*3.2.1 Pharmacological activities*

Pharmacologically, pinocembrin can exhibit anti-inflammatory, [48] antioxidant, [49] antibacterial [50] and neuroprotective activities [51]. They mainly use Pinocembrin for the treatment of ischemic stroke. Moreover, current studies have shown that pinocembrin may have an effect of reversing Parkinson's disease (PD) and Alzheimer's disease (AD) in affected patients [52]. It has also been shown to exhibit anti-pulmonary fibrosis and vasodilating effects. Pinocembrin undergoes several pathways to perform its pharmacological effects. In addition, pinocembrin could also ease blood brain barrier (BBB) disruption and neurological injury by interfering and reducing the levels of inflammatory factors and reactive oxygen species (ROS). Also, pinocembrin is known to preserve mitochondrial integrity via the activation of the signal-regulated kinase/nuclear factor erythroid 2-related factor 2 (Erk1/2-Nrf2) pathway extracellularly [53]. Pinocembrin also attenuates apoptosis by affecting the p53 pathway, influencing the Bax-Bcl-2 ratio and cytochrome C release [54].

#### *3.2.2 Works done on pinocembrin*

The brain of rats has been demonstrated to be protected against apoptosis and oxidation induced by ischemia–reperfusion both in vivo and in vitro. Pinocembrin attenuates blood–brain barrier injury induced by global cerebral ischemia–reperfusion in rats [55]. Further research work is also showing that Pinocembrin has the potential of giving positive outcomes in the treatment of ischemic stroke. This is because it can significantly cause a reduction in the regions of cerebral infarction in rats and cerebral ischemia and reduce the level of cerebral oedema and apoptosis of the cells in the nerve [47]. Shen et al., [47] concluded that pinocembrin exhibits several effects on, Parkinson's disease, ischemic stroke, solid tumors, Alzheimer's disease, and some other diseases because of possibility of releasing inflammatory factors by halting several signaling pathways, such as PI3K/AKT and MAPK. Antioxidant role is also known in pinocembrin because of its ability to reduce the release of NO, nNOS, ROS and iNOS.

#### **3.3 Biosynthesis of polyphenols**

Polyphenols constitute an integral class of key secondary metabolites with multiple phenolic hydroxyl groups including flavonoids, stilbenes, phenolic acids, and tannins (hydrolysable and condensed) [56] synthesized mainly by a metabolic pathway termed phenylpropanoid [57].

The biological synthetic routes of polyphenols involve the phenylpropanoid and shikimic acid metabolism pathways [58]. In Salvia species, polyphenols found are mainly reduced by the phenylpropanoid metabolic pathway [57–60] and most derivatives have synonymous basic structures [61].

Tyrosine and Phenylalanine are precursor compounds of the phenylpropanoid metabolic pathway, and their biosynthetic pathways make up two (2) parallel branches of this pathway involving five rate-limiting enzymes [62, 63]. These enzymes consist of phenylalanine ammonia-lyase (PAL); which is a key regulatory enzyme in plant metabolism, cinnamic acid-4-hydroxylase (C4H) and 4-coumarate: coenzyme A (COA) ligase (a peculiar regulatory enzyme in the phenylalanine branch), rosmarinic acid synthase (a key enzyme in catalytic synthesis) and tyrosine aminotransferase (the initial key enzyme and rate-limiting enzyme in tyrosine metabolism pathway), [64].

Caffeic acid derivatives are phenolic acids derived from Salvia species which are mostly produced via esterification of caffeic acid with danshensu [65, 66]. Caffeic acid originates from the class of phenyl propionic acid, [67] and it is the fundamental structural unit of phenolic acids [68]. Phenylalanine is the precursor compound of caffeic acid, which helps in the production of caffeic acid through the action of C4H and PAL enzymes.

**15**

*Pharmacological Role of Biosynthetic Products DOI: http://dx.doi.org/10.5772/intechopen.96977*

(caffeoyl-40-HPLA).

acid synthesis [61].

*3.3.1 Pharmacology of polyphenols*

*3.3.2 Works done on polyphenols*

are phenolic acids are.

effects of these phenolic acids [83].

It plays a key role in the metabolic pathway of phenylpropanoid and is a precursor compound of rosmarinic acid [69, 70]. Studies have speculated that, catalysis of caffeoyl CoA in the main synthetic route of rosmarinic acid, caffeic acid. Subsequently, caffeoyl CoA and 4-hydroxyphenyl acetic acid is catalysed by hydroxycinnamoyl-CoA: hydroxyphenyllactate hydroxycinnamoyl transferase (rosmarinic acid synthase (RAS)) to earn caffeoyl-40-hydroxy phenylacetic acid

The reaction is finally catalyzed by CYP98A14 to rosmarinic acid [71]. Rosmarinic acid is employed in the formation of Salvianolic acid E under the action of enzymes and other reactions which are then transformed into salvianolic acid B and other compounds. This observation seeks to infer that rosmarinic acid is the core constituent unit of a series of complex phenolic acids, such as salvianolic acids [72, 73]. Complex phenolic compounds formation is based mostly on rosmarinic

The phenylpropanoid metabolic pathway is an important upstream pathway for

They exhibit numerous pharmacological activities, such as anti-cardiovascular, [75] anti-oxidation [76], anti-tumor [77] anti-inflammatory [78]. Other pharmacological activities exhibited by polyphenols include; anti-hypertensive (caffeic acid, chlorogenic acid and salvianolic acid A), memory and cognitive impairment improvement (rosmarinic acid, total salvianolic acid), hypoglycemic (Salvianolic acid B), antiviral (Protocatechuic aldehyde, Magnesium lithospermate B, rosmaric

Chang et al., [80] have illustrated that phenolic acids exhibit better antioxidant properties because of their mechanism of action including, inhibition of free radical generation, free radical scavenging and lipid peroxidation. A study showed that rosmarinic acid, danshensu and caffeic acid were as effective as the positive control (quercetin), which scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals in a concentration-dependent way. On the other hand, ferulic acid was less effective [81]. Other studies have shown that danshensu and salvianolic acid B showed greater scavenging activities against HO·, −, DPPH, O2-, and 2,20-and-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS) than the other constituents. Among them, the half-maximal inhibitory concentration (IC50) of salvianolic acid B and danshensu were not significantly different, and there was no obvious difference in the scavenging actions of hydroxyl radicals [82]. Thus, hydroxyl radical scavengers

Studies on inhibition of spontaneous lipid peroxidation in liver tissue of polyphenols in mice lead to the formation to the following order after testing all the seven polyphenols. Rosmarinic emerged the most efficacious followed by caffeic acid, protocatechuic aldehyde, chlorogenic acid, ferulic acid, and danshensu. 3-hydroxycinnamic acid was studied in hydrogen peroxide -induced liver lipid peroxidation in rodents' model. Also, other in vitro studies confirmed the antioxidants

Salvianolic acid B was found to be effective in the reduction of myocardial ischemia–reperfusion injury. Ischemia–reperfusion model was established by ligating the left circumflex artery in Sprague–Dawley (SD) rats against myocardial ischemia–reperfusion injury and the concentration and apoptotic index of

producing flavonoids such as anthocyanins, isoflavonoids, and flavonoids [74].

acid), prevents and treats cancer (Danshensu, Protocatechualdehyde) [79].

#### *Pharmacological Role of Biosynthetic Products DOI: http://dx.doi.org/10.5772/intechopen.96977*

*Bioactive Compounds - Biosynthesis, Characterization and Applications*

Pinocembrin for the treatment of ischemic stroke. Moreover, current studies have shown that pinocembrin may have an effect of reversing Parkinson's disease (PD) and Alzheimer's disease (AD) in affected patients [52]. It has also been shown to exhibit anti-pulmonary fibrosis and vasodilating effects. Pinocembrin undergoes several pathways to perform its pharmacological effects. In addition, pinocembrin could also ease blood brain barrier (BBB) disruption and neurological injury by interfering and reducing the levels of inflammatory factors and reactive oxygen species (ROS). Also, pinocembrin is known to preserve mitochondrial integrity via the activation of the signal-regulated kinase/nuclear factor erythroid 2-related factor 2 (Erk1/2-Nrf2) pathway extracellularly [53]. Pinocembrin also attenuates apoptosis by affecting the

p53 pathway, influencing the Bax-Bcl-2 ratio and cytochrome C release [54].

The brain of rats has been demonstrated to be protected against apoptosis and oxidation induced by ischemia–reperfusion both in vivo and in vitro. Pinocembrin attenuates blood–brain barrier injury induced by global cerebral ischemia–reperfusion in rats [55]. Further research work is also showing that Pinocembrin has the potential of giving positive outcomes in the treatment of ischemic stroke. This is because it can significantly cause a reduction in the regions of cerebral infarction in rats and cerebral ischemia and reduce the level of cerebral oedema and apoptosis of the cells in the nerve [47]. Shen et al., [47] concluded that pinocembrin exhibits several effects on, Parkinson's disease, ischemic stroke, solid tumors, Alzheimer's disease, and some other diseases because of possibility of releasing inflammatory factors by halting several signaling pathways, such as PI3K/AKT and MAPK. Antioxidant role is also known in pinocembrin because of its ability to reduce the

Polyphenols constitute an integral class of key secondary metabolites with multiple phenolic hydroxyl groups including flavonoids, stilbenes, phenolic acids, and tannins (hydrolysable and condensed) [56] synthesized mainly by a metabolic

The biological synthetic routes of polyphenols involve the phenylpropanoid and shikimic acid metabolism pathways [58]. In Salvia species, polyphenols found are mainly reduced by the phenylpropanoid metabolic pathway [57–60] and most

Tyrosine and Phenylalanine are precursor compounds of the phenylpropanoid

Caffeic acid derivatives are phenolic acids derived from Salvia species which are mostly produced via esterification of caffeic acid with danshensu [65, 66]. Caffeic acid originates from the class of phenyl propionic acid, [67] and it is the fundamental structural unit of phenolic acids [68]. Phenylalanine is the precursor compound of caffeic acid, which helps in the production of caffeic acid through the action of

metabolic pathway, and their biosynthetic pathways make up two (2) parallel branches of this pathway involving five rate-limiting enzymes [62, 63]. These enzymes consist of phenylalanine ammonia-lyase (PAL); which is a key regulatory enzyme in plant metabolism, cinnamic acid-4-hydroxylase (C4H) and 4-coumarate: coenzyme A (COA) ligase (a peculiar regulatory enzyme in the phenylalanine branch), rosmarinic acid synthase (a key enzyme in catalytic synthesis) and tyrosine aminotransferase (the initial key enzyme and rate-limiting enzyme in tyrosine

*3.2.2 Works done on pinocembrin*

release of NO, nNOS, ROS and iNOS.

pathway termed phenylpropanoid [57].

derivatives have synonymous basic structures [61].

**3.3 Biosynthesis of polyphenols**

metabolism pathway), [64].

C4H and PAL enzymes.

**14**

It plays a key role in the metabolic pathway of phenylpropanoid and is a precursor compound of rosmarinic acid [69, 70]. Studies have speculated that, catalysis of caffeoyl CoA in the main synthetic route of rosmarinic acid, caffeic acid. Subsequently, caffeoyl CoA and 4-hydroxyphenyl acetic acid is catalysed by hydroxycinnamoyl-CoA: hydroxyphenyllactate hydroxycinnamoyl transferase (rosmarinic acid synthase (RAS)) to earn caffeoyl-40-hydroxy phenylacetic acid (caffeoyl-40-HPLA).

The reaction is finally catalyzed by CYP98A14 to rosmarinic acid [71]. Rosmarinic acid is employed in the formation of Salvianolic acid E under the action of enzymes and other reactions which are then transformed into salvianolic acid B and other compounds. This observation seeks to infer that rosmarinic acid is the core constituent unit of a series of complex phenolic acids, such as salvianolic acids [72, 73]. Complex phenolic compounds formation is based mostly on rosmarinic acid synthesis [61].

The phenylpropanoid metabolic pathway is an important upstream pathway for producing flavonoids such as anthocyanins, isoflavonoids, and flavonoids [74].

## *3.3.1 Pharmacology of polyphenols*

They exhibit numerous pharmacological activities, such as anti-cardiovascular, [75] anti-oxidation [76], anti-tumor [77] anti-inflammatory [78]. Other pharmacological activities exhibited by polyphenols include; anti-hypertensive (caffeic acid, chlorogenic acid and salvianolic acid A), memory and cognitive impairment improvement (rosmarinic acid, total salvianolic acid), hypoglycemic (Salvianolic acid B), antiviral (Protocatechuic aldehyde, Magnesium lithospermate B, rosmaric acid), prevents and treats cancer (Danshensu, Protocatechualdehyde) [79].

#### *3.3.2 Works done on polyphenols*

Chang et al., [80] have illustrated that phenolic acids exhibit better antioxidant properties because of their mechanism of action including, inhibition of free radical generation, free radical scavenging and lipid peroxidation. A study showed that rosmarinic acid, danshensu and caffeic acid were as effective as the positive control (quercetin), which scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals in a concentration-dependent way. On the other hand, ferulic acid was less effective [81]. Other studies have shown that danshensu and salvianolic acid B showed greater scavenging activities against HO·, −, DPPH, O2-, and 2,20-and-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS) than the other constituents. Among them, the half-maximal inhibitory concentration (IC50) of salvianolic acid B and danshensu were not significantly different, and there was no obvious difference in the scavenging actions of hydroxyl radicals [82]. Thus, hydroxyl radical scavengers are phenolic acids are.

Studies on inhibition of spontaneous lipid peroxidation in liver tissue of polyphenols in mice lead to the formation to the following order after testing all the seven polyphenols. Rosmarinic emerged the most efficacious followed by caffeic acid, protocatechuic aldehyde, chlorogenic acid, ferulic acid, and danshensu. 3-hydroxycinnamic acid was studied in hydrogen peroxide -induced liver lipid peroxidation in rodents' model. Also, other in vitro studies confirmed the antioxidants effects of these phenolic acids [83].

Salvianolic acid B was found to be effective in the reduction of myocardial ischemia–reperfusion injury. Ischemia–reperfusion model was established by ligating the left circumflex artery in Sprague–Dawley (SD) rats against myocardial ischemia–reperfusion injury and the concentration and apoptotic index of

the plasma level of myocardial enzymes (cardiac troponins (CTn) I and creatine kinase-MB (CKMB)), endothelin (ET), superoxide dismutase (SOD), nitric oxide (NO), malondialdehyde (MDA), and histological changes of the heart were determined. The outcome was observed that salvianolic acid B significantly increased the plasma levels of CTn I, CKMB, MDA, and ET contents; decrease in T-SOD and NO contents; reduction in infarct size; and improved myocardial ultrastructure. It was concluded that salvianolic acid B has an impact against conditions such as myocardial ischemia–reperfusion injury via the regulation of reducing oxidative stress, active oxygen metabolism, and myocardial apoptosis [84]. A study conducted by [85] also stated that salvianolic acid which is a phenolic could also be effective in alleviating ischemic-reperfusion injury. It could also prevent myocardial ischemia–reperfusion injury through an increased glucose condition by adjusting the NADPH oxidase 2 (Nox2)/reactive oxygen species (ROS)/ phosphorylated-c-Jun N-terminal kinase 2 (p-JNK2)/NF-κB pathway to reduce transient receptor potential cation channel, member 6 (TRPC6)/Ca2+ influx, subfamily C [86].

Anti-thrombotic effects which are through its actions on blood rheology has also been known to be a possible action of salvianolic acid in *S. miltiorrhiza*. It also acts as to prevent platelet aggregation by targeting P2Y1 or P2Y12 receptors, which are novel target receptors required for anti-platelet aggregation. Salvianolic acid B experimentally, only antagonizes the action of platelet P2Y12 receptors, while salvianolic acid A and C are P2Y12 and P2Y1 receptor inhibitors [87].

Other studies by [88] have also illustrated that caffeic acid can inhibit plateletmediated thrombosis by P-selectin expression, repression of ADP-induced platelet aggregation, ATP release, and Ca2+ mobilization and attenuate the activation of ERK, p38, JNK, and integrin αIIbβ3. It could also increase cAMP expression levels.

Better antiplatelet and anti-thrombotic therapeutic efficacy have also been demonstrated in Danshensu when compared to other constituents. Several contributions have been made through its ability to selectively suppress balancing the ratio of thromboxane A2 (TXA2)/prostacyclin (PGI2) and the expression of cyclooxygenase (COX)-2 [89].

Several studies have been conducted on the anti-liver injury activity of polyphenols and from [90] salvianolic acid B protects liver cells by enhancing lysosome-associated membrane protein 1 (LAMP1) expression and preserving lysosomal membrane integrity through scavenging ROS. Salvianolic A has also been concluded by [91, 92] that it protects acute hepatic injury after inducing mice models with concanavalin A. The outcome of the liver function markers, alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) showed that salvianolic acid A significantly reduced ConA-induced AST and ALT activity. Also, there was a reduction in the hepatotoxic cytokine levels, such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α; improvement in the increased NF-κB level and cleaved caspase-3; and reversal of B-cell lymphoma-extra-large (Bcl-xL) expression [79].

Wang et al. [90] concluded that salvianolic acid B seems to be effective and safe, and it could develop this natural component into a potential therapeutic agent for the management of glioma. This is because of its inhibitory actions on the human glioma U80 cells, which its initiation leads to p38-activation-mediated ROS production.

Reviews conducted by Rasouli et al. [93] throws more light on the importance of polyphenols from foods. This because they are beneficial in most health conditions including pernicious human diseases (HDs). Also, people who followed a specific diet particularly polyphenol-rich diets are of lower risk of several ranges of chronic diseases, such as diabetes, obesity, cancer, and heart disease.

**17**

*Pharmacological Role of Biosynthetic Products DOI: http://dx.doi.org/10.5772/intechopen.96977*

*Arcangelisia flava* and *Cortex rhellodendri* [94].

thalifendine, and demethyleneberberine [94].

and antioxidant activities, in inflammatory diseases.

treatment of diarrhea associated with infections.

Berberine is a quaternary ammonium salt and it's from a group of isoquinoline alkaloids termed 2,3–methylenedioxy-9,10-dimethoxyprotoberberine chloride; C20H18NO4+. It is highly concentrated in the roots, stem bark, rhizomes and of numerous plants including *Rhizoma coptidis, Tinospora cordifolia, Coptis chinensis, Hydrastis canadensis, Berberis vulgaris, Berberis aquifolium, Berberis aristata,* 

Berberine comprises of several derivatives such as berberrubine, jatrorrhizine

Pharmacologically, almost all parts of the plant have been shown to have several properties. These pharmacological properties of berberine includes antiemetic, antipyretic, tonic, antimicrobial, antipruritic, antiarrhythmic, sedative, antioxidant, anti-inflammatory, hypotensive, antinociceptive, anticholinergic and cholagogue actions, and it has been used sometimes like dysentery cholecystitis, cholelithiasis, leishmaniasis, jaundice, malaria and gall stones [95]. Berberine has been used for treating diarrhoea and gastrointestinal disorders for a long time [96, 97]. It has multiple pharmacological effects including; antimicrobial activity against 54 microorganisms, [98] inhibition of intestinal ion secretion and smooth muscle contraction, inhibition of ventricular tachyarrhythmia, reduction of inflammation, stimulation of bile secretion and bilirubin discharge [99]. Moreover, [100] have reviewed that berberine to possess pharmacological activities such as insulin secretion promotion, insulin resistance reduction, increased insulin secretion, inhibiting gluconeogenesis in the liver, stimulating glycolysis in peripheral tissue cells, reducing intestinal absorption of glucose, and regulating lipid metabolism, and modulating gut microbiota. Also, it is significant in the treatment of diabetic nephropathy, diabetic neuropathy, and diabetic cardiomyopathy because of its anti-inflammatory

Antidiabetic activity of berberine has been conducted by Pang et al., [101] His review article highlighted several mechanisms with which berberine act to improve glucose control. A bibliometric review conducted between 1985–2018 also outlines that berberine has significant antibacterial and antipyretic effects and is a commonly used drug for treating infectious diarrhoea and amoebiasis. Berberine has significant antipyretic and antibacterial effects and its commonly used for the

Zhao et al., [102] also added., that berberine has an improved activity in improving nonalcoholic fatty liver disease by halting glucogenesis and comprehensively regulating lipid metabolism, and its effect on inhibiting lipogenesis in the liver was much stronger. He also suggested that weight loss may partly mediate the improvement and would be a drug of choice for NAFLD patients and glucose metabolic disorder. But they, therefore, require future clinical trials to confirm these effects. The review article by Zhu et al., [103] threw more light on the mechanism of action of berberine. It was stated that berberine potentially works through an increase in insulin sensitivity, LDLR mRNA stabilization, improvement of mitochondrial function, regulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, alleviation of oxidative stress, and regulation of gut microenvironment being the major targets of berberine in the treatment of NAFLD.

**3.4 Biosynthesis of berberine**

*3.4.1 Pharmacological activity*

*3.4.2 Works done on berberine*
