxidant, anti-cancerous, and antidepressant [93]. Withanolides are secondary metabolites composed of a steroid backbone coupled to a lactone or its derivatives found in Withania somnifera (commonly known as Ashwagandha or Indian ginseng). These metabolites are widely used as memory, stamina enhancers, and nerve tonics and have cardioprotective, neuroprotective, anti-diabetic, and antioxidant properties [94].

1.6 Conclusion

Bioactive compounds of different origins will make a significant change in future life and are the birthplace of several therapeutic drugs present in concordance with natural therapies across the globe. More preference is given to natural therapies as they are reliable based on their side effects and dosage. So, these natural therapeutics are essential to be used as drugs from a disease treatment point of view. As these compounds got the spotlight recently, their reference could be gained from literature scripted thousands of years ago by different civilizations. However, a scientific study including isolation, identification, and confirmation of these compounds are in waiting and required for the growth of the next generation of therapeutics that will be natural. In addition, several aspects should be focused on, including various quality assessment tests of raw materials with the combinations that make them efficient in contending with present medicines. Additionally, new and leading-edge technologies for purification, in vivo studies, and clinical trials are required for the best use of these compounds in various spheres of life, which can be food (betterment of nutrient content), therapeutics (finding of newer treatment technology), cosmetics, etc., with safety and efficacy. The scientists believe that the usage of bioactive compounds from different origins in the present scenario of nutraceuticals and functionalized foods, in addition to the advanced health claims, is not so far.

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