*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].

**19**

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

*3.5.2 Works done on aristolochic acid*

and his conclusions show its outcomes are very desirable.

changes in the morphology of glomeruli was not seen.

*3.6.1 Pharmacological activities of canthaxanthin*

age-related macular degeneration, and cancer [126].

**3.6 Biosynthesis of canthaxanthin**

of aristolochic acids and aristo lactams [112].

*3.5.1 Pharmacological activities of aristolochic acid*

Aristolochiaceae family of plants produces aporphine alkaloid, 4,5 dioxoaporphine, which is referred to as possible intermediates of the precursors

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].

Aristolochia species that contain aristolochic acid is Aristolochia triangularis. Oliveira et al., [118] had revealed several studies such as the antiproliferative effect,

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

Canthaxanthin is a carotenoid, and it's one class identified to possess a lot of colou-

Antioxidant and free radical scavenging properties [125]. Canthaxanthin alters the onset of many diseases such as cataracts, atherosclerosis, multiple sclerosis,

ration. 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].

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

*Bioactive Compounds - Biosynthesis, Characterization and Applications*

can be considered for further research.

**3.5 Biosynthesis of aristolochic acid**

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

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.

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].

**18**

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].
