Keywords

8.1 Introduction

8.1.1 Physiology of Metabolism

Living cells are actively engaged in conducting various processes, sustaining the survival of cells, depending on highly orchestrated biochemical reactions. The body of any living being is a beautifully sophisticated factory. It recognizes unprocessed substances (food), some of these substances are burned to produce energy, some are used to generate complete objects, some are stored, and unused goods are removed from the body to maintain homeostasis in the body. Storage products are used for growth and development. Metabolism is a general concept that constitutes all biochemical changes that are taking place in living organisms to sustain life. Metabolism processes are important for growth and reproduction and enable living organisms to maintain their structure as well as to respond to their environmental needs. Another general term is metabolic processes that describe the sequence of chemical reactions that either break down higher molecular weights and complex compounds into smaller units (catabolism) or the creation of larger molecules from smaller ones (anabolism). For example, eating bread or rice breaks the starch into glucose units in food canal bread or rice. These glucose units are further catabolized to release energy and perform various biological functions, including muscle contractions. In contrast, an anabolic reaction assembles glucose molecules to form glycogen as a storage form. Metabolic processes never stop or are inactive, but these processes are continuous depending on internal or external stimuli.

8.1.2 Cell: The Metabolic Processing Center

Cells are the workstation of metabolic processes (both catabolic and anabolic), but the body of living organisms is composed of different types of cells, including hepatic cells, neural cells, renal cells, reproductive cells, and muscle cells. A typical animal cell is the main two parts of the nucleus and the membrane-bounded space called cytoplasm. Cytoplasm is a semifluid substance of a cell that fills the cytoplasm with different organelles inside the cytosol, small units that perform unique metabolic functions. One of these organelles is a capsule-like mitochondria (cell powerhouse), which generates energy through various energy-generating pathways.

Carbohydrates are an essential source of energy for various reactions. Glycolysis is a basic metabolic pathway present in all species through which glucose is converted into energy-release products (ATPs), NADH, and two pyruvate molecules. Glycogen, which is processed as glucose in vertebrates, is synthesized through the glycogenesis process when blood glucose levels increase and break through the glycogenolysis process (glucose deficiency/glucose supply shortness). Glucose is also synthesized from noncarbohydrate sources known as gluconeogenesis under stress conditions. In addition, the pentose phosphate pathway makes a cell capable of switching glucose 6-phosphate (G6P), a glucose derivative, to ribose 5-phosphate (used to synthesize nucleotides as well as nucleic acids) and various other monosaccharides. NADPH, produced via the pentose pathway, is an important reductant present in the cells. In vertebrates, glucose is transported through circulatory blood throughout the body. As the energy level in the body decreases, the glucose contained in the form of glycogen in the liver and muscle is converted through the glycolysis process. Some cells in different organs (brain, red blood cells, and skeletal muscle cells) need a continuous supply of glucose to meet energy requirements.

Protein metabolism consists of different biochemical processes required for protein and amino acid synthesis (anabolism) and protein degradation by catabolism. Necessary amino acids must be supplied or taken from external sources in the form of a diet. Amino acids derived after protein breakdown are accelerated to provide precursors for gluconeogenesis and protein resynthesis, as well as to facilitate the process of DNA replication and cell proliferation, such as immune system cells, wound care, and other processes. Proteins have a particular and complex metabolism role, proteins do not act as energy sources for the growth and development of the organism, but they also make up raw materials for the construction of the body. When the proteins are fully digested, the free amino acids released pass through the portal circulation and are then dispersed across the body and provide substrates for various synthetic transformations associated with the creation of tissue components. Proteins in each tissue are supposed to be synthesized within the same cell locality, but influential factors are responsible for the mixture of amino acids in the correct order as well as in the correct proportions (Rose 1933). The proteins have various important positions in the structure as well as the functions of muscle, hemoglobin, hormones, fibrin, and receptors.

As amino acids are degraded from ketoacidosis through the process of oxidative deamination or transamination (the amino acid group is separated from the amino acid to form urea), acetyl coenzyme A may also be produced. Acetyl coenzyme A enters the citric acid cycle to generate ATP. In standard situations, protein metabolism is suppressed due to the presence of glucose levels in the circulation of the blood. A small amount of glucose is required to increase the level of insulin in circulatory blood to block protein breakdown (Kovacevic and McGivan 1983).

Lipids include a wide collection of water-insoluble (hydrophobic) organic molecules, which are removed from tissues by nonpolar solvents due to their insolubility in aqueous solutions. The body of the organism is divided into various structures, such as the plasma membrane/triglycerols globule, in adipocytes, or into the plasma associated with proteins, as well as in the lipoprotein unit or albumin.

Lipids are the key basis of the power to conduct routine functions in the body, and they also have a hydrophobic shield. In addition to this lipid, it also performs other functions, including fat-soluble vitamins acting as regulators or coenzymes, and prostaglandins as well as steroid hormones that contribute to the maintenance of homeostasis in the body. Lipid undergoes a process of emulsification in the small intestine, particularly in the duodenum. The method of emulsification is mediated by bile salts, as well as by mechanical peristalsis mixing. Bile salts (cholesterol derivatives) are formed in hepatocytes and stored in the gallbladder. Bile salts consist of a sterol ring structure having a side chain in which a glycine or taurine molecule is covalently bound by an amide linkage. Bile salts cooperate with lipid particles found in diet and watery duodenal compounds, which in small intestines stabilize the lipid unit as it grows smaller and thus prevents them from coalescing. Synthesized lipids are used for a number of purposes. Triglycerols are found within chylomicrons and are initially broken down in the skeletal muscle and adipocyte capillaries, as well as in the heart, lungs, kidneys, and liver. Chylomicrons containing triacylglycerol are converted to free fatty acids and glycerol with the aid of lipoprotein lipase. Free fatty acids obtained from TAG hydrolysis are then transported to the circulation of serum albumin in the blood; free fatty acids are oxidized in the cells to generate energy. Released TAG glycerol is primarily used by liver cells to produce glycerol 3-phosphate, entering either glycolysis or gluconeogenesis by oxidation to dihydroxyacetone phosphate. Released TAG fatty acids require hydrolytic action, mediated by hormone-sensitive lipase, and fatty acids are removed from TAG carbon 1/carbon 3. In addition, certain lipases are specified for diacylglycerol, or other fatty acids are extracted by monoacylglycerol. Hormonal regulation of lipolysis involves the degradation of triglycerides by the action of lipases. Epinephrine, glucagon, and insulin regulates the concentration of blood glucose, moreover insulin also decrease fat deposition. However, if some change occurs in the metabolism of these biomolecules, various kinds of metabolic disorders are induced, such as irregular carbohydrate metabolism leading to diabetes, altered lipid metabolism leading to dyslipidemia, and cardiovascular disease and altered protein metabolism leading to malnutrition and several other conditions.

8.2 Introduction to Metabolic Disorders

Metabolic syndrome, which originated in 1920, was initially explained as a combination of intestinal obesity and other metabolic deformities in cardiovascular disease and type 2 diabetes mellitus (Alić et al. 2017). Recently, however, the definition of MetS is the product of numerous research reports (Alić et al. 2017; Haffner et al. 1992; Kaplan 1989). Metabolic disorder occurs when normal metabolic functions do not occur, and these changes in these processes are either higher or lower in the quantity of vital substances needed to maintain health. Metabolic disorder thus involves a category of threatening causes that greatly raises the prevalence of multiple diseases such as cardiovascular disease, obesity, diabetes, dyslipidemia (increased triglyceride levels, LDL, and VLDL but decreased HDL), increased blood pressure, abnormal glucose metabolism, etc. in addition to lower body obesity and/or raised insulin resistance (IR). Lifestyle changes, especially eating behaviors and physical activity, are predicted by two independent risk factors for the development of metabolic syndrome, more than genetic factors (only 10%) for the occurrence of metabolic disorder (Weiss et al. 2013; Reilly et al. 2005; Mozaffarian et al. 2011). Some studies have indicated that overall dietary habits instead of nutrients are not responsible for metabolic syndrome. Dietary activities as well as physical activity are expected to be linked to insulin resistance. However, day-to-day study findings that describe the role of dietary patterns such as sugar-sweetened drink intake (Hu 2013) may be more closely linked to the development of metabolic disorder and CVD rather than physical activity or sedentary lifestyle (Casazza et al. 2009). The prevalence of metabolic disorders has increased over the past decades due to an increase in the sedentary lifestyle associated with excess calorie intake. Elevated physical activity and healthy eating habits are the main factors for reducing or reversing the rise in weight as well as its negative effects.

Various research groups are trying to develop a diagnostic condition for the proper identification of metabolic disorders. The World Health Organization (WHO) and the European Community, the American Association of Clinical Endocrinology (AACE), and the National Heart, Lung, and Blood Institute (NHLBI) have tried to research diabetes and insulin resistance (EGIR) (Alić et al. 2017). The National Heart, Lung, and Blood Institute (NHLBI) Concepts are components of the scientific program that has been proposed to classify patients with metabolic disorders due to coronary inhibitory disease. These guidelines are intended to promote the accessibility and ease of use of these requirements in clinical practice (Nikolić et al. 2007). Among the five (5) criteria that have been identified, a patient may have at least three (3) criteria, such as elevated blood glucose levels, hypertension, elevated triglycerides, and low HDL levels, as well as increased waist perimeter.

8.3 Association of Significant Dietary Habits with Metabolic Syndrome

The incidence of metabolic syndrome is growing at an accelerated rate, but no treatment has been available to date. Different foods consumed have a wide variety of interactions between nutrients and foods. Rodríguez and Moreno (2006) investigated the relationship between the dietary factors and CVD or MetS or any particular distinguishing parameters of MetS. Historically, dietary guidelines involve lower fat consumption due to higher caloric density relative to proteins or carbohydrates. Current studies have indicated that the form of fat consumed is predicted to be responsible for dehydration. Similarly, the quantity of carbohydrates is not important, as is their quality and their source. Dietary patterns are an attempt to examine the relationship between diet and disease (Kant 2004; Newby and Tucker 2004; Hu 2002). Dietary habits are very useful to prescribe diets, due to the general dietary habits that might be easy for the public to understand. Earlier research indicated that an inappropriate dietary pattern is a key factor linked to MetS components, including obesity, dyslipidemia, hypertension (HTN), and CVD (Hu 2002; Pierce et al. 2002). As a result, the incidence of MetS is growing worldwide, and understanding the association of dietary patterns with MetS and its constituents may help to reduce the incidence of metabolic disorders (el Bilbeisi et al. 2017) (Table 8.1).

Table 8.1 Association of dietary patterns with metabolic syndromes and possible treatments
Full size table

8.4 Causes of Metabolic Disorders

The basic cause of any metabolic disorder is an abnormal and uncontrolled metabolic process, which can occur at both biochemical and genetic levels. Popular examples are diabetes due to unregulated glucose metabolism, which can cause various effects in the body such as oxidative stress, hormonal imbalance, and hematological deficiency (Kanikarla-Marie and Jain 2016).

8.5 Role of Polyphenols in Health

Polyphenols are flexible phytochemicals in the diet and are highly attenuated by the scientific community due to their various biological activities, bioavailability, and bio-accessibility, and these polyphenols are used to avoid various chronic diseases. Epidemiological studies have shown that consumption of food containing high levels of polyphenols can be used to avoid cancer and other chronic diseases, including cardiovascular diseases, neurodegenerative diseases, type 2 diabetes, renal failure, hepatic damage, and obesity (Del Rio et al. 2013). Recent studies have documented that long-term intakes of polyphenol-rich diets serve as a protection mechanism against various forms of cancer, type 2 diabetes, osteoporosis, pancreatitis, cardiovascular diseases, gastrointestinal diseases, lung diseases, and neurodegenerative diseases (Fujiki et al. 2015; Xiao and Hogger 2015; Martín-Peláez et al. 2013; Fraga et al. 2010). These protective dominant activities of polyphenols are based on their “biochemical scavenging theory” which explains that polyphenol compounds neutralize free radicals by forming stabilized chemical complexes and therefore inhibit the formation of free radicals (Sroka and Cisowski 2003). Other evidence supports the anti-stress behavior of polyphenols such as hydrogen peroxide formation, which promotes and controls immune responses, such as cell growth (Sroka and Cisowski 2003; Saeidnia and Abdollahi 2013).

During the digestion process polyphenols show preabsorptive interaction, phenols present in the diet reduce the transport of thiamine as well as folic acid and also alter the activity of drugs through interactions that influence drug transporters or enzymes involved in these drug transformation reactions, therefore inhibition as well as increase in bioavailability depends on the status. For example, the iron chelating and inhibitory effects of polyphenols on iron absorption may be due to poor iron status (Hurrell and Egli 2010). Mechanistic cause may be that people who eat rich food inhibit the absorption of iron, including sorghum, beans, and millet.

Earlier studies indicated that isoflavones found in soy products have a negative effect on the risk of estrogen-sensitive breast cancer and endometrial cancer, suggesting endocrine disrupting activity of these compounds (Yang et al. 2015; Carbonel et al. 2015). In the 1990s, considerable emphasis was placed on the use of polyphenols for various human health-related issues, which also decreases the incidence of many diseases, including CVD, DM, and cancer (Hertog et al. 1993). Polyphenols are elevated against LDL-mediated atherosclerosis due to their antioxidant properties (Lusis 2000).

8.6 Polyphenols and Their Role in the Human Body

Polyphenols are plant-based secondary metabolites that are abundantly present in foods that are appropriate for consumption, owing to their high antioxidant capacity, and their ingestion along with diet/diet use reduces the prevalence of various diseases such as coronary heart disease (Hertog et al. 1993; Virgili and Marino 2008). The beneficial effects of polyphenols on cardiovascular disease were due to their antioxidant properties, although the present study stated that they were vasodilatory, suggesting their ability to stabilize lipids and associated variables and to change the mechanism of apoptosis in vascular endothelium (Andújar et al. 2012). Evidence is growing quite rapidly, all of which suggesting that polyphenols are capable of preventing neuronal disorders such as Alzheimer’s disease and Parkinson’s disease by reducing inflammatory stress signaling and by up-regulation of gene expression that encodes antioxidant enzymes and cytoprotective proteins (Cabrera et al. 2006). Polyphenols are known to function as separate molecules and are also capable of interacting with receptors and enzymes and preventing diseases and enhancing human health (Murakami and Ohnishi 2012). Dietary proteins and polyphenols are both nutritious and dietary surpluses (inhibits various diseases and increases metabolic activity) and contribute to the development of food structure and enhance the functional capacity of food. Polyphenols in the form of capsules is found to be more effective; therefore, encapsulation techniques have been continuously increased due to various factors, including the efficacy of the capsule forming agent, the stabilization of the capsule forming agent, and the release of the capsulated compounds. Over the last decades, polyphenolic compounds have been shown to reduce numerous chronic as well as degenerative diseases such as obesity, cardiovascular diseases, and neurodegenerative diseases (Landgrave-Gómez et al. 2015) and to prevent cancer by influencing bacterial metabolizing enzyme, thereby reducing the overall risk of cancer (dos Reis et al. 2019).

8.7 Metabolic Syndrome and Oxidative Stress

Oxidative stress can be defined as an imbalance between the generation of reactive oxygen/reactive nitrogen species (ROS/RNS) and their elimination by antioxidant enzymes. Antioxidant enzymes are found in cells and molecules, which are subdivided into water-/lipid-soluble enzymes, or their origins may be endogenous/exogenous (dietary). Administration of different synthetic pharmaceutical agents enhances the resistance of LDL to oxidation (Brennan et al. 2002). This imbalance between free radicals and the antioxidant system causes oxidative damage to various structural and functional biomolecules such as proteins, fats, nucleic acids, and carbohydrates. Antioxidants shield the body from the harmful effects of free radicals. Supplementation of exogenous antioxidants defends the body against oxidative stress (Azab and Albasha 2018).

Reactive oxygen species (ROS) are mostly formed in mitochondria via the electron transport chain during aerobic respiration. However, most electrons enter complex III of the transport chain of electrons, and approximately 1–3% of electrons react prematurely with oxygen and create superoxide radicals (Kausar et al. 2018). Free radicals play a very important role in various physiological functions in the body, such as the production of O− and NO by neutrophils and macrophages, aiding the progression of phagocytosis and removing bacteria. Superoxide radicals in phagocytic cells are known to function as nonselective antibiotics and destroy any infective bacteria (as well as neutrophils) and cause damage to neighboring tissue cells; these free radicals often cause inflammatory reactions and encourage cell proliferation (mitotic division) of fibroblasts. Endogenous ROS/RNS is produced by a variety of processes, such as inflammation and activation of immune cells, ischemia and anxiety, incidence of cancer and infectious diseases, and aging. However, exogenous ROS/RNS are created due to contamination (water, air) by consuming alcohol, smoking, heavy metals, certain drugs (tacrolimus and cyclosporine), rays, cooking, and various solvents such as benzene. These compounds are decomposed after entering the body (Dasgupta and Klein 2014).

These ROS damage all macromolecules, including proteins, lipids, and nucleic acids, causing protein and nucleic acid modulation. In addition, these free radicals initiate and evolve various diseases such as diabetes, heart attacks, atherosclerosis, hepatic diseases, and cancer (Halliwell 2007). Oxidative stress is also responsible for the development of cancer and stimulation of ontogenesis. DNA breakage and start of ROS to AP-1 and NF-kB signal transduction procedures have been shown to trigger transcription of genes associated with the regulation of cell growth as well as the initiation of cancer.

Lipid peroxidation products are produced when hydrogen atoms are removed from unsaturated fatty acids. Accelerated lipid peroxidation affects membrane fluidity and integrity of biomolecules (membrane-bound proteins or cholesterol). These oxidizable lipids may attack neighboring proteins, resulting in an increased formation of protein carbonyls (Almroth et al. 2005). It has been stated that free radical induces peroxidation of membrane lipids, and even oxidative damage to DNA is correlated with a number of chronic health problems such as cancer, atherosclerosis, weakening of the nervous system, and aging (Finkel and Holbrook 2000).

The increase in the production of reactive oxygen species and a decrease in the activity of the anti-oxidative enzymatic defense system lead to oxidative stress. Oxidative stress causes damage only when the antioxidant system is unable to combat the formation of ROS. Under regulated physiological circumstances, ROS is neutralized/weakened under in vivo conditions by various antioxidant systems. O− is then converted to H2O2 by the action of superoxide dismutase (SOD), and hydrogen peroxide is reduced by the action of glutathione peroxide (GSH-Px), catalase, and peroxiredoxins (Fridlyand and Philipson 2006; Wood et al. 2000). In addition, ROS may also be neutralized or made less active in vivo by different endogenous molecules (albumin, uric acid) or by various exogenous dietary antioxidants (vitamin C or vitamin E). Attention has been based on the possibility that oxidative stress leads to the development of metabolic syndrome. Experimental evidence has shown that obesity is associated with elevated levels of ROS, increased expression of NAPH oxidase and lower levels control the expression of antioxidant enzymes, and that it induces major disruptions in the production of adiponectin, IL-6, and MCP-1. Previous studies indicated that the administration of NADPH oxidase inhibitor reduces the development of ROS in adipocytes, improves the irregularity of adipocytokines, and reduces the occurrence of diabetes, hyperlipidemia, and hepatic steatosis.

8.8 Phytotherapeutic and Metabolic Disorders

Various foods and beverages rich in different polyphenols are used for the treatment of various metabolic disorders, such as green tea, nuts, red wine, grape seeds, berries, and dark chocolate, containing various monomeric flavonols (catechins) and their oligomers (proanthocyanidins), which are a major source of content (Del Rio et al. 2013). Green tea (Camellia sinensis L.) plant contains high levels of flavonols (catechins) and alkaloid caffeine has some metabolic effects. Nagao et al. (2007) study reported that the treatment of green tea revealed substantial reductions in body weight, BMI, waist circumference, and body fat mass. It has been found that caffeine has the ability to interfere with the energy balance by rising energy consumption and reducing energy intake. Suliburska et al. (2012) reported that green tea containing epigallocatechingallate (EGCG) decreases BMI and waist circumference in obese patients. This weight-reducing effect of tea depends on the effects of caffeine and catechins on the adrenergic system. Caffeine (1,3,7-trimethylxantine), a purine alkaloid, suppresses the phosphodiesterase enzyme that hydrolyzes cyclic adenosine monophosphate (cAMP) to AMP. Diepvens et al. (2007) reported that cAMP signal is activated by beta-adrenergic stimulation, causing adrenergic effects such as reduced appetite while increasing energy intake and lipolysis. Evans and Bahng (2014) reported that caffeine up-regulates the expressions of uncoupling protein and increases thermogenesis by inhibiting phosphodiesterase and activation of cAMP protein kinase A. Catechins present in green tea affect the inactivation of catecholamines, inhibit the enzyme catechol-O-methyltransferase (COMT), and cause overstimulation of adrenergic receptors (Shixian et al. 2006). Similarly, caffeine-induced suppression of phosphodiesterase cause inactivation of COMT by growing energy intake, fat oxidation and lipid breakdown (Diepvens et al. 2007). Previous studies have shown that the administration of green tea enhances the lipid profile by substantially reducing LDL cholesterol (Basu et al. 2010; Suliburska et al. 2012; Chu et al. 2017; Belcaro et al. 2013) and triglycerides. Green tea reduces oxidative stress as well as cardiac alterations in dialysis and reverses neuronal inflammation (Mandel et al. 2008).

Anthocyanin water-insoluble compounds are commonly found in a number of fruits (grapes, cherries, cranberries, strawberries, blueberries, blackberries, currants) and vegetables (beetroot, red cabbage, and red onions). Anthocyanin has antioxidant potential due to its electron/hydrogen atoms that donate and receive free radicals from various hydroxyl groups (Wang et al. 1999). Blueberries (Vaccinium myrtillus L.) are packed with anthocyanidins, chlorogenic acid, flavonoids, and stilbenes, including pterostilbene and resveratrol. Blueberries have a variety of preventive and therapeutic potentials, such as ability to reduce oxidative pressure and inflammatory reactions and protection from cardiovascular disorders, hypertension, and diabetes (Naseri et al. 2018). Diet rich in blueberry protects the metabolic syndrome associated with a proinflammatory disorder in obese people elevating adiponectin expression and inhibits the expression of NF-kB in the liver (Vendrame et al. 2013). In addition, blueberries also have the potential to reduce triglycerides, fasting insulin, abdominal fat mass, liver weight, body weight, total fat mass and increase skeletal and adipose muscle PPAR activity. Food products rich in anthocyanins regulate the glycemic level as well as the effect on LDL-C (Yang et al. 2017).

Pomegranate contains polyphenols, primarily ellagitannins and anthocyanins, which can be used for the treatment of various metabolic disorders. In vivo studies have shown that pomegranate has the potential to reduce blood glucose, improve insulin sensitivity, inhibit 5-007-glucosidase, and increase the activity of glucose transporter 4 (GLUT4). In addition to this, pomegranate causes anti-inflammatory effects by altering the peroxisome proliferator-activated receptor pathway expressions, and current research has shown that pomegranate also reduces blood pressure during metabolic syndrome. Cocoa produces many polyphenols, including catechins, anthocyanins and proanthocyanidins. Epidemiological studies have confirmed that cocoa polyphenols cause cardiovascular beneficial effects in humans. Cocoa polyphenols modulate some primary signaling pathways, such as Toll as receptor 4/NF-a-B signal transduction and transcription activation. Cocoa polyphenols release NO by stimulating the endothelial NO synthase, which is responsible for the dilation of blood vessels and also serves as a cardioprotective agent. Consumption of dark chocolates rich in flavonoids by healthy individuals increase the coronary flow rate reserve but is expected to be free flavonoid white chocolate (Shiina et al. 2009). Blood pressure lowering of cocoa activity can be explained by a number of mechanisms, such as NO elevation, which shows an antihypertensive effect (Napoli and Ignarro 2009). In addition, flavanols are capable of suppressing angiotensin-converting enzyme activity under in vitro conditions.

Curcumin derived from Curcuma longa (turmeric) conducts a number of biological activities, in particular turmeric rhizomes. Curcumin analogs are the major bioactive components of curcumin, demethoxycurcumin, and bisdemethoxycurcumin (Teiten et al. 2014). Curcumin and curcuminoids have small oral bioavailability due to their small intestinal absorption and fast metabolism (Liu et al. 2016). Curcumin possesses a range of therapeutic properties, such as anti-inflammatory, anticancer, hypoglycemic, antioxidant, antiviral, and antimicrobial activity, and shows that curcumin can be used as an adjuvant for multiple illnesses (Gupta et al. 2013). Many specific biological functions of curcumins can be explained by their ability to interact directly with various cell signaling molecules associated with inflammation and cancer, etc. In addition, curcumin modulates activities of different transcription factors, growth factors, inflammatory factors, cytokine, protein kinase, and enzymes (Milani et al. 2017). Various clinical studies have shown that curcumin can be used for the treatment of metabolic syndrome.

Yang et al. (2014) estimated the impact of curcumin extract (95% curcumin) on weight, glucose, and lipid profile against metabolic syndrome. Curcumin treatment substantially raises HDL-C levels, but decreases LDL-C levels. De Melo et al. (2018) studied that the administration of curcuminoids and/or curcumin decreases HbA1c without affecting homeostasis. Both alone and in combination, curcuminoids reduce the concentration of fasting blood glucose in people with dysglycemic conditions (pre-diabetes, diabetes, or metabolic syndrome, but not in nondiabetic or euglycemic individuals).

Olive oil is used as a food supplement; it primarily contains more oleic acid, but less of other biologically active ingredients such as vitamins and polyphenols. Olive oil also contains more than 230 compounds such as tocopherols, fatty alcohols, triterpenic alcohols, squalene, plant sterols, and polyphenols such as oleuropein and its metabolites (hydroxytyrosol and tyrosol) (Ruiz-Canelol) Polyphenols, especially hydroxytyrosol and tyrosol, have an anti-inflammatory effect and also affect cell multiplication and apoptosis in cancer cells. Curcumin is used as a treatment to prevent cardiovascular disease; improves BP; regulates glucose levels, endothelial function, and oxidative stress; and reduces triglycerides and total and LDL-C, but increases HDL-C and decreases inflammatory markers such as C-reactive protein and IL-6 (Estruch et al. 2006). Intake of olive oil along with various other phenols at different concentrations increases HDL-C, decreases both total cholesterol and oxidative stress bioindicators, and decreases triglyceride levels in circulatory plasma. Various flavonoids and phenolic acids found in the flower extract, including kaempferol, quercetin, and their glucosides, are capable of raising glucose and oleic uptake in both human skeletal muscle cells and liver cells under in vitro conditions (Ho et al. 2017). Clinical trials have shown that an elderflower extract can be used as a supplementary or functional food for the treatment of diabetes.

8.9 Role of Secondary Metabolites in Type 1 and Type 2 Diabetes Mellitus

Secondary metabolites (polyphenols) are known as flavonoids, phenolic acids, stilbenes and lignans. Flavonoids are further subdivided into flavones, flavonols, flavanols, flavanes, isoflavones, and anthocyanins. Several studies have documented the antidiabetic efficacy of some dietary polyphenols used to prevent type 1 and type 2 diabetes (Kim et al. 2016). Different mechanistic approaches are suggested that contribute to the maintenance of glucose homeostasis by the following means: suppression of carbohydrate digestion and absorption of glucose in the intestine; stimulation of insulin secretion from pancreatic β-cells; altering the release of glucose from the liver; and activating insulin receptors and glucose uptake in insulin-sensitive tissue (Hanhineva et al. 2010). Flavonoids include antioxidant action, central nervous system effects, and increased insulin sensitivity (Prasain et al. 2010). Anthocyanins include flavonoids that have an enormous dietary value and are mostly consumed in combination with diets such as fruits and vegetables (Guo and Ling 2015). Quercetin is commonly used in human diets due to its antidiabetic and anti-inflammatory activities (Vinayagam and Xu 2015; Li et al. 2016).

Momordica charantia (bitter melon) is a cucurbitane-type triterpenoid carantine (a steroidal glycoside similar to a mixture of stigmasterol glucoside and β-sitosterol glucoside) and also a polypeptide-p, vicine, and a ribosome inactivating momordin protein with hyperglycemic activity (Tan et al. 2008; Joseph and Jini 2013). Previous studies recorded that bitter melon extract suppresses glucose absorption in the intestines (Grover and Yadav 2004; Chaturvedi 2012), inhibits significant glucose metabolism enzymes (Shibib et al. 1993), and decreases gluconeogenesis in the liver (Tsai et al. 2012). Previous studies have confirmed that M. charantia increases the activity of AMP-activated protein kinase (AMPK) pathway (essential for the control of lipid and glucose metabolism in cells) and decreases the expression of phosphoenol pyruvate carboxykinase (Shih et al. 2014). Polypeptide-p is also known as “plant insulin,” and clinical trials have shown that the treatment of polypeptide-p substantially lowers blood sugar (Baldwa et al. 1977). Current studies have shown that the addition of cucurbitane-type triterpenoid (known as compound K16) lowers both the blood glucose level and the lipid content, thus enhancing glucose tolerance. Compound K16 is also reported to have an up-regulatory effect on insulin signaling pathway-released protein expression (Jiang et al. 2016).

Diosgenin (3b-hydroxy-5-spirostene), 4-hydroxyisoleucine, and the soluble dietary fiber fraction of fenugreek seed are mainly bioactive compounds examined (Fuller and Stephens 2015). Significant aglycone saponin has been reported to possess glucose-reducing potential by regenerating pancreatic beta-cells as well as stimulating insulin secretion (Kalailingam et al. 2014) and antioxidant potential and helping to differentiate adipocytes and increasing insulin-dependent glucose transport (Uemura et al. 2010). 4-Hydroxyisoleucine is a branched amino acid derivative usually present in plants and serves as a measure of the total free amino acid content in fenugreek seeds (Fuller and Stephens 2015). 4-Hydroxyisoleucine reveals both insulinotropic and antidiabetic properties by stimulating glucose-dependent insulin secretion and also reduces insulin resistance in the muscles and liver (Jetté et al. 2009). Fenugreek seeds are rich in fiber (50–65 g of fiber/100 g of seed), and these soluble dietary fibers increase glycemic control. These hypoglycemic properties of fibers are due to inhibition of lipid hydrolyzing and carbohydrate hydrolyzing enzymes in the digestive system (Hannan et al. 2007). Fenugreek seed is also known as galactomannan because it lowers the rate of glucose absorption (Srichamroen et al. 2009). It can also be concluded that fenugreek seed can be used as an effective remedy for type 2 diabetes, obesity, and dyslipidemia due to hypoglycemic and anti-dyslipidemic properties.

Ivy gourd (C. grandis) is suspected to imitate the action of insulin. C. grandis has a hypoglycemic effect by insulin secretion by influencing glucose-associated enzymes (Sauvaire et al. 1996). Clinical studies recorded C. grandis extract reduces the level of glucose-6-phosphatase and lactase dehydrogenase in glycolytic pathways and also restores the function of lipoprotein lipase in lipolytic pathways. In addition, both animal and human studies have shown that C. grandis can be used as a dietary supplement for diabetes.

Earlier studies indicated that extracts of cinnamon species possess antidiabetic properties (Akilen et al. 2012; Chen et al. 2012; Cheng et al. 2012; Verspohl et al. 2005). The presence of procyanidin oligomers in cinnamon is suspected to be responsible for antidiabetic activity (Lu et al. 2011; Chen et al. 2012). Several studies support the hypoglycemic activity of different cinnamon species. Chen et al.’s (2012) study showed that C. cassia extract can promote lipid deposition in adipose tissues and the liver, but Cinnamomum tamala extract typically increases insulin concentrations in the blood and pancreas. This antidiabetic activity is caused by the presence of procyanidin oligomer components in these extracts (Chen et al. 2012). Cinnamon extract therapy increases insulin resistance, hyperglycemic activity, and lipid metabolism (Sheng et al. 2008).

Secondary metabolites as inhibitors of alpha-glucosidase are used for the treatment of type 2 diabetes.

The role of glycosidases is to catalyze the hydrolysis of glycoside bonds in polysaccharides and glycoconjugates, to contribute to various biological functions such as carbohydrate digestion, glycoconjugate lysosomal breakdown, and posttranslational changes in cell glycoproteins (Davies et al. 2005; Vocadlo and Davies 2008). Specifically, the terminal stage of starch digestion and disaccharides present in the human diet at higher concentrations is catalyzed in mammals’ 5-007-glucosidase (AG) in the mucosal brush border of the small intestine. 5-007-glucosidase (AG) inhibitors interrupt the degradation of carbohydrates in the small intestine and also decrease the blood volume of postprandial glucose. As a result, glycosidase inhibition greatly affects the metabolism of polysaccharides, the production of glycoproteins, cell interactions, and the extension of the formulation of new therapeutic molecules used against different diseases, including diabetes, obesity, metastatic cancer, and viral infection (Kajimoto and Node 2009; Stutz and Wrodnigg 2011). AGs present in the brush wider cells of the small intestine possess selectively hydrolyzing property at the terminal end (1 → 4)-linked α-glucose residues (starch or disaccharides) and release an individual α-glucose molecule (Bischoff 1994). AG inhibitors have been extensively studied and numerous AG inhibitors have been marketed, such as acarbose, miglitol, voglibose, and 1-deoxynojirimycin (DNJ) and anti-glucosidase anti-type 2 diabetes drugs, a chronic situation in which the body is immune to the normal impact of insulin, resulting in an efficient blood glucose regulation (Olokoba et al. 2012). Plants have different phytochemicals, some of which have a health-promoting effect. Different plants have been tested for different bioactive compounds that have the ability to control type 2 diabetes. Various extracts of leaves, roots, barks, and fruits from different medicinal plants, herbs, and other plants have been studied to exhibit inhibitory activity against AG (Kawada et al. 2006). Thiocyclitol, a 13-membrane ring compound commonly known as 13-MRT, has been used against diabetes because it is capable of inactivating maltase and sucrase enzymes, respectively (Oe and Ozaki 2008). Therefore, vegetables rich in AGI activities could be helpful in controlling type 2 diabetes, since vegetables are rich in fiber and/or have higher nitrate content; they are stated to be able to reduce both cholesterol and blood pressure.

8.10 Plant Metabolism and Secondary Metabolites

Metabolites have various functions such as fuel, structure, signaling, stimulating, and inhibitory roles on enzymes, catalytic activity (usually in the form of enzyme cofactors), and defensive activity, and they often interact with other organisms. Plant metabolites are classified into two: primary and secondary metabolites. Primary metabolites contain carbohydrates, fatty acids, amino acids, and nucleic acids and are commonly used for cell maintenance (Kliebenstein and Osbourn 2012), whereas secondary metabolites are essential for normal growth, development, and plant protection. Secondary metabolites have various important functions, such as being used in pharmaceuticals, food additives, flavorings, and other industrial applications. Plants have been shown to use these secondary metabolites for protection due to their antibiotic, antifungal, and antiviral activity, which has a potential to defend plants from pathogenic infections (Kossel 1891). Secondary metabolites are categorized on the basis of their chemical structure (e.g., rings containing sugar), their composition (containing nitrogen or not), their solubility in different solvents, or their pathway by which they are synthesized (e.g., phenylpropanoid producing tannins). All these secondary metabolites (phenolics, terpenes, steroids, alkaloids, and flavonoids) are having biological significance (Bourgaud et al. 2001).

8.11 Importance and Main Role of Secondary Metabolites

Primary metabolites have a broad variety of defensive functions against microorganisms such as viruses, bacteria, fungi, and herbivores (arthropods and vertebrates). Secondary metabolites also perform special roles, including acting as competitive weapons against (1) other bacteria, fungi, amoebae, plants, insects, and other species; (2) metal transporting agents; (3) symbiosis agents between microbes and plants, nematodes, insects, and higher animals; (4) sex hormones; and (5) differentiation agents. Although antibiotics are not needed for sporulation, some secondary metabolites (including antibiotics) stimulate spore formation and slow down or stimulate germination, (6) protect dormant or initiated spore from amoebae intake, or (7) clean up the immediate environment of competing microorganisms during germination (Demain and Fang 2000).

8.12 Antioxidant Potential of Plant Phenols

Antioxidant significantly inhibits oxidation of oxidizing substrates when present at low concentrations (Halliwell 2007). Plants function as a source of exogenous (dietary) antioxidants. It has been estimated that two-thirds of plant species are medicinally important and also have significant antioxidant potential (Krishnaiah et al. 2011). Antioxidants may be synthesized under in vivo conditions (e.g., reduced glutathione (GSH), superoxide dismutase (SOD), etc.) or taken as supplementary dietary antioxidants (Halliwell 2007; Sies 1997). The antioxidant potential of plants is gradually attenuated by accelerated oxidative stress as one of the causative agents for the development of various diseases, such as neurodegenerative and cardiovascular diseases. In addition, supplementation of exogenous antioxidants or enhancement of the functions of endogenous antioxidant system to combat the detrimental effects of oxidative stress (Alam et al. 2013). Polyphenols are distinguished by one or more aromatic rings having one or more hydroxyl groups. The antioxidant potential of phenolic compounds depends on the presence of free hydroxyls and the conjugation of side chains to aromatic rings (Moran et al. 1997). In addition to their individual ability, they also associate with other physiological antioxidants, including ascorbate or tocopherol, and synergistically improve and enhance their biological effects (Croft 1998). It has been shown under experimental conditions that the antioxidant capacity of plant phenolics depends on various factors, such as electron donation, power reduction, and metal ion chelating capability (Rice-Evans et al. 1997).

8.13 Classification of Secondary Metabolites

Approximately 20% of plant species have been studied to contain alkaloids such as terpenoid indole alkaloids, tropane alkaloids, and purine alkaloids (Ziegler and Facchini 2008). Terpenoids are another class of secondary metabolites containing more than 40,000 monoterpene, sesquiterpene, and diterpene (Aharoni et al. 2005) compounds with substantial antioxidant activity under in vitro conditions. Plant polyphenols are classified into five main groups, such as phenolic acids, flavonoids, lignans, stilbenes, and tannins (Duthie et al. 2000; Myburgh 2014; Blokhina et al. 2003). Flavonoids and phenolic acids are one of the main groups of plant phenols, biosynthetically derived from acetate as well as shikimate acid pathways, some of which are derived from phenylalanine or tyrosine shikimate pathways (Dewick 2009) (Table 8.2).

Table 8.2 Classification of polyphenolic compounds and their natural sources
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figure a

8.14 Role of Secondary Metabolites in Thyroid Disease

Growth, development, reproductive functions, and metabolism are the normal physiological functions maintained by the endocrine system. Similar hormones are produced by different endocrine glands: thyroid hormones (T3, T4), ovaries (estrogen, progesterone), testis (testosterone), and adrenal glands (catecholamines, mineralocorticoids, glucocorticoids, androgens). The natural growth and production of body thyroid hormones is very significant. Thyroid hormones are the main regulators of the basal metabolic rate (Oppenheimer et al. 1987).

Among endocrine disorders, thyroid disorder is very common, and different environmental conditions and substances may interfere with the biosynthesis and metabolism of thyroid hormones (Yen 2001; Mondal et al. 2016; Boas et al. 2009; Pearce and Braverman 2009; Zoeller 2010) and nutritional factors, especially when the diet is deficient in iodine (Divi and Doerge 1996). Moudgal et al. (1958) researched the antithyroid activity of flavonoids, such as inhibition of thyroid biosynthesis and reduction of iodine uptake (Gaitan 1996) and, in addition, the antithyroid and goitrogenic effects of pearl millet, a staple food eaten by local and poor people in various African and Asian countries. Pearl millet produces glycosyl flavones, apigenin and luteolin. Flavonoids reduce both the organification and the release of thyroid hormones.

Reactive oxygen species are formed at the active site by compound-mediated oxidation of the phenolic suicide substrate, and inactivation occurs by covalent binding of these radicals to the catalytic amino acid radical(s) of compound II (Divi and Doerge 1994). Myricetin and naringin demonstrate a noncompetitive inhibition of tyrosine iodination with respect to iodine ion and linear mixed-type suppression with respect to hydrogen peroxide. Myricetin and naringin interact with TPO compounds I and II, but do not bind to enzymatic iodinating organisms or native TPO.

Biochanin A is considered to be a substituent substrate for iodination by means of a competitive bond between tyrosine and the alternative substrate (biochanin A) for the enzymatic iodinate species (EOI). This results in the complete blockade of tyrosine iodination due to the higher affinity of biochanin A (Divi and Doerge 1994). Biochanin A possesses an inhibitory effect on the development of thyroid peroxidase, which can cause TSH to increase, contributing to the growth of thyroid gland and goiter, particularly when taken at higher concentrations. Divi et al. (1997) reported that soy products (genistein and daidzein) are capable of inhibiting thyroperoxidase tyrosine iodination activity. Soya intake leads to a sharp rise in TSH levels, with a remarkable link between the basal levels of daidzein and thyrotropin (Hampl et al. 2008). It has been studied that catechins possess the ability to inhibit the activity of thyroperoxidase as well as decrease the levels of T3 and T4 in serum while increasing the amount of TSH level (Chandra and De 2010). In addition to this, green as well as black tea extract alters physiology, architectures such as thyroid gland enlargement, hypertrophy and/or thyroid follicle hyperplasia, and inhibition of thyroid peroxidase activity and 50-deiodinase type I, elevation in the thyroid function Na+-K+-ATPase, with decreased serum T3, T4, and TSH levels. In addition, treatment with genistein and daidzein lowers the overall T3 and T4 and raises the TSH level in orchiectomized middle-aged rats (Šošić-Jurjević et al. 2010).

8.15 Plant Polyphenols and Hepatitis

The liver is the largest and key gland that is strongly engaged in a range of metabolic activities, such as energy output, glucose storage (glycogen) and its metabolism, and the use of carbohydrate for cholesterol synthesis. The liver plays an important role in transforming excess fatty acids into ketone bodies, which serve as a source of energy during fasting and starvation. It also helps to preserve homeostasis (Chiang 2014). Hepatitis is a common liver disease caused by various strains of hepatitis A, B, and C viruses. The most popular forms are hepatitis B (HBV) and hepatitis C viruses (HCV). HBV is a significant cause of liver cirrhosis and hepatocellular carcinoma (Tomé-Carneiro et al. 2013).

Various phytochemicals, such as wogonin and polyphenols (geranin), have both in vitro and in vivo antihepatic activity (Zhang et al. 2016; Xiong et al. 2015). These polyphenolic compounds prevent entry of the virus, inhibit viral antigen secretion, and inhibit DNA replication (Parvez et al. 2016). Green tea also contains several useful flavonoids, such as EGCG, which is well-known to inhibit the entry of HBV into hepatocytes by inducing clathrin-dependent endocytosis of sodium taurocholate by co-transporting polypeptide from plasma membrane and protein degradation, as well as inhibiting clathrin-mediated transferrin endocytosis (Huang et al. 2014). While epicatechins are present in green tea, they inhibit the replication of the viral genome via cyclooxygenase-2 and also reduce viral inflammation (Lin et al. 2013). These flavonoids inhibit HCV entry into hepatoma cell lines and primary human hepatocytes (Calland et al. 2015; Ciesek et al. 2011). In addition to this, delphinidin, which is present in blue-purple flowers and berries, induces bulging of the viral envelope in order to prevent HCV from binding to the cell surface (Calland et al. 2015). Delphinidin acts directly on viral particles and prevents the entry of HCV. Delphinidin is likely to prevent the docking of the virus to the cell surface and to function at an early stage of entry. In addition, Calland et al. (2015) reported that delphinidin is active against all HCV genotypes and shows its impact on virion itself. Delphinidin prevents both HCVpp and HCVcc infections and acts on the viral particle. In addition, apigenin inhibits HCV replication by lowering the mature miRNA122 level, as miRNA122 acts as a positive liver-specific miRNA for replication control (Shibata et al. 2014). Microarray analyzes the expression levels of mature miRNAs, such as miR122 and miR103, which is decreased by apigenin (Ohno et al. 2013). Shibata et al. (2014) reported that inhibition of extracellular signal-regulated kinase (ERK) activity was due to decreased phosphorylation of the RNA-binding protein trans-activation response (TRBP) (Paroo et al. 2009). The levels of the mature miR122 are increased by the overexpression of the TRBP (SD). It is evident that the reduction in miR122 maturation also depended on the activity of TRBP inhibited by apigenin (Ohno et al. 2013). In addition, quercetin has been reported to have antiviral activity against various viruses. Quercetin substantially reduces the replication of the viral genome, the formation of infectious HCV particles, and the specific infectivity of newly developed viral particles (Rojas et al. 2016). In addition to quercetin, HCV is decreased by inhibiting NS3 protease activity (Bachmetov et al. 2012). It prevents HCV replication of the genome and reduces HCV-specific infectivity by influencing the morphogenesis of infectious particles. Quercetin is the active substance responsible for inhibiting the activity of NS3 protease and eventually reducing the development of HCV (Bachmetov et al. 2012).

8.16 Secondary Metabolites in the Prevention of Hepatorenal Toxicity

The liver and kidney are two main organs involved in different metabolic processes, such as glucose metabolism, drug transformation, and xenobiotic excretion (Abdel-Daim et al. 2014). The liver and kidney are also extremely exposed to different toxic chemicals (Abdel-Daim et al. 2013; Al-Sayed and Abdel-Daim 2014). Oxidative stress is known to be a key factor in renal failure, liver damage, atherosclerosis, inflammation, and carcinogenesis (Abdel-Daim et al. 2014; Abdel-Daim and Ghazy 2015). Oxidative stress has also been experimentally associated with liver damage and hepatic fibrosis. Continuous hepatocellular damage delays the mechanism of regeneration of damaged tissues and overpowers the protective capacity of the liver. ROS and lipid peroxidation products are produced in wounded hepatocytes that stimulate the transformation of hepatic stellate cells (HSCs) into fibrogenic myofibroblast-like cells and form collagen mass in the liver (Li et al. 2012; Shin et al. 2010). The danger of cellular injury can also be avoided by the use of antioxidants such as dietary polyphenols due to antioxidant potential and numerous other health-promoting effects.

Natural antioxidants, including dietary polyphenols, can also prevent the risk of cell injury (Han et al. 2007). The hepatoprotective potential of polyphenols was assessed by examining the activity of various liver-specific enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, cholesterol, and protein in control serum and treated mice. The nephroprotective effect of plant polyphenols has been estimated by analyzing various functional renal enzymes such as uric acid, urea, and creatinine levels in the circulatory serum.

Proanthocyanidins are natural antioxidants found in a large range of plants, such as fruits and vegetables (Bagchi et al. 2000). These proanthocyanidins have a wide range of pharmacological and therapeutic activity against oxidative stress. Proanthocyanidin derived from grapes is used as a dietary supplement due to its numerous health benefits, such as hepatoprotective, cardioprotective, anti-fibrogenic, and chemopreventive activities (Li et al. 2012). Proanthocyanidins are complex polymers of polyhydroxy flavan-3-ol constitutive groups, the most common of which are (+) -catechin and (−)-epicatechin in the case of procyanidin form, or (+) gallocatechin, and (−)-epigallocatechin, in the case of prodelphinide form (Hellström et al. 2007). Earlier studies indicated that proanthocyanidins have a higher potential to defend tissues/cells against free radical and lipid peroxidation attacks than vitamins C and E and β-carotene (Bagchi et al. 2000). Grape seed proanthocyanidin extract has a higher protective activity against thioacetamide-mediated hepatic fibrosis in the liver (Li et al. 2012), while GSPE also protects the liver against the fibrogenic activity of dimethylnitrosamine in rats (Shin et al. 2010). In addition, GSPE has an important protective role against acetaminophen-mediated liver and kidney damage by decreasing oxidative stress and ALT activity and inhibiting apoptosis and necrotic cell death (Bagchi et al. 2000). GSPE also protects against cyclosporine A- and cisplatin-induced nephropathy and restores renal function. This nephroprotective potential of GSPE has been explained due to its antioxidant activity, restores the tubular damage, and increases the process of regeneration (Ulusoy et al. 2012) (Table 8.3).

Table 8.3 Diverse group of phytotherapeutics having bioactive potential against metabolic disorders
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8.17 Secondary Metabolites in Tuberculosis and Their Potency Against Tuberculosis

Mycobacterium tuberculosis (Mtb), a highly infectious bacterium, causes tuberculosis (TB) and affects one-third of the world’s population. Treatment against tuberculosis began 73 years ago when streptomycin was discovered, numerous medications were put on the market, but the disease remains at the top of causes of death worldwide. Tuberculosis infection occurs by swallowing bacteria through alveolar macrophages; bacilli bypass and multiply continuously by preventing phagosome-lysosome fusion. More and more macrophages and other immune cells are then transported to the site of infection, leading to the creation of an organized cellular architecture known as granuloma (Barry et al. 2009). It has been stated that if HIV patients are infected with tuberculosis, the death rate of these patients has been estimated to be one in every three HIV patients (World Health Organization 2016). There are various types of drugs available for tuberculosis treatment as described below.

8.17.1 First Line Drugs

The first-line medications are used for the treatment of new patients. These patients are not expected to have any resistance to any of the TB medications, e.g., (rifampin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin, and pyrazinamide (PZA).

8.17.1.1 Isoniazid

Isoniazid (INH) was developed in 1952 and has been used to treat tuberculosis as a particular antituberculosis medication and one of the most effective drugs (Bernstein et al. 1952). INH is not active under anaerobic conditions. It is only active against rising bacilli tubers. INH joins mycobacterial cells by passive diffusion (Bardou et al. 1998). Mycobacterium tuberculosis is particularly susceptible to isoniazid. Hepatotoxicity and neurotoxicity are the side effects of isoniazid.

8.17.1.2 Rifampicin

Rifampicin (RIF) is an antituberculosis drug that was introduced in 1972. It binds the β-subunit to RNA polymerase (rpoB) (Ramaswamy and Musser 1998). RNA polymerase is the key transcription enzyme responsible for the expression of mycobacterial genes and eventually inhibits the activity of bacterial transcription and thus destroys the organism. Rifampicin is active against vigorously growing and nongrowing bacilli (Mitchison 1979). RIF has very few adverse reactions. It can cause gastrointestinal discomfort. Hepatotoxicity occurs less often than with isoniazid.

8.17.1.3 Ethambutol

Ethambutol (EMB) is chemically referred to as dextro-2, 2′-(ethylenediimino)-di-1-butanol. It is an effective first-line and anti-mycobacterial medication used in the treatment of tuberculosis. It plays a key role in drug-resistant TB chemotherapy (American Thoracic Society 2003). EMB improves the effects of other medications such as aminoglycosides, quinolones, and rifamycin. Nausea, vomiting, stomach pain, color blindness, swelling of lips or eyes, loss of appetite, headache, rash, itching, breathlessness, swelling of the face, dizziness, blurred vision, and numbness or tingling of the fingers or toes are typical side effects of ethambutol (Jnawali and Ryoo 2013).

8.17.1.4 Pyrazinamide

Pyrazinamide (PZA) is a first-line drug used to treat tuberculosis. It is a short-term chemotherapy drug used in the treatment of MDR-TB (Mitchison 1985). It is an effective drug because it inhibits semi-dormant bacilli living in acidic environments (Mitchison 1985). Pyrazinamide is an active agent against M. tuberculosis at 5.5 acid pH (Konno et al. 1967). Hypersensitivity and gastrointestinal upset are common side effects of pyrazinamide.

8.17.1.5 Streptomycin

Streptomycin (SM) was the first drug used in the treatment of TB in 1948 (British Medical Research Council 1948). It is an antibiotic aminocyclitol glycoside that destroys vigorously developing bacilli tubers with a minimum inhibitory concentration (MIC) of 2–4 μg/mL and is ineffective against nongrowing bacilli (Mitchison 1985). It inhibits protein synthesis and interferes with translation rereading as it binds to 16S rRNA (British Medical Research Council 1948; Gale 1981). The most common side effects of streptomycin are ototoxicity, nephrotoxicity, vestibular impairment, hearing loss and renal toxicity.

8.17.2 Second-Line Medications

8.17.2.1 Fluoroquinolone

Fluoroquinolones (FQs) are commonly used for the treatment of bacterial infections, gastrointestinal and urinary tract infections, sexually transmitted diseases, and chronic osteomyelitis (Spies et al. 2008). They are used as second-line medications for the treatment of tuberculosis. Levofloxacin, moxifloxacin, ciprofloxacin, and ofloxacin are FQs medications. They exhibit antimicrobial and antibiotic properties and have excellent in vitro and in vivo anti-TB activity (Bartlett et al. 2000; Wang et al. 2006). But they also display numerous side effects such as rash, dizziness, headache, and gastrointestinal intolerance.

8.17.2.2 Aminoglycosides (Kanamycin, Amikacin, and Capreomycin)

Drugs used in the treatment of multidrug-resistant tuberculosis are aminoglycosides (KAN), amikacin (AMK), and cyclic polypeptide capreomycin (CAP). All these drugs demonstrate their effect at the stage of protein translation. AMK and KAN have a high degree of cross-resistance between them (Alangaden et al. 1995; Jugheli et al. 2009; Maus et al. 2005). CAP is a possible candidate to replace AMK or KAN and is structurally dissimilar to aminoglycosides (Johansen et al. 2006; World Health Organization (WHO) 2008). When CAP resistance develops among MDR-TB cases, the risk of treatment failure and mortality increases (Migliori et al. 2008). Changes in 16S rRNA are due to AMK/KAN and CAP drug resistance (Alangaden et al. 1995; Maus et al. 2005; Johansen et al. 2006; Via et al. 2010). The side effects of these medications are renal toxicity and hearing loss.

8.17.2.3 Ethionamide and Prothionamide Ethionamide

Since 1956, ethionamide (ETH, 2-ethylisonicotinamide) has been used as an antituberculosis medication and is a derivative of isonicotinic acid. Ethionamide and prothionamide PTH (2-ethyl-4-pyridinecarbothioamide) are active agents of EtaA/EthA (a monooxygenase) (DeBarber et al. 2000) and inhibit targets such as isoniazid (INH) (Banerjee et al. 1994). Ethionamide undergoes many changes until it enters the bacterial cell. Flavin monooxygenase oxidizes the sulfate group and is then converted to 2-ethyl-4-aminopyridine. The intermediate products formed between ethionamide and 2-ethyl-4-aminopyridine tend to be toxic to mycobacteria, but the structure of these intermediate products is unknown. These intermediate products can be highly unstable compounds. The side effects of ethionamide are stomach issues.

8.17.2.4 P-Aminosalicylic Acid

P-Aminosalicylic acid (PAS) was used to treat TB in amalgamation with isoniazid and streptomycin. It was the first antibiotic to demonstrate anti-TB activity (Zhang et al. 1992). Once rifampicin and other potent drugs have been discovered, their use as a first-line drug has been discontinued. While PAS benefits are minimal and very toxic, PAS is still used for the treatment of XDR TB. Gastrointestinal disorders are the most common side effects associated with PAS.

8.17.2.5 Cycloserine

Cycloserine (CS) is used as an antibiotic in the treatment of TB. Since its action mechanism is still not quite clear, it is thought that cycloserine prevents the TB bacteria from producing peptidoglycans. These peptidoglycans are needed for the development of bacterial cell walls. This results in the weakening of the cell wall of the bacteria, which destroys the bacteria. Compared to other drugs, cycloserine has high gastric tolerance and lacks cross-resistance to other compounds. The biggest downside of this drug is that it induces psychological side effects. Cycloserine is the basis of care for MDR and XDR TB (Caminero 2006).

Sr. no.

First-line drugs

Adverse effects

Second-line drugs

Adverse effects

References

1.

Isoniazid

Hepatotoxicity and neurotoxicity

Fluoroquinolones

Gastrointestinal intolerance, rashes, dizziness, and headache

Bardou et al. (1998), Wang et al. (2006)

2.

Rifampicin

Gastrointestinal upset and hepatotoxicity

Aminoglycosides (kanamycin, amikacin, and capreomycin)

Renal toxicity, hearing loss

Mitchison (1979), Zaunbrecher et al. (2009)

3.

Ethambutol

Dizziness; blurred vision; color blindness; nausea; vomiting; stomach pain; loss of appetite; headache; rash; itching; breathlessness; swelling of the face, lips, or eyes; numbness or tingling in the fingers or toes

Ethionamide/prothionamide ethionamide

Gastrointestinal side effects

Jnawali and Ryoo (2013)

4.

Pyrazinamide

Hypersensitivity reactions and gastrointestinal upset

p-Aminosalicylic acid

Gastrointestinal disturbances

Zhang and Mitchison (2003), Leung et al. (2010)

5.

Streptomycin

Ototoxicity and nephrotoxicity, vestibular dysfunction, auditory damage, renal toxicity

Cycloserine

Adverse psychiatric effects

British Medical Research Council (1948), Gale (1981)

8.18 Therapeutic Use of Phytopolyphenols

In view of these details, some alternate therapeutic methods are required to cure this life-threatening disease. At present, more attention is paid to plant polyphenols due to their limited side effects, which is why polyphenol compounds could be a good option for combating and reducing the percentage of tuberculosis. Mycobacterium tuberculosis H37Rv (ATCC 27294) is a commonly used target strain for the evaluation of anti-TB efficacy of any medication or other therapeutic agents (Pauli et al. 2005).

Various secondary metabolites such as green tea polyphenol (9-epigallocatechin-3-gallate) have been found to inhibit Mtb survival in human macrophages (Anand et al. 2006). The downregulation of the host molecule tryptophan aspartate containing coat protein (TACO) expression of the epigallocatechin-3-gallate gene was followed by inhibition of Mtb survival within macrophages as assessed by flow cytometry and colony counts. Anand et al. (2006) studied that pre-treatment with EGCG inhibited mycobacterial entry by 18% as analyzed by fluorescence-activated cell sorting (FACS) for the detection of percent of lipoarabinomannan (LAM) fluorescence (indicating the number of bacteria present) using monoclonal anti-LAM antibody. At 12 o’clock, survival was reduced to just 26%. In the case of post-treatment EGCG, survival at 48 h was reduced to 55%. However, the colony forming unit (CFU) of the related THP-1 macrophages experiment did not suggest survival at 12 h of infection. LAM is a cell wall antigen of mycobacteria and can be found in macrophages even after the bacteria have partially degraded or are transformed into lysosomes (Anand et al. 2006). It is evident from the above data that the EGCG is actually hindering entry of M. tuberculosis and prevents the survival of the pathogen. In addition, dihydro-β-agarofuran sesquiterpenes (15-007-acetoxy-6β, 9β-dibezoyloxydihydro-β-agarofuran) isolated from the leaves of Celastrus vulcanicola Donn. show anti-TB activity against the strain MDR in which the MIC values are 0.0062 mg/mL, naphthoquinones, plumbagin, and its dimers maritinone and 3.3′-biplumbagin from Diospyros anisandra S.F.Blake, plumericin isolated from Plumeria bicolor Ruiz & Pav MIC values 0.0015–0.002 mg/mL and MBC (minimum bactericidal concentration) values 0.003–0.004 mg/mL and, 3′-biplumbagin from Diospyros anisandra. In addition, a compound called 7-methyljuglone was isolated from the roots of Euclea natalensis (Lall et al. 2005). This compound demonstrated activity against intracellular strain Mtb Erdman within macrophages J774.1 at a concentration of 0.57 μg mL plus 1. Minimum inhibitory concentrations of 7-methyljuglone were documented to be approximately four times higher against drug-resistant isolates. In addition, Chamaedorea tepejilote Liebm. (Arecaceae) and Lantana hispida Kunth are medicinal plants from which ursolic acid (UA) and oleanolic acid (OA) are extracted (used in traditional Mexican medicine). These two compounds are used to treat respiratory problems such as colds, cough, bronchitis, and pneumonia (Jiménez-Arellanes et al. 2013). Jiménez-Arellanes et al. (2013) stated that these two compounds had intracellular anti-TB activity in the infected Mtb macrophage cell line J774A. Mtb-infected BALB/c mice have been used to test the anti-TB activity of UA and OA. Compared to the control animals, UA- and OA-treated animals showed higher expressions of IFN-Δ and TNF-5-007 in the lungs (Jiménez-Arellanes et al. 2013). Jiménez-Arellanes et al. (2013) reported that the UA and OA combination was found to be very successful in destroying intracellular Mtb.