Open access peer-reviewed chapter
Abstract
A product such as hydrated carbons (carbohydrates), lipids, proteins, and nucleic acids play significant roles in plants metabolically. But there are other natural organic products manufactured by plants, some of the products are complex molecules, which are not primary metabolites. These biosynthetic products have possesses a variety of therapeutic merits in drug discovery. Some biosynthetic products show numerous appreciable therapeutic effects making them beneficial for trimming down polypharmacy and as viable candidates for the management of chronic diseases such as diabetes and hypertension in patients. The chapter discusses the pharmacological role of some biosynthetic products from plants and animals.
Keywords
- alkaloids
- phytosterols
- biosynthesis
- amino acids
- pharmacological
- terpenes
1. Introduction
Natural products are mostly produced by a living organism. A product such as carbohydrates, lipids, proteins, and nucleic acids play significantly impact on the primary role in in plants in terms of their metabolic reactions. Moreover, other natural organic compounds have also been known to be produced by plants, with which some of them are complex molecules, which are not primary metabolites. Different organisms may produce the same compounds through different pathways (e.g., convergent evolution), even if they are widely separated phylogenetically. The same organism may produce some compounds via over one biosynthetic path. There may be over one path available, such as in a changed linear process or metabolic grid. Even if the same compound is present in two different organisms, they may be formed via different pathways. This, however, is more likely for metabolites with simple structures. It derives the major precursors from the metabolism of carbohydrate (sugars), protein (amino acids), and lipid (fatty acid). The pathway derived biosynthetically for aromatic amino acids is an integral source of aromatic compounds such as flavonoids, phenols, and some alkaloids. Glycolysis yields an important metabolite such as acetyl-CoA and also via the beta-oxidation of fatty acids and also used in the tricarboxylic acid cycle (TCA) in the manufacture of organic acids, which are also starting materials for secondary metabolites. Also, acetyl-CoA plays important role in synthesizing terpenes, which forms a distinct class of metabolites.
2. Animal biosynthetic product
Animals contain many unique small molecules, including bioactive secondary metabolites. The compounds are protective, offensive or involved in communication [1]. Most of this product is also biologically effective, and they include the following.
2.1 Terpenes
Terpenes occur widely in nature. They are a large and varied class of hydrocarbons, which are produced by a wide variety of plants and by some animals. Terpenes are biosynthetically derived from isoprene units with the molecular formula C5H8. In bacteria and plants, isoprene precursor’s dimethylallyl pyrophosphate and isopentenyl pyrophosphate can be made either via the mevalonate or deoxyxylulose phosphate pathways, but in animals’ mevalonate is the source of these precursors [2]. The mevalonate pathway is the universal source of the terpenoid C5 precursor’s isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). In this pathway, three molecules of acetyl-CoA are condensed to 3-hydroxy-3-methylglutaryl-CoA with subsequent reduction to mevalonate, which is converted to IPP and DMAPP. Terpenes can exist as hydrocarbons or have oxygen-containing compounds such as hydroxyl, carboxyl, ketone, or aldehyde groups. After chemical modification of terpenes, it refers to the resulting compounds as terpenoids [3].
In the biochemical pathway of terpenoid synthesis, prenyltransferases take part in the condensation of activated forms of isoprene units. They link IPP with an isopentenyl diphosphate isomer of DMAPP in a “head-to-tail” manner. The linear chains of phenyl diphosphates that are formed in the reaction may also be changed through dimerization or cyclization by terpene synthase, forming terpenoids with new functions. They classify the resulting terpenes in order of size into hemiterpene, monoterpenes, sesquiterpenes, diterpene, triterpene, tetra terpenes, and polyterpenes. Hemiterpene comprises a single isoprene unit and changed into oxygen-containing derivatives called hemiterpenoids [3].
We have found terpenoids to be useful in the prevention and therapy of several diseases, including cancer, and also to have antimicrobial, antifungal, antiparasitic, antiviral, anti-allergenic, antispasmodic, antihyperglycemic, anti-inflammatory, and immunomodulatory properties [3].
2.2 Carnitine
Vaz and Wanders, [4] have described that carnitine plays a vital role in energy production in living organisms in terms of metabolism since it enables activated fatty acids to enter the mitochondria, where broken down via β-oxidation. Carnitine is present in all animal species, including other multiple micro-organisms and plants. They maintain its homoeostasis through endogenous synthesis, absorption from dietary sources and efficient tubular reabsorption by the kidney. Animal tissues contain relatively high amounts of carnitine, varying between 0.2 and 6 μmol/g, with the highest concentrations in heart and skeletal muscle. Apart from the diet being the primary source of carnitine, most mammals can synthesize carnitine internally [4].
Carnitine synthesis is from two amino acids; precisely lysine and methionine. Lysine serves as the carbon backbone of carnitine and the 4-N-methyl groups emanate from methionine [5]. Proteins in mammals contain N’trimethyl-lysine (TML) residues. N-methylation of these lysine residues occurs as a post-translational event in proteins such as calmodulin, myosin, actin, cytochrome c and histones. This reaction mostly catalysed by specific methyltransferase, which uses S-adenosylmethionine as a methyl donor. TML is the first metabolite of carnitine biosynthesis is released through the action of Lysosomal hydrolysis of these proteins. TML is first hydroxylated on the 3-position by TML to yield 3-hydroxy TML (HTML). Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). In the irrevocable step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase to yield carnitine [4]. Carnitine has an important role in the transport of activated long-chain fatty acids from the cytosol to the mitochondrial matrix where β-oxidation takes place. Second, they involve carnitine in transferring the products of peroxisomal β-oxidation, including acetyl-CoA, to the mitochondria for oxidation to CO2 and H2O in the Krebs cycle.
Pharmacologically, carnitine has possessed several effects on bone mass, male infertility, cognitive support, [6] metabolic function improvement, [7] neuroprotective effects in Alzheimer’s dementia [8] and Parkinson’s disease, [9] protection against oxidative stress damage, [10] congestive heart failure, hypertrophic heart disease, and peripheral arterial disease treatment [11]. They have also shown it to improve peripheral vasodilator activity [12].
From [13] the ability of an agent to control endothelial dysfunction is through upsetting the balance between the production of a vasodilator such as nitric oxide and vasoconstrictor, such as endothelin-1 substances in response to physical or chemical stimuli. This is because it is through that imbalance that leads to endothelial dysfunction, which is one of the initial steps in atherogenesis [14]. They relate endothelial dysfunction to cardiovascular risk factors such as arterial hypertension, dyslipidemia, diabetes, and obesity [15, 16]. They have therefore investigated carnitine gas in rats’ models to cause an endothelium-dependent dilatation in arteries, since endothelial nitric oxide seemed to be the main mediator of vasodilatation [17]. For the cardioprotective ability of carnitine to serve as a cardioprotective agent, isolated rat working heart through different antioxidant mechanisms in most of the cases [18]. In terms of insulin resistance, this is where a 20 weeks treatment with carnitine in animal obese models resulted in a reduction in body weight, abdominal adiposity, plasmatic insulin, and liver triglyceride content [19]. Several, studies have been conducted on the antioxidant properties of carnitine and was due mainly to a reduction in both lipid peroxidation and free radical generation [20]. A decreased expression of inducible NO synthase and protein nitration, and inhibition of tubular necrosis and neutrophil infiltration in transplanted kidneys [21] . For antioxidant study [22] also revealed that carnitine and its derivatives fundamental mechanisms as participating in redox signalling that affects transcription factors (Nrf2, PPARα, NF-κB, etc.) and activating the vitagene network.
2.3 Pheromone
Pheromone plays a key role in sexual communication and reproduction in many insects such as the moth’s species. In some insects, the pheromone is biosynthesized and released by specialized sex pheromone glands (PGs) that are along the intersegmental membrane between the 8th and 9th abdominal segments of females. Although the general pathway of sex pheromone synthesis in most species has not been established and the molecular mechanisms remain poorly understood [23]. Although de novo synthesis is more prevalent in the species studied to date, there are multiple examples of pheromone components derived from host precursors. Sometimes, such as leucine, used as starting material for fatty-acid derived sex pheromone biosynthesis by Holomelina spp. (Lepidoptera: Arctiidae), the putative plant-derived precursor is extensively elaborated by a typically de novo pathway. In other cases, it converts a highly elaborated host precursor to a pheromone component through a simple chemical transformation. While they originally reported the utilization of host precursors for pheromone biosynthesis in some insects, subsequent studies showed that pheromone biosynthesis was only or partially de novo [23].
The analysis of different pheromone glands in different species has revealed the occurrence of unusual fatty acids that have been proposed as precursors of pheromone components. Many lepidopteran sex pheromones are produced by P-oxidation steps with desaturase systems. However, only a few studies have a combination of different fatty acyl intermediates been used to show experimentally a pheromone biosynthetic pathway [23].
From [24] sex pheromone biosynthesis in moths begins with a palmitic or stearic acid moiety that is synthesized de novo in the PG through modifications of the fatty acid biosynthetic pathway. Through a series of enzymatic reactions such as desaturation, chain-shortening reaction, reduction, acetylation, and oxidation, it then converts the palmitic or stearic acids to the final pheromone components in a step-wise manner. Therefore, different enzymes are likely to be involved in the different reactions, and to date, the genes encoding 4 different classes of enzymes that are essential for this pathway have been functionally identified desaturases (Des), fatty acid reductases (FARs), fatty acid transport proteins (FATPs), and acyl-CoA-binding proteins (ACBPs) [24].
Pheromones, a chemical or blend of chemicals released by an organism that causes a specific behavioral or physiological reaction in one or more conspecific individuals are important mediators of communication for bacteria, plants, and animals in these environments. Pheromone systems of insects have proved to be some of the richest intellectual sources for the nascent science of chemical ecology the composite pheromones can be classed into six behaviorally functional groups: sex, aggregation, dispersal (spacing or epideictic), alarm, recruitment (trail), and maturation [24].
Pheromones are noted to function as opposite-sex attractants, same-sex repellents, and mother-infant bonding attractants and as menstrual cycle modulators [25]. A review article by [26] concluded that pheromones have aphrodisiac activity.
2.4 Melanin
Melanin is an abundant biological pigment that is present in mammalian which is located in areas such as skin, hair, eyes, ears and the nervous system. Birds’ feathers, squid’s ink, insects, plants and many other biological systems have been also known to contain melanin. It classifies melanin into three groups: eumelanin, pheomelanin and allomelanins. We term nervous system melanins as neuromelanin. Eumelanin colours commonly present as black or brown in animals [27].
Amino acid tyrosine is needed in the production of melanin, but its actions are catalyzed enzymatically by tyrosinase. In their primary biosynthetic pathway, tyrosine is hydroxylated to form the catecholamine 3,4-dihydroxyphenylalanine (DOPA), which is then oxidized to form 3,4-dioxyphenylalanine (dopa quinone) before cyclization to 5,6-indole quinones and their subsequent polymerization to form melanin [27].
Mason-Raper pathway can also produce melanin, and it started by the usage of tyrosine to form dihydroxyphenylalanine by tyrosinase through an oxidation reaction. The product (dihydroxyphenylalanine) formed is then oxidized by the same enzyme to dopa quinone, which rearranges spontaneously to leuco dopa chrome and then to dopa chrome. An unusual trait of dopa chrome that of decolorizing slowly if held under a vacuum allowed the identification of the subsequent intermediate 5,6-dihydroxy indole-2 carbolic acid, which loses its carboxyl group to become 5,6-dihydroxy dole. Upon exposure to air 5,6-dihydroxy indole is oxidized to indole 5,6-quinone and then to melano chrome, a purple compound that polymerizes to melanin [27].
Similar to the biosynthesis of eumelanin, melanin known as pheomelanin is biologically synthesized, except that it incorporates a precursor containing sulphur in the structure.
It has revealed melanin from natural sources to exhibit a broad spectrum of biological activities such as UV radiation protection, enzymatic lysis, and damage by oxidants, and resistance to drugs by pathogens, protection of insects against bacteria and antiviral protection. They have shown melanin to chelate metal ions and to act as a physiological redox buffer [27]. With this in mind, several studies have pharmacologically shown that melanin is indeed effective as an antioxidant, [28, 29, 30] Immunomodulatory and enhancement, [31, 32, 33, 34] hepatoprotective, [35] anticarcinogenic effects, [36] and anti-inflammatory [37].
Studies conducted in
Melanins from various sources exhibit significant antioxidant activity, melanin protects pigmented cells and adjacent tissues by adsorbing potentially harmful substances, which are then slowly released in nontoxic concentrations, Besides, melanin could also interact with orally administered drugs and a vehicle for drug delivery, Melanin extracted from different species of tea displays protective effects against hydrazine-induced liver injury, a remarkable anti-inflammatory effect of melanin has been reported [34].
2.5 Cholesterol
The most ubiquitous sterol in the animal system is present as cholesterol. But plant lack cholesterol notwithstanding, they contain structurally similar other sterol and similar biosynthetic pathway exist both in plants and animals and some prokaryotes. In humans, Normal healthy adults synthesize cholesterol at a rate of approximately 1 g/day and consume approximately 0.3 g/day. A relatively constant level of cholesterol in the body (150–200 mg/dL) is maintained primarily by controlling the level of de novo synthesis, which is partly regulated in part by the dietary intake of cholesterol [40].
Cholesterol is biosynthesized from a 2-carbon metabolic intermediate, acetyl-CoA hooked end to end involving several enzymatic reactions and finally gets converted into the 27-carbon molecule of cholesterol. Metabolism (catabolism) of lipids, carbohydrates and proteins leads to the formation of AcetylCoA. The process of cholesterol synthesis has five major steps where the conversion of Acetyl-CoAs to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is the first. HMG-CoA is converted to mevalonate, followed by the formation of an isoprene-based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2 from mevalonate. It, therefore, converts the IPP to squalene, where cholesterol is formed from squalene as the last step. The reaction is repeated with the units of Acetyl-CoA. Two moles of acetyl-CoA are condensed in a reversal of the thiolase reaction, forming acetoacetyl-CoA. Acetoacetyl-CoA and the third mole of acetyl-CoA are converted to HMG-CoA by the action of HMG-CoA synthase. HMG-CoA is converted to mevalonate by HMG-CoA reductase, HMGR (it binds this enzyme in the endoplasmic reticulum, ER). HMGR requires NADPH as a cofactor, and two moles of NADPH are consumed during the conversion of HMG-CoA to mevalonate. The reaction catalyzed by HMGR is the rate-limiting step of cholesterol biosynthesis. Mevalonate is then activated by three successive phosphorylations, yielding 5-pyrophosphomevalonate. Phosphorylation mevalonate and successive reactions maintain their solubility since otherwise, these are insoluble in water [40].
Cholesterol from both diet and synthesis is utilized in the formation of membranes and the synthesis of the steroid hormones and bile acids, regulating membrane fluidity and permeability as a cell membrane structural component, formatting lipid rafts with sphingolipid to mediate cell-to-cell recognition, adhesion, and communication [40].
3. Biosynthesis of plant origin
Different plants not only synthesize different aromatic secondary metabolites but also synthesize varying amounts of them at specific times and in specific subcellular compartments. One would expect that regulation of the differential biosynthesis of sometimes very complex molecular structures might involve regulation of the supply of the precursors influencing the rate-limiting step for carbon flow through the shikimate pathway. Recent data on transgenic potatoes give some sign that this is indeed the case [41].
3.1 Biosynthesis of terpenoid compounds
Some terpenoids play an important role in plant growth and development, such as gibberellin, as plant hormones regulate plant development. Other terpenoids play a role in the interaction between plants and the environment, such as participating in plant defence systems as phytoalexins and interspecies competition as interspecific sensing compounds. Terpenoids make up one of the largest and structurally diverse groups of naturally occurring compounds [42]. Mevalonic acid is mostly employed as a terpenoid synthetic racemate; however, mevalonic acid dimethoxy acetal may be resolved as its quinine salt. The acetates of the individual enantiomers of mevalonolactone are much less soluble than the racemate, and these may determine the purity and chirality of biosynthetic mevalonate. The steric course of many terpenoid biosynthetic processes has been followed using the stereospecifically deuterated and tritiated 2R,3R- [2-'H]-, 2S,3R- [2-3H]-, 3R,4R- [4–3 H] -, 3R,4S- [4- HI-, and 3R,5R- [S 3 H]-mevalonate. Several routes for preparing 5S- [5-3H] mevalonate have been described. [l-3H] Isopentenal is a substrate for liver alcohol dehydrogenase and this affords 1 s- [l-3H] isopentenyl, which may then be converted into mevalonic acid. Alternatively, [5-3H] mevalonic acid can be reduced enzymatically with mevalonate reductase to afford 5S-[5-3H] mevalonic acid. The hemithioacetal of mevalonate and coenzyme-A is reduced by 3-hydroxy-3-methylglutaryl COA reductase.” The steric course of this reduction is now known and they can also adapt this to afford 3R,5S- [5-3H] mevalonic acid. They have reported a mevalonate kinase assay [13]. An enzyme system capable of forming the mono- and pyro-phosphates of mevalonic acid, isopentenyl pyrophosphate and dimethylallyl pyrophosphate has been isolated ‘From orange-juice vesicles and shown to convert isopentenyl pyrophosphate and dimethylallyl pyrophosphate into linalool [42].
3.1.1 Pharmacology of terpenoids
Antitumour, [43] anti-inflammatory, antibacterial effects, cardiovascular effects, antimalarial, hypoglycemic effect, and transdermal absorption promotion have been investigated to give such pharmacological activities. Other activities apart from the mentioned above include insect resistance, immunoregulation, anti-oxidation, antiaging, and neuroprotection have also been known [3].
3.1.2 Works done on terpenoids
They have conducted several studies on terpenoids and their outcomes are promising. For antitumour activity, they have shown that perillyl alcohol which contains terpenoids plays a preventive and therapeutic role in cancer. The results showed that the administration of perillyl alcohol in rats can significantly reduce the incidence and multiplicity of colonic invasive adenocarcinoma caused by the injection of carcinogen azomethane [43]. Paeoniflorin which is a monoterpene glycoside compound isolated from the root of
3.2 Biosynthesis of pinocembrin
In plant propolis, pinocembrin is one of the most abundant flavonoid, and it could also be commonly found in a most plants. Biological synthesis plays a significant part in synthesizing pinocembrin owing to its increased yield and low cost in production. They can extract pinocembrin from product of nature but that methodology is of high production cost and reduced yield. Biological synthesis from microorganisms features the advantages of low cost and large product yield, which compensate for the lack pinocembrin natural sources [47].
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, 58, 59, 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.
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
Other studies by [88] have also illustrated that caffeic acid can inhibit platelet-mediated 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.
3.4 Biosynthesis of berberine
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
Berberine comprises of several derivatives such as berberrubine, jatrorrhizine thalifendine, and demethyleneberberine [94].
3.4.1 Pharmacological activity
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 and antioxidant activities, in inflammatory diseases.
3.4.2 Works done on berberine
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 treatment of diarrhea associated with infections.
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. Also, the reduction of DNA methylation and that of proprotein convertase subtilisin/Kexin 9 (PCSK9) expression is also involved in the pharmacological mechanisms of berberine involved in the management of NAFLD. Several mechanisms such as the immunologic mechanism in relation to the treatment of NAFLD, drug combinations, development of berberine derivative, delivery routes, and drug dose can be considered for further research.
From Cicero and Baggioni, [104] a good deal of preclinical evidence supports the role of berberine in the management of cerebral ischemia, Alzheimer’s disease, anxiety, mental depression, and schizophrenia. However, most of these data have been obtained purely through experimental models [105]. Of particular interest is the potential antidepressant activity of berberine, it was found to inhibit the immobility time in mice in both tail suspension test and forced swim test. These two antidepressant models all gave effects in a dose-independent manner [106]. Regarding the bioactivities of berberine reported, monoamine oxidase (MAO)-A activity is noted to be inhibited. From Kong et al., [107] (MAO)-A is an enzyme needed to catalyze the deamination of catecholamines oxidatively, and thus inhibiting degradation of these neurotransmitters. Levels of norepinephrine, serotonin and dopamine, neurotransmitters are increased due to induction by MAO-A enzyme after acute and chronic administration of berberine in mice [107]. Under Kulkarni and colleague’s data, Arora and Chopra [106] revealed the protective antidepressant-like activity of berberine against the reserpine-induced biogenic amine depletion (a monoamine depletion) mostly employed in the induction of depression in animals.
However, to there is therefore no conclusive data on the evaluation of the potential antidepressant effects of berberine in higher mammals such as humans [108].
The review article by Td et al., [100] has shown that berberine has the potential of reversing neurodegenerative effects in diseases such as Alzheimer, Huntington’s disease, Parkinson’s and because of its antioxidant activity. They have also conducted antiviral activity on berberine by Warowicka et al., [94] and he observed berberine could regulate the MPK/mTOR, MEK–ERK, and NF-κB signaling routes, which are needed for viral replication. It is deduced that it provides adequate supports to the host immune response, thus leading to viral clearance. Berberine and its derivatives might promise agents to be considered in future in the fight against the recent pandemic SARS-CoV-2, which is the causative agent responsible for causing COVID-19.
3.5 Biosynthesis of aristolochic acid
Roots and rhizomes of most Aristolochia species contain mixtures of nitro phenanthrene-carboxylic acids. The key acid is the aristolochic acid I. The aristolochic acids; a group of substituted 10-nitro-1-phenanthrene acids have been known to occur in most species of the genus Aristolochia, and other members of the family Aristolochiaceae [109, 110]. Aristolochic acids emanate from aporphines through oxidative cleavage of the hetero ring. They stated that the results were consistent with the observation that the aristolochic acids rises from aporphines via oxidative cleavage of the hetero ring. Because the pathway from tyrosine to the product runs through dopa, which is an amino acid that undergoes reversible transamination in plants [111].
In all cases, aristolochic acid I and the structurally related alkaloid magnoflorine could be shown in the roots and rhizomes. The biogenetic relationship with the aporphine alkaloids was due to both the structure of aristolochic acid and its occurrence with magnoflorine. Aporphine skeleton could yield aristolochic acids through oxidative cleavage of the heterocyclic ring. Benzylisoquinoline norlaudanosoline is a key intermediate in the biosynthetic pathway, which can be formed from tyrosine or a biochemical equivalent. Aporphine skeleton is also produced from norlaudanosoline through the phenol oxidation and dienol-benzene rearrangement [110].
Aristolochiaceae family of plants produces aporphine alkaloid, 4,5- dioxoaporphine, which is referred to as possible intermediates of the precursors of aristolochic acids and aristo lactams [112].
3.5.1 Pharmacological activities of aristolochic acid
It has been reported by Okhale et al., [112] that Aristolochic acid antirheumatics, as diuretics, in the treatment of oedema, to facilitate childbirth, in wound healing and for less common conditions such as cough, hemorrhoids, and asthma. Aristolochic acids also possess antibacterial [113, 114] antifungal, antiviral, and antitumor effects and in more recently, have been used in the pharmaceutical industry as convention usage [115, 116]. Herbal preparations with active constituents being aristolochic acids have been used for different illnesses such as urinary tract infection, hepatitis, vaginitis, oedema, upper respiratory tract infection, eczema, bronchitis, headache, oral ulcer, neuralgia, dysmenorrhea, arthralgia, hypertension, cerebrovascular accident, heart failure and pneumonia [117].
3.5.2 Works done on aristolochic acid
Aristolochia species that contain aristolochic acid is Aristolochia triangularis. Oliveira et al., [118] had revealed several studies such as the antiproliferative effect, and his conclusions show its outcomes are very desirable.
Several studies have reported that aristolochic acid is the potential of causing carcinogenic effects in humans [119]. Nephrotoxic effects of the renal cortex and further damage to the liver and bladder when much of it is ingested; likely because of the formation of bulky chemical DNA adducts. AA is dA-AA formation is the most abundant and mutagenic form of DNA adduct associated with. In exons 2–11 of TP53, mutation results from bulky chemical DNA adducts, primarily of A: T base pairs [120, 121] have also conducted potential nephrotoxic effects of aristolochic acids and also proposed possible molecular mechanism of such effect. This is through induction of oxidative/nitros active stress and mitochondrial dysfunction, apoptosis induction, inflammatory responses induction, and fibrosis. A pharmacokinetic study conducted by [122] also added up that Aristolochic nephrotoxicity comprises dose-dependent and progressive tubular damage, even though significant changes in the morphology of glomeruli was not seen.
3.6 Biosynthesis of canthaxanthin
Canthaxanthin is a carotenoid, and it’s one class identified to possess a lot of colouration. Canthaxanthin is biologically synthesized from the precursor, β-carotene, ketolase enzyme (BKT in algae and CRTW in bacteria) serves as the enzyme for the reaction. The allylic 4-position to a carbonyl group is oxidized in the β-ring, producing echinenone as intermediate product. The same enzyme sequentially transforms the 40-carbon atom in the second β-ring to a carbonyl [123, 124]. This is also a substrate for the synthesis of another keto carotenoid astaxanthin which is of commercial interest. The enzyme β-carotene hydroxylase introduces hydroxyl (OH) groups into the canthaxanthin rings at positions 3,30, resulting in astaxanthin formation [125].
3.6.1 Pharmacological activities of canthaxanthin
Antioxidant and free radical scavenging properties [125]. Canthaxanthin alters the onset of many diseases such as cataracts, atherosclerosis, multiple sclerosis, age-related macular degeneration, and cancer [126].
3.6.2 Works done on canthaxanthin
Studies have shown that canthaxanthin show significantly higher free radical scavenging and antioxidant properties than other xanthophylls and carotenes, and they can also scavenge reactive oxygen species and quench singlet oxygen. Also, it has been revealed in in vivo experiments that the supplementation of canthaxanthin led to a significant decrease in lipid peroxidation to preventing induced rats liver DNA damage [126]. They have also found it in cell detoxification of lipopolysaccharides. With respect to uses of canthaxanthin in humans, less comprehensive studies have been conducted to elucidate its effects and safety. It is popularly employed as natural skin-tanning agent, and cosmetics (Figure 1).
Figure 1.
A summary of biological activities and health-promoting properties of biological metabolite.
4. Conclusion
It employs most of these bioactive products in complementary medicine, and others are under clinical study. They can source bioactive products from plants, animal and some micro-organisms. They are produced mostly via a sequence of physiological processes or synthesized exogenously. Many biosynthetic products exhibit one therapeutic effect. These several biosynthetic metabolites have many pharmacological effects, thus making them useful candidates for drug discovery.
References
- 1.
Fewer DP and Metsa-Ketela (2020). A pharmaceutical model for the molecukar evolution of microbial natural products. The FEBS Journal. Blackwell Publishing Ltd 287 (7) : 1429-1449 - 2.
Walsh, C. T., and Tang, Y. (2017) Natural Product Biosynthesis: Chemical Logic and Enzymatic Machinery , Royal Society of Chemistry, London - 3.
Yang, W., Chen, X., Li, Y., Guo, S., Wang, Z., Yu, X., 2020. Advances in Pharmacological Activities of Terpenoids - 4.
Vaz, F.D.M., Wanders, R.J.A., 2002. Carnitine biosynthesis in mammals 429, 417-429 - 5.
Tanphaichitr, V., Horne, D. W. and Broquist, H. P. (1971) Lysine, a precursor of carnitine in the rat. J. Biol. Chem. 246 , 6364-6366 - 6.
Pekala, J., Bodkowski, R., Nowakowski, P., 2011. L-Carnitine - Metabolic Functions and Meaning in Humans Life - 7.
Ramsay RR, Zammit VA. Carnitine acyltransferases and their influence on CoA pools in health and disease. Mol Aspects Med. 2004;25: 475-493 - 8.
Shenk JC, Liu J, Fischbach K, et al. The effect of acetyl-Lcarnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer’s disease. J Neurol Sci. 2009;283:199-206 - 9.
Zhang H, Jia H, Liu J, et al. Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson’s disease. J Cell Mol Med. 2010;14:215-225 - 10.
Vanella A, Russo A, Acquaviva R, et al. L -propionyl-carnitine as superoxide scavenger, antioxidant, and DNA cleavage protector. Cell Biol Toxicol. 2000; 16:99-104 - 11.
Arsenian MA. Carnitine and its derivatives in cardiovascular disease. Prog Cardiovasc Dis. 1997; 40:265-286 - 12.
Paulson DJ, Traxler J, Schmidt M, Noonan J, Shug AL. Protection of the ischaemic myocardium by L-propionylcarnitine: effects on the recovery of cardiac output after ischaemia and reperfusion, carnitine transport, and fatty acid oxidation. Cardiovasc Res. 1986;20:536-541 - 13.
Mingorance, C., Rodriguez-rodriguez, R., Justo, M.L., Herrera, M.D., 2011. Pharmacological effects and clinical applications of 69, 279-290 - 14.
Mombouli JV, Vanhoutte PM. Endothelial dysfunction: from physiology to therapy. J Mol Cell Cardiol. 1999;31:61-74 - 15.
Félétou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol. 2006;291:H985–H1002 - 16.
Victor VM, Rocha M, Solá E, Bañuls C, Garcia-Malpartida K,Hernández-Mijares A. Oxidative stress, endothelial dysfunction and atherosclerosis. Curr Pharm Des. 2009;15:2988-3002 - 17.
Herrera MD, Bueno R, De Sotomayor MA, Pérez-Guerrero C, Vázquez CM, Marhuenda E. Endothelium-dependent vasorelaxation induced by L-carnitine in isolated aorta from normotensive and hypertensive rats. J Pharm Pharmacol. 2002;54:1423-1427 - 18.
Ferrari R, Ceconi C, Cargnoni A, et al. The effect of propionylL-carnitine on the ischemic and reperfused intact myocardium and on their derived mitochondria. Cardiovasc DrugsTher. 1991;5:57-65 - 19.
Schönekess BO, Allard MF, Lopaschuk GD. Propionyl L-carnitine improvement of hypertrophied heart function is accompanied by an increase in carbohydrate oxidation. Circ Res. 1995;77:726-734 - 20.
Mister M, Noris M, Szymczuk J, et al. Propionyl-L-carnitine prevents renal function deterioration due to ischemia/reperfusion. Kidney Int. 2002;61:1064-1078 - 21.
Azzollini N, Cugini D, Cassis P, et al. Propionyl-L-carnitine prevents early graft dysfunction in allogeneic rat kidney transplantation. Kidney Int. 2008;74:1420-1428 - 22.
Surai PF (2015) Silymarin as a natural antioxidant: An overview of the current evidence and perspectives. Antioxidants . MDPI AG 4(1): 204-247 - 23.
Martinez T, Fabrias G and Camps F (1990) Sex pheromone biosynthetic pathway in Spodoptera littoralis and its activation by a neurohormone. Journal of Biological Chemistry . Elsevier 265(3): 1381-1387 - 24.
Tillman, J.A., Seybold, S.J., Jurenka, R.A., Blomquist, G.J., 1999. Insect pheromones — an overview of biosynthesis and endocrine regulation 29, 481-514 - 25.
Baxi KN, Dorries KM, Eisthen HL. Is the vomeronasal system really specialized for detecting pheromones? Trends Neurosci 2006; 29: 1-7 - 26.
Semwal, A., Kumar, R., Vir, U., Teotia, S., Singh, R., 2013. Pheromones and their role as aphrodisiacs : A review. J. Acute Dis. 2, 253-261 - 27.
Abdelhalim, M.A.K., Haseeb, A., 2016. Pharmacological Properties of Melanin and its Function in Health MiniReview Pharmacological Properties of Melanin and its Function in Health - 28.
Felix CC, Hyde JS, Sarna T, Sealy RC. Interactions of melanin with metal ions. Electron spin resonance evidence for chelate complexes of metal ions with free radicals, J. Am. Chem. Soc. 1978; 100: 3922-3926 - 29.
Shcherb VV, Babitskaya VG, Kurchenko VPN, Ikonnikova, NV, Kukulyanskaya TA. Antioxidant properties of fungal melanin pigments. Appled biochemistry and microbiology. 2000; 36: 491-495 - 30.
Wu Y, Shan L, Yang S, Ma A. Identification and antioxidant activity of melanin isolated from Hypoxylon archeri, a companion fungus of Tremella fuciformi . Journal of Basic microbiology. 2008; 48: 217-221 - 31.
Pugh ND, Balachandran P, Lata H, Dayan FE, Joshi V, Bedir E, Makino T, Moraes R, Khan I, Pasco DS. Melanin: dietary mucosal immune modulator from Echinacea and Other botanical supplements. Int Immunopharmacol. 2005; 5:637-647 - 32.
Pugh ND, Tamta H, Balachandran P, Wu X, Howell J, Dayan FE, Pasco DS. The majority of in vitro macrophage activation exhibited by extracts of some immune enhancing botanicals is due to bacterial lipoproteins and lipopolysaccharides. Int Immunopharmacol. 2008; 8:1023-1032 - 33.
Sava V, Galkin B, Hong MY, Yang PC, Huang GS. A novel melanin-like pigment derived from black tea leaves with immuno-stimulating activity. Food Research International 2001, b.; 34:337-343 - 34.
ElObeid AS, Kamal-Eldin A, Abdelhalim MAK and Haseeb AM (2017) Pharmacological Properties of Melanin and its Function in Health. Basic & Clinical Pharmacology & Toxicology . Blackwell Publishing Ltd 120(6): 515-522 - 35.
Sava VM, Hung YC, Blagodarsky VA, Hong MY, Huang GS. The liver-protecting activity of melanin-like pigment derived from black tea. Food Research International. 2003; 36:505-511 - 36.
Kamei H, Koide T, Kojima T, Hasegawa M, Umeda T. Suppression of growth of cultured malignant cells by allomelanins, plant-produced melanins. Cancer Biother Radiopharm. 1997. a.; 12: 47-49 - 37.
Hong Y, Song B, Chen H-D and Gao X-H (2015) Melanocytes and Skin Immunity. The Journal of Investigative Dermatology Symposium 17: 37-39 - 38.
El-Obeid A, Al-Harbi S, Al-Jomah N and Hassib A (2006) Herbal melanin modulates tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) production. Phytomedicine . Phytomedicine 13(5): 324-333 - 39.
Thomas J, Shentu TP and K. D (2012) Cholesterol: Biosynthesis, Functional Diversity, Homeostasis and Regulation by Natural Products. Biochemistry . InTech. Available at:www.intechopen.com (accessed 29/03/21) - 40.
Ling WH and Jones PJH (1995) Dietary phytosterols: A review of metabolism, benefits and side effects. Life Sciences . Life Sci, 195-206 - 41.
Hanson, J. R. (1972). Biosynthesis of Terpenoids Compounds. The Chemical Society, 1, 41-43 - 42.
Chen TC, Fonseca COD, Schönthal AH. Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy. Am J Cancer Res. 2015;5(5):1580-1593 - 43.
Bi X, Han L, Qu T, et al. Anti-Inflammatory effects, SAR, and action mechanism of monoterpenoids from Radix Paeoniae alba on LPS-stimulated RAW 264.7 cells. Molecules. 2017;22(5):715. doi:10.3390/molecules22050715 - 44.
Raut JS, Shinde RB, Chauhan NM, Karuppayil SM. Terpenoids of plant origin inhibit morphogenesis, adhesion, and biofilm formation by Candida albicans. Biofouling. 2013;29(1):87-96. doi: 201310.1080/08927014.2012.749398 - 45.
Gao S, Liu Z, Li H, Little PJ, Liu P, Xu S. Cardiovascular actions and therapeutic potential of tanshinone IIA. Atherosclerosis. 2012;220(1):3-10. doi:10.1016/j.atherosclerosis.2011.06.041) - 46.
Shen, X., Liu, Y., Luo, X., & Yang, Z. (2019). Advances in Biosynthesis, Pharmacology, and Pharmacokinetics of Pinocembrin, a Promising Natural Small-Molecule Drug. MDPI, 1-14 - 47.
Wu, C.X.; Du, G.H. Effects of pinocembrin on inflammation in rats with focal cerebral ischemia reperfusion injury. J. Shandong Med. College 2015, 37, 247-250 - 48.
Said, M.M.; Azab, S.S.; Saeed, N.M.; El-Demerdash, E. Antifibrotic Mechanism of Pinocembrin: Impacton Oxidative Stress, Inflammation and TGF-β/Smad Inhibition in Rats. Ann. Hepatol. 2018, 17, 307-317 - 49.
Celerino de Moraes Porto, I.C.; Chaves Cardoso de Almeida, D.; Vasconcelos Calheiros de Oliveira Costa, G.; Sampaio Donato, T.S.; Moreira Nunes, L.; Gomes do Nascimento, T.; Dos Santos Oliveira, J.M.; Batista da Silva, C.; Barbosa Dos Santos, N.; de Alencar E Silva Leite, M.L.; et al. Mechanical and aesthetics compatibility of Brazilian red propolis micellar nanocomposite as a cavity cleaning agent. BMC Complement. Altern. Med. 2018, 18, 219 - 50.
Liu, R.; Gao, M.; Yang, Z.H.; Du, G.H. Pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia-reperfusion both in vivo and in vitro. Brain Res. 2008, 1216, 104-115 - 51.
Rasul A, Millimouno FM, Ali Eltayb W, Ali M, Li J and Li X (2013) Pinocembrin: A novel natural compound with versatile pharmacological and biological activities. BioMed Research International . Hindawi Limited 2013. Available at: /pmc/articles/PMC3747598/ (accessed 29/03/21) - 52.
Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J.P.E.; Tognolini, M.; Borges, G.; Crozier, A. Dietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid. Redox Signal. 2013, 18, 1818-1892 - 53.
Gao, M.; Zhang, W.C.; Liu, Q.S.; Hu, J.J.; Liu, G.T.; Du, G.H. Pinocembrin prevents glutamate-induced apoptosis in SH-SY5Y neuronal cells via decrease of bax/bcl-2 ratio. Eur. J. Pharmacol. 2008, 91, 73-79 - 54.
Meng F, Liu R, Gao M, Wang Y, Yu X, Xuan Z, Sun J, Yang F, Wu C and Du G (2011) Pinocembrin attenuates blood-brain barrier injury induced by global cerebral ischemia-reperfusion in rats. Brain Research . Elsevier 1391: 93-101 - 55.
Mena P, Ascacio-Valdés JA, Gironés-Vilaplana A, Del Rio D, Moreno DA and García-Viguera C (2014) Assessment of pomegranate wine lees as a valuable source for the recovery of (poly)phenolic compounds. Food Chemistry . Food Chem 145: 327-334 - 56.
Kallscheuer N.; Vogt, M.; Marienhagen, J. A novel synthetic pathway enables microbial production of polyphenols independent from the endogenous aromatic amino acid metabolism. ACS Synth. Biol. 2017, 6, 410-415 - 57.
Chen, Z.J.; Wu, J.Q.; Ma, Y.; Wang, P.; Gu, Z.X.; Yang, R.Q. Advances in biosynthesis, regulation and bioactivity of phenolic acids in plant food raw materials. Food Sci. 2018, 39, 321-328 - 58.
Schenck, C.A.; Maeda, H.A. Tyrosine biosynthesis, metabolism, and catabolism in plants. Phytochemistry 2018, 149, 82-102 - 59.
Zhou, W.; Huang, Q.; Wu, X.; Zhou, Z.; Ding, M.; Shi, M.; Huang, F.; Li, S.; Wang, Y.; Kai, G. Comprehensive transcriptome profiling of Salvia miltiorrhiza for discovery of genes associated with the biosynthesis of tanshinones and phenolic acids. Sci. Rep. 2017, 7, 10554 - 60.
Liu, F. Effect of PAP2 transcription factor on synthesis of salvianolic acids. Master’s Thesis, Shaanxi Normal University, Xi’an, China, 2011 - 61.
Neta, M.; Moran, O.; Rinat, O.; Noga, S.P.; Biruk, A.; Aaron, F.; Gad, G.; Avichai, P.; David, W.; Michal, O.S. Phenylalanine and tyrosine levels are rate-limiting factors in production of health promoting metabolites in Vitis vinifera cv. Gamay Red cell suspension. Front. Plant Sci. 2015, 6, 538 - 62.
Huang, Q.; Sun, M.; Yuan, T.; Wang, Y.; Shi, M.; Lu, S.; Tang, B.; Pan, J.; Wang, Y.; Kai, G. The AP2/ERF transcription factor SmERF1L1 regulates the biosynthesis of tanshinones and phenolic acids in Salvia miltiorrhiza. Food Chem. 2019, 274, 368-375 - 63.
Ma, P.; Liu, J.; Zhang, C.; Liang, Z. Regulation of Water-Soluble Phenolic Acid Biosynthesis in Salvia miltiorrhiza Bunge. Appl. Biochem. Biotechnol. 2013, 170, 1253-1262 - 64.
Jiang, R.W.; Lau, K.M.; Hon, P.M.; Mak, T.; Woo, K.S.; Fung, K.P. Chemistry and biological activities of caffeic acid derivatives from Salvia miltiorrhiza. Curr. Med. Chem. 2005, 12, 237-246 - 65.
Zhao, S.J.; Zhang, G.Y.; Liu, D.; Hu, Z.B. Advances in pharmacology and biosynthesis of water-soluble phenolic acids from Salvia miltiorrhiza. Chin. Tradit. Drug 2004, 3, 107-110 - 66.
Razzaghi-Asl, N.; Garrido, J.; Khazraei, H.; Borges, F.; Firuzi, O. Antioxidant properties of hydroxycinnamicacids: A review of structure- activity relationships. Curr. Med. Chem. 2013, 20, 4436-4450 - 67.
Zeng, F.; Chen, Y.B.; Xia, C.N.; Zhong, G.X. Advances in the synthesis and bioactivity of caffeic acid derivatives. Zhejiang Chem. Ind. 2012, 43, 24-28 - 68.
Ma, X.H.; Ma, Y.; Tang, J.F.; He, Y.L.; Liu, Y.C.; Ma, X.J.; Shen, Y.; Cui, G.H.; Lin, H.X.; Rong, Q.X.;et al. The Biosynthetic Pathways of Tanshinones and Phenolic Acids in Salvia miltiorrhiza. Molecules 2015, 20, 16235-16254 - 69.
Rong, Q.X.; et al. The Biosynthetic Pathways of Tanshinones and Phenolic Acids in Salvia miltiorrhiza. Molecules 2015, 20, 16235-16254 - 70.
Xu, Z.; Luo, H.; Ji, A.; Zhang, X.; Song, J.; Chen, S. Global Identification of the Full-Length Transcripts and Alternative Splicing Related to Phenolic Acid Biosynthetic Genes in Salvia miltiorrhiza. Front. Plant Sci. 2016, 7, 100 - 71.
Sundaram, S.; Tripathi, A.; Gupta, D.K. Metabolic modeling of Rosmarinic acid biosynthetic pathway. Bioinformation 2010, 5, 168-172 - 72.
Di, P.; Zhang, L.; Chen, J.; Tan, H.; Xiao, Y.; Dong, X.; Zhou, X.; Chen, W. 13C tracer reveals phenolic acidsbiosynthesis in hairy root cultures of Salvia miltiorrhiza. ACS Chem. Biol. 2013, 8, 1537-1548 - 73.
Pandey, R.P.; Parajuli, P.; Koffas, M.A.G.; Sohng, J.K. Microbial production of natural and non-natural flavonoids: Pathway engineering, directed evolution and systems/synthetic biology. Biotechnol. Adv. 2016, 34, 634-662 - 74.
Mattera, R.; Benvenuto, M.; Giganti, M.G.; Tresoldi, I.; Pluchinotta, F.R.; Bergante, S.; Tettamanti, G.;Masuelli, L.; Manzari, V.; Modesti, A.; et al. Effects of Polyphenols on Oxidative Stress-Mediated Injury in Cardiomyocytes. Nutrients 2017, 9, 523 - 75.
Eghbaliferiz, S.; Iranshahi, M. Prooxidant activity of polyphenols, flavonoids, anthocyanins and carotenoids: Updated review of mechanisms and catalyzing metals. Phytother. Res. 2016, 30, 1379-1391 - 76.
Hussain, T.; Tan, B.; Yin, Y.; Blachier, F.; Tossou, M.C.; Rahu, N. Oxidative stress and inflammation: What polyphenols can do for us? Oxid. Med. Cell. Longev. 2016, 2016, 7432797 - 77.
Brglez Mojzer, E.; Knez Hrnˇciˇc, M.; Škerget, M.; Knez, Ž.; Bren, U. Polyphenols: Extraction methods, antioxidative action, bioavailability and anticarcinogenic effects. Molecules 2016, 21, 901 - 78.
Wang, J., Xu, J., Gong, X., Yang, M., Zhang, C., & Li, M. (2019). Biosynthesis, Chemistry, and Pharmacology of Polyphenols from Chinese Salvia Species: A Review. 1-23 - 79.
C.C.; Chang, Y.C.; Hu, W.L.; Hung, Y.C. Oxidative stress and Salvia miltiorrhiza in aging-associated cardiovascular diseases. Oxidative Med. Cell. Longev. 2016, 2016, 4797102 - 80.
Adomakobonsu, A.G.; Chan, S.L.; Pratten, M.; Fry, J.R. Antioxidant activity of rosmarinic acid and its principal metabolites in chemical and cellular systems: Importance of physico-chemical characteristics. Toxicol. In Vitro 2017, 40, 248-255 - 81.
Zhao, G.R.; Zhang, H.M.; Ye, T.X.; Xiang, Z.J.; Yuan, Y.J.; Guo, Z.X.; Zhao, L.B. Characterization of the radical scavenging and antioxidant activities of danshensu and salvianolic acid B. Food Chem. Toxicol. 2008, 46, 73-81 - 82.
Zhang, X.X.; Zhang, S.; Huang, X.Y.; Li, G.; Wang, Z.H.; Ma, C.Y. Anti-lipoperoxidation of Several Organic Polyphenol Acids in vitro. Coll. Life Sci. 2014, 26, 398-402 - 83.
Xue, L.; Wu, Z.; Ji, X.P.; Gao, X.Q.; Guo, Y.H. Effect and mechanism of salvianolic acid B on the myocardial ischemia-reperfusion injury in rats. Asian Pac. J. Trop. Med. 2014, 7, 280-284 - 84.
Zhang, W.; Song, J.K.; Zhang, X.; Zhou, Q.M.; He, G.R.; Xu, X.N.; Rong, Y.; Zhou, W.X.; Du, G.H. Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation. Chin. J. Nat. Med. 2018, 16, 184-193 - 85.
Meng, Y. Danshen (Salvia miltiorrhiza) Prevents Myocardial Ischemia Reperfusion Injury by Regulate Nox2/ROS/JNK2/NF-κB pathway and Recude TRPC6/Ca2+ influx under High Glucose Condition. Anhui Med. Univ. 2016, 206 - 86.
Liu, X.; Gao, Z.G.; Wu, Y.; Stevens, R.C.; Jacobson, K.A.; Zhao, S. Salvianolic acids from antithrombotic Traditional Chinese Medicine Danshen are antagonists of human P2Y 1 and P2Y 12 receptors. Sci. Rep. 2018, 8, 11380 - 87.
Lu, Y.; Li, Q.; Liu, Y.Y.; Sun, K.; Fan, J.Y.; Wang, C.S.; Han, J.Y. Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases. Sci. Rep. 2015, 5, 13824 - 88.
Yu, C.; Qi, D.; Lian, W.; Li, Q.Z.; Li, H.J.; Fan, H.Y. Effects of Danshensu on Platelet Aggregation and Thrombosis: In Vivo Arteriovenous Shunt and Venous Thrombosis Models in Rats. PLoS ONE 2014, 9, e110124 - 89.
Huang M, Wang P, Xu S, Xu W, Xu W, Chu K and Lu J (2015) Biological activities of salvianolic acid B from Salvia miltiorrhiza on type 2 diabetes induced by high-fat diet and streptozotocin.Pharmaceutical Biology . Informa Healthcare 53(7): 1058-1065 - 90.
Xu, X.; Hu, Y.; Zhai, X.; Liu, M.; Chen, Z.; Tian, X.F.; Zhang, F.; Gao, D.Y.; Ma, X.C.; Lv, L.; Yao, J.H. Salvianolic acid A preconditioning confers protection against concanavalin A-induced liver injury through SIRT1-mediated repression of p66shc in mice. Toxicol. Appl. Pharmacol. 2013, 273, 68-76 - 91.
Wang, Z.S.; Luo, P.; Dai, S.H.; Liu, Z.B.; Zheng, X.R.; & Chen, T. Salvianolic acid B induces apoptosis in human glioma U87 cells through p38-mediated ROS generation. Cell. Mol. Neurobiol. 2013 - 92.
Rasouli, H., Farzaei, M. H., & Khodarahmi, R. (2017). Polyphenols and their benefits : A review Polyphenols and their benefits : A review. International Journal of Food Properties, 00(00), 1-42 - 93.
Warowicka, A., Nawrot, R., & Goździcka, A. (2020). Antiviral activity of berberine. Archives of Virology, 165(9), 1935-1945. https://doi.org/10.1007/s00705-020-04706-3 - 94.
Khosrokhavar R, Ahmadiani AS (2010) Antihistaminic and anticholinergic activity of methanolic extract of barberry fruit (Berberis vulgaris) in the Guinea-Pig Ileum. J Med Plants 13:99-105 - 95.
Akhter MH, Sabir M, Bhide NK (1979) Possible mechanism of antidiarrheal effect of berberine. Indian J Med Res 13:233-241 - 96.
Rabbani GHBT, Knight J, Sanyal SC, Alam K (1987) Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholera. J Infect Dis 13:979-984 - 97.
Amin AH, Subbaiah TV, Abbasi KM (1969) Berberine sulfate: antimidrobial activity, bioassay, and mode of action. Can J Microbiol 13:1067-1076 - 98.
Sabir M (1971) Study of some pharmacological actions of berberine. Indian J Physiol Pharmacol 13:111-132 - 99.
Ahmed T, Gilani AUH, Abdollahi M, Daglia M, Nabavi SF and Nabavi SM (2015) Berberine and neurodegeneration: A review of literature. Pharmacological Reports . Elsevier B.V., 970-979 - 100.
Pang B, Zhao LH, Zhou Q, Zhao TY, Wang H, Gu CJ and Tong XL (2015) Application of berberine on treating type 2 diabetes mellitus. International Journal of Endocrinology . Hindawi Publishing Corporation. Available at:https://pubmed.ncbi.nlm.nih.gov/25861268/ (accessed 30/03/21) - 101.
Zhao, L., Cang, Z., Sun, H., Nie, X., Wang, N., & Lu, Y. (2017). Berberine improves glucogenesis and lipid metabolism in nonalcoholic fatty liver disease. 1-8. https://doi.org/10.1186/s12902-017-0165-7 - 102.
Zhu, X., Bian, H., & Gao, X. (2016). The Potential Mechanisms of Berberine in the. 1-12 - 103.
Cicero, A. F. G., & Baggioni, A. (2016). Berberine and Its Role in Chronic Disease. 27-45 - 104.
Kulkarni SK, Dhir A (2010) Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 24(3):317-324 - 105.
Kulkarni SK, Dhir A (2008) On the mechanism of antidepressant-like action of berberine chloride. Eur J Pharmacol 589:163-172 - 106.
Kong LD, Cheng CH, Tan RX (2001) Monoamine oxidase inhibitors from rhizoma of Coptis chinensis. Planta Med 67:74-76 - 107.
Kumar A, Ekavali Chopra K et al (2015) Current knowledge and pharmacological profile of berberine: an update. Eur J Pharmacol 761:288-297 - 108.
Comer, F., Tiwari, H. P., & Spenser, I. D. (1969). Biosynthesis of aristolochic acid1. Canadian Journal of Chemistry, 47(1), 481-487 - 109.
Schutte, H. R., Orban, U., & Mothes, K. (1967). Biosynthesis of Aristolochic Acid. 1, 70-72 - 110.
Spenser, I. D. (2015). Biosynthesis of aristolochic acid. February 2011. https://doi.org/10.1139/v69-070 - 111.
Okhale, S., Egharevba, H., Ugbabe, G., & Igoli, J. O. (2019). Aristolochic acids in herbal medicine : Public health concerns for consumption and poor regulation of botanical products in Nigeria and West Africa. February. https://doi.org/10.5897/JMPR2018.6691 - 112.
American herbal product Association (AHPA) (2017). Botanical Identity References Compendium Aristolochic acid. Avialable at http://www.ahpa.org/Resources/TechnicalGuidance/ScientificAffairs/BotanicalAuthenticationProgram/AHPABotanicalIdentityReferencesCompendium.aspx - 113.
Refik Gökmen M, Cosyns JP, Arlt VM, Stiborová M, Phillips DH, Schmeiser HH, Simmonds MSJ, Cook HT, Vanherweghem JL, Nortier JL and Lord GM (2013) The epidemiology, diagnosis, and management of aristolochic acid nephropathy: A narrative review. Annals of Internal Medicine , 469-477 - 114.
Kupchan SM, Doskotch RW (1962). Tumor inhibitors I. Aristolochic acid, the active principle of Aristolochia indica. Journal of Medicinal Chemistry 5(3):657-659 - 115.
Zhang H, Cifone MA, Murli H, Erexson GL, Mecchi MS, Lawlor TE (2004). Application of simplified in vitro screening tests to detect genotoxicity of aristolochic acid. Food and chemical Toxicology 42(12):2021-2028 - 116.
Li W, Chen Z, Liao Y, Liu H (2005a). Separation methods for toxic components in Traditional Chinese Medicines. Analytical Sciences 21(9):1019-1029 - 117.
De Oliveira, M.R.; Peres, A.; Gama, C.S.; Bosco, S.M.D. Pinocembrin Provides Mitochondrial Protection by the Activation of the Erk1/2-Nrf2 Signaling Pathway in SH-SY5Y Neuroblastoma Cells Exposed to Paraquat. Mol. Neurobiol. 2017, 54, 6018-6031 - 118.
Debelle, F. D., Vanherweghem, J. L., & Nortier, J. L. (2008). Aristolochic acid nephropathy: A worldwide problem. Kidney International, 74(2), 158-169 - 119.
Barnes, J. L., Zubair, M., John, K., Poirier, M. C., & Martin, F. L. (2018). Carcinogens and DNA damage. 0, 1213-1224 - 120.
Anger EE, Yu F and Li J (2020) Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches. International Journal of Molecular Sciences . MDPI AG 21(3): 1157 - 121.
Chen, S., Fan, M., Tseng, C., Ho, Y., & Ã, K. H. (2007). Pharmacokinetics and nephrotoxicity of aristolochic acid in rabbits. 50, 180-188 - 122.
Wu, G. G. G., Yuan, M., Shen, S., Ma, X. X. X., Fang, J., Zhu, L. L., Sun, L., Liu, Z. Z. Z. Z., He, X. X., Huang, D., Li, T. T., Li, C. C. C., Wu, J. C. J. J., Hu, X., Li, Z., Song, L. L., Qu, K., Zhang, H. H. H. H. H. H. P., Gao, P., … McCall, C. E. (2014). Supporting Information. In Nature. https://doi.org/10.1016/j.cmet.2014.08.003 - 123.
Karadas F, Erdoğan S, Kor D, Oto G and Uluman M (2016) The effects of different types of antioxidants (Se, vitamin E and carotenoids) in broiler diets on the growth performance, skin pigmentation and liver and plasma antioxidant concentrations. Revista Brasileira de Ciencia Avicola 18(1): 101-115 - 124.
Manimala MRA and Murugesan R (2014) In vitro antioxidant and antimicrobial activity of carotenoid pigment extracted from Sporobolomyces sp. isolated from natural source. Journal of Applied and Natural Science 6(2): 649-653 - 125.
Palozza P and Krinsky NI (1992) Astaxanthin and canthaxanthin are potent antioxidants in a membrane model. Archives of Biochemistry and Biophysics . Arch Biochem Biophys 297(2): 291-295 - 126.
Rosa AP, Scher A, Sorbara JOB, Boemo LS, Forgiarini J and Londero A (2012) Effects of canthaxanthin on the productive and reproductive performance of broiler breeders. Poultry Science . Elsevier 91(3): 660-666