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\begin{document}

\title{Glycoside flavonoids of genus Morus: Phytochemistry, Biosynthesis and
Pharmacological activities}



\author[1]{Maryam Fatima}%
\author[2]{Mohd Nadeem Bukhari}%
\author[3]{Jehangir Shah Syed Bukhari}%
\author[1]{Mudasir A. Dar}%
\author[4]{Zhen Ouyang}%
\affil[1]{Jiangsu University}%
\affil[2]{BRIN}%
\affil[3]{Hunan University}%
\affil[4]{Jiangsu University School of Pharmacy}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Traditional natural products have been the focus of research to explore
their medicinal properties. One such medicinally important plant is
Morus alba, which is growing very quickly, especially in Asia, and has
tremendous pharmacological activities due to the presence of
phytochemicals in various parts of this plant. In this review, we
provide a comprehensive summary of the phytochemistry, biosynthetic
pathways, and pharmacological activities of glycoside flavonoids in the
leaves of Morus alba has been studied. In the past centuries, mulberry
has been considered a food source for silkworms, and its leaves are used
to feed animals for livestock. However, in recent years, mulberry has
attained a special place in research because of its phytochemical
composition and benefits to human health, including antioxidant,
anticancer, antidiabetic, and immunomodulatory effects. Phytochemicals
are bioactive compounds present in plants that work with nutrients and
dietary fiber to protect against diseases. Morus alba also contains many
phytochemicals, such as flavonoids, phenols, and anthocyanins. The
biosynthetic pathway is greener and more efficient for producing
structurally diverse natural products. This pathway acts as an
alternative to chemical synthesis and microbial transformation, which
suffer from complex routes, difficult isomer separation, and high cost.
The mechanism of the flavonoid biosynthesis pathway in mulberry leaves
is not yet clear, and currently, this is a much-needed topic for
scientists to explore.%
\end{abstract}%



\sloppy


\textbf{Introduction}

The presence of natural products in animals, plants, and minerals plays
a vital role in the field of medicinal chemistry; therefore, researchers
from antiquity are working on the extraction, isolation, identification,
biological activities, and many properties of these natural organic
products. Conventional medicines depend on phytochemical-rich plant
extracts to cure many diseases because medicines obtained from natural
sources are less toxic and have fewer side effects than synthetic
medicines {[}1{]}. For the remedy of many health issues, to remove pain
and discomfort, such as fragrance and flavor in food, everyone depends
on the plant kingdom for their needs, and medicinal plants play a vital
role in developing countries. Medicinal plants are the best source for
the discovery of new compounds that lead to new drugs {[}2{]}. Medicinal
plants of the Moraceae family are known for their versatile applications
in many fields such as agriculture, cosmetics, food, and
pharmaceuticals. One example of the family Moraceae is Morus alba
(mulberry), which is the most commonly used medicinal plant in Asia,
especially in China. Mulberry is highly produced in China and grows
throughout many regions such as Asia, Africa, America, Europe, and
India. The leaves of mulberry are only known for sericulture. But the
leaves are not used in sericulture but can be used as medicines as well
{[}3{]}. Mulberry is a rich source of many bioactive compounds such as
flavonoids, amino acids, vitamins, polysaccharides, and steroids, which
are used for the treatment of many infections and internal diseases.
Among these components, flavonoids have attracted more attention in
recent studies because of their anti-inflammatory, anti-aging, and
anti-hyperglycemic activities. {[}4,5{]}. Flavonoids belong to the
polyphenolic family and incorporate at least 6000 molecules, primarily
divided into phlobaphenes, aurones, isoflavonoids, flavones, flavonols,
and anthocyanins {[}6{]}. Flavonoid compounds commonly found in mulberry
are kuwanon (flavons), sangenon (flavanols), rutin (flavons), quercetin
(flavonols), and catechins (flavanols).

Plants have an amazing tendency to identify changes in the environment,
and then the rapid response to increases the opportunity and lowers the
risk. The basic need to respond to these changes is the integration of
growth, development, and metabolism, which leads to the evolution of
many other mechanisms to regulate cellular functions. One of the
mechanisms is glycosylation, which involves a large multigene family of
glycosyltransferases (GTs). Glycosyltransferases can identify lipophilic
small molecules, including hormones and secondary metabolites, as well
as biotic and abiotic toxins in the environment {[}7,8{]}. Glycosylation
of flavonoids increases their solubility and stability in plants.
Flavonoids exist mainly in their glycosylated forms in plants. The final
step in the biosynthesis of these glycosides is glycosylation, which
plays a variety of roles in plant metabolism. Glycosyltransferases
(GTFs) establish natural glycosidic linkages. They catalyze the transfer
of saccharide moieties from an activated nucleotide sugar (also known as
a glycosyl donor) to a nucleophilic glycosyl acceptor molecule, the
nucleophile of which can be oxygen-, carbon-, nitrogen-, or
sulfur-based. GTFs play an important role in glycosylation, and it is
important to understand the chemistry of these enzymes in mulberry
leaves.

\textbf{1. Phytochemistry of Mulberry leaves}

\textbf{1.1 Nutritional values Mulberry leaves}

The main components of mulberry leaves with pharmacological properties
are phenols, polysaccharides, steroids, amino acids, lignins, and
volatile components. The leaves of mulberry are also a good source of
ascorbic acid. It contains carotene, vitamin B1, folic acid, folinic
acid, and vitamin D. The nutritional composition of mulberry leaves in
dry condition is 15.31-30.91\% protein, 2.09-7.92\% fat, 9.9-13.85\%
crude fiber, 27.60-43.6\% neutral dietary fiber (NDF) and 11.3-17.24\%
ash {[}9{]}. Evidence suggests that mulberry leaves also contain some
additional therapeutic agents such as Moran 20k and 1-deoxynojirimycin
(DNJ) as antidiabetic agents, and isoprene-substituted flavanones such
as Kuwanon C and kuwanon as antimicrobial agents {[}10,11{]}. The
nutritional values are shown in Figure 1.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Fig.1.} Nutrition's present in Mulberry leaves

Following are the most common bioactive components isolated or extracted
from the mulberry leaves:

\textbf{1.2 Flavonoids}

The \emph{Morus} plants are known to be abundant in flavonoids and are
shown in figure 2. The flavonoids in the mulberry leaves are mainly in
the forms of quercitin and kaempferol {[}12{]}. Kuwanons,
moracinflavans, moragols andmorkkotins are some of the main flavonoids
found in mulberry leaves. The total contents of isoquercetin, rutin,
kaempferol and astragalin are ranging from 4.34 mg/g to 0.53 mg/g
{[}13{]}.The major antioxidant flavonoids are flavonol, glycosides,
rutin, quercitin-3-(6-malonylglucoside) and isoquercitin have been
extracted from the leaves of mulberry {[}4{]}. The flavonoids possess
many medicinal properties like anti-inflammatory, antioxidant,
antiallergic, antithrombotic, hepatoprotective, antiviral and
carcinogenic in human being.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Flavonol glycosides & mg/100g (Dried weight)\tabularnewline
\midrule
\endhead
Quercetin-3-(6-malonylglucoside) & 754-1046\tabularnewline
Rutin & 487-659\tabularnewline
Isoquercitrin & 168-220\tabularnewline
Astragalin & 26-36\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1:} Flavonol glycosides in mulberry leaves\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Fig. 2} . The structure of flavonoids present in mulberry
leaves.

\textbf{1.3 Alkaloids}

The alkaloids present in large concentration in mulberry leaves are
aurantiamide acetate, 1-deoxynojirimycin (1-DNJ) which is most potent
glycosidase inhibitor that decrease the blood sugar level, D-fagomine
(FAG), 2-O- \selectlanguage{greek}α\selectlanguage{english}Dgalactopyranosyl-deoxynojirimycin (GAL-DNJ),
4-O-\selectlanguage{greek}β-\selectlanguage{english}D-dlucopyranosyl-fagomine (Glu-FAG), isofagomine,
cis-5-hydroxypipecolic acid, trans-5-hydroxypipecolic acid,
methylpyrrolidine carboxylic acid and pipecolic acid.The main active
constituent in Mulberry leaves is 1-Deoxynojirimycin (DNJ) and has
attracted attention of many researchers because of its effective and
specific inhibition of different enzymes involved in wide range of
important biological processes such as maturation of the sugar chains in
glycoproteins, intestinal digestion {[}14{]}. The DNJ acts as an
antithyperglycemic agent which slow down the rate of carbohydrate
degradation to monosaccharides and it can also interrupt glucose
absorption and then reduce post prandial blood glucose levels {[}15{]}.
The structure of DNJ is same as the sugars is shown in figure 3.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Fig. 3} .The chemical structure of alkaloid

\textbf{1.4 Anthocyanins}

A natural phenolic compound anthocyanins are responsible for the colors
of fruits, flowers and leaves. Anthocyanins are the best source for the
health benefits as it act as antioxidant, anti-inflammatory etc.
Anthocyanins has very high inhibitory ability on lipid oxidation and has
antimetastatis activity to inhibit migration of B16-F1 cells
{[}16,17{]}.

\textbf{1.5 Polysaccharides}

Polysaccharides are the main active bioactive components of mulberry
leaves. Polysaccharides are long-chain macromolecular polymers that are
generally used as thickeners and gelling agents in the food industry
because of their ability to retain water and form hydrogels. These
mulberry leaf polysaccharides have received increasing attention because
of their multiple biological activities. These polysaccharides promote
insulin expression and regulate liver glucose metabolism {[}18{]}. In
mulberry leaves, polysaccharides are mainly present in the inner
epidermal cells {[}19{]}. Glucose, galactose, arabinose, fructose,
xylose, rhamnose, glucuronic acid, galacturonic acid, mannose, and
sorbose are monosaccharides that combine with each other and form many
types of polysaccharides in mulberry leaves {[}20{]}.

\textbf{1.6 Amino acids}

Amino acids are the building blocks for the synthesis of proteins which
includes antioxidant enzymes. Some of the amino acids can directly
scavenge oxygen free radicals. Out of 20 essential amino acids present
in mulberry leaves, four amino acids, Asparagine, Alanine, Proline and
GABA were observed and their structures are shown in figure 4. Mulberry
leaves contains high amino acid contents which are nutritively superior
and also promote growth and development of silkworm {[}21,22{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Fig.4.} Chemical structure of amino acid present in mulberry
leaves

\textbf{2. Biosynthesis}

The biosynthetic pathway is greener and more efficient for producing
structurally diverse natural products. This pathway acts as an
alternative to chemical synthesis and microbial transformation, which
suffer from complex routes, difficult isomer separation, and high cost.
Biosynthesis, also known as anabolism, is a simple compound that is
joined together and forms a macromolecule using enzymes. Extreme
reaction conditions and many toxic chemicals are required for the
chemical synthesis of flavonoids {[}23{]}. One of the advantages of
biosynthesis is the production of rare and expensive natural products
because of the development of molecular biological tools and
availability of genome information from a variety of organisms.
Biosynthesis can be used in simple and complex transformations without
disturbing the blocking and deblocking steps, which are common in
organic synthesis {[}24{]}. The mechanism of the flavonoid biosynthesis
pathway in mulberry leaves is not yet clear, and currently, this is a
much-needed topic for scientists to explore. Flavonoids are synthesized
through the shikimate pathway followed by the phenylpropanoid metabolic
pathway and possess approximately 15 carbon atoms arranged in three
aromatic rings linked as C6-C3-C6 {[}25{]}. Several enzymes are involved
in the shikimate pathway, which is a six-step reaction in the
biosynthesis of shikimic acid. The reaction as shown in figure 5 begins
with a simple aldol condensation reaction of phosphoenolpyruvic acid and
D-erythrose 4-phosphate {[}Dias MC, Pinto DCGA, Silva AMS. (2021) Plant
flavnoids: Chemical Characteristics and Biological Activity. Molecules,
26:5377.{]}. The end product of chorismic acid is converted into the
amino acid phenylalanine by the action of prephenate-aminotransferase
(PhAT) and aromate-dehydrate (ADT) enzymes {[}Tariq H, Asif S, Andleeb
A, Hano C, Abbasi BH. (2023) Flavonoid Production: Current trends in
plant metabolic engineering and de novo microbial production.
Metabolites, 13:124.{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Fig. 5.} Shikimate pathway

The biosynthesis of flavonoids starts with the condensation of one
p-coumaroyl-CoA molecule (shikimate-derived, B ring) with three
molecules of malonyl-CoA (polyketid origin, A ring) to give chalcone
(2'4'6'4-tetrahydroxychalcone) catalyzed by chalcone synthase (CHS)
enzymes. Chalcones are subsequently isomerized to flavanone by chalcone
flavanone isomerase (CHI). The pathway diverges from these central
intermediates into several side branches, each providing a different
class of flavonoids.

The initial steps in this pathway are referred to as the general
phenylpropanoid pathway {[}26{]}. In phenylpropanoid pathway, an
aromatic amino acid, phenylalanine first converted to p-coumaroyl-CoA
through the activity of phenylalanine ammonia lyase (PAL), cinnamic acid
4-hydroxylase (C4H), and 4-coumarate-CoA ligase (4CL). PAL catalyzed the
deamination of phenylalanine to trans-cinnamic acid in the first
committed step called as deamination of phenylalanine to trans-cinnamic
acid {[}27{]}. In the phenylpropanoid pathway, the second step involves
the activity of C4H, a cytochrome P450 monooxygenase, in plants. This
enzyme catalyzes the hydroxylation of trans-cinnamic acid and generates
p-coumaric acid. This was the first oxidation reaction {[}28{]}. The
third step in the general phenylpropanoid pathway involves the
activation of p-coumaroyl-CoA by the action of 4-courmarate: CoA ligase.
In plants, the activity of 4CL is positively correlated with anthocyanin
and flavonol content in response to stress {[}29{]}, whereas PAL, C4H,
and 4CL are generally coordinately expressed {[}30{]}. Chalcone synthase
(CHS) catalyzes the stepwise condensation of three acetate units to
yield naringenin chalcones. In vitro, naringenin chalcone is transformed
into naringenin by chalcone isomerase (CHI) {[}31{]}. Naringenin is a
very important flavonoid frame catalyzed by FNS I and FNS II (flavone
synthases I and II) and IFS (isoflavone synthase) to form flavones and
isoflavones respectively {[}32{]}. Naringen can also be catalyzed by
flavanone-3-hydroxylase (F3H), flavonol-3'-hydroxylase (F3'H) and
flavonol-3'5'-hydroxylase (F3'5'H) to synthesized dihydro-myricetin,
dihydro-kaempferol and dihydro-quercetin, respectively {[}33{]}. The
flavonol synthase (FLS) converted dihydro flavonols into flavonols (like
kaempferol, quercetin and myricetin), which further was catalyzed by
dihydroflavonol 4-reductase (DFR) to generate leucoanthocyanidins
{[}34{]}, further catalyzed by leucoanthocyanidin dioxygenase (LDOX) to
produce anthocyanidins {[}35{]}. anthocyanidins and leucoanthcyanidins
were again converted to proanthocyanidins catalyzed by
leucoanthocyanidin reductase (LAR) and anthocyanidine reductase (ANR),
repectively {[}36{]}. variations in anthocyanins is then responsible for
the stabilization of vacuolar anthocyanins which includes glycosylation,
methylation and acylation {[}37{]}.

In general phenylpropanoid pathway shown in figure 6 is common to all
the downstream metabolites like flavonoids and lignin. The metabolic
pathway continues through a series of enzymatic modifications to yield
flavonols, dihydroflavonols and anthocyanins.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Fig.6.} Phenylpropanoid pathway for flavonoids

There are some factors which influence the expression of the genes
involved in the biosynthesis pathways for flavonoids and leading to the
changes in their availability. Those factors can be the environmental
conditions (like light, water availability and temperature), the
hormones (like jasmonic acid) and also some physical injuries {[}38{]}.

\textbf{3. Pharmacological activities}

The presence of general phytochemicals and biological activities of
mulberry leaves are shown in figure 7. Mulberry leaves used widely as a
medicine in Asian countries especially in China. The Mulberry leaves are
rich in flavonoids and many other bioactive compounds which functions to
lowering the blood sugars, reducing blood lipids, resisting viruses,
aging and also helps in enhancing the immunity. The major bioactive
ingredients in plants are flavonoids. The flavonoids act as effective
antioxidants and metals chelators because of the phenolic compounds. The
flavonoids can also be a potent anticancer promoters and cancer
chemopreventive agents.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}

\textbf{Fig.7.} Pharmacological applications of mulberry leaves

\textbf{3.1 Antioxidant}

The working of anti-oxidants is shown in figure 8. The substances which
hold back the deterioration by oxidation like of fats, oils, foods etc.,
some components like Vitamin C, Vitamin E etc. responds to the damaging
effects of oxidation in a living organism. The free radicals possessing
an unpaired electron which are considered as fragments of molecules that
are generally very reactive. They are continuously produced in the cells
as by-products of metabolism {[}39{]}. Plants naturally have tendency to
develop some specific anti-oxidative defense enzymes like catalase,
peroxidase, polyphenol oxidase, ascorbate peroxidase and glutathione
reductase etc. to control the free radicals of oxygen under various
environmental stress conditions {[}40{]}. To avoid threats related to
the oxidative stress, antioxidant is required in the form of food
supplement {[}41{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image8/image8}

\end{center}
\end{figure}

\textbf{Fig.8.} Working of anti-oxidants

Wide range of flavonoids present in the mulberry leaves which make it a
very good antioxidant agent. The strong antioxidative properties of
mulberry leaves are because of the presence of higher values of phenolic
and flavonoid compounds {[}42,43{]}. Flavonoids with high antioxidant
activity can be used in many ways, like (i) it can inhibit reactive
oxygen species inhibition, (ii) leukocyte immobilization, (iii) inhibit
nitric oxide and (iv) xanthine oxidase inhibition {[}44{]}. As the
flavonoids have physiological functions in plants, it's an important
part of the human diet {[}45{]}.The higher amount of quercetin in
mulberry leaves maybe responsible for the reduction of oxidation process
{[}5,46{]}. Three flavonoids quercetin, rutin and isoquercetin are
considered as main antioxidant components in mulberry leaves ethanol
extracts {[}4{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image9/image9}

\end{center}
\end{figure}

\textbf{Fig.9.} Flavonoids as Antioxidants

\textbf{3.2 Anticarcinogenesis}

Flavonoids have been considered as high impact on the cancer prevention
and some selected isoflavones have tendency to inhibit cancer in a
number of animal models. Some studies revealed that the flavonoids
inhibit carcinogenesis \emph{in vitro} and significant results also
indicates that they also do it \emph{in vivo} {[}47,48{]}. Flavonoids
are the dominant class of phenolic compounds in mulberry leaves.

The mulberry leaves shows effective cytotoxic behavior against the
cancer cells and the mechanism is shown in figure 10. Many anticancer
compounds found in mulberry leaves like Kaempferol, Kuwanon S, Morusin,
with strong activity towards cytotoxic cell lines Hela, MCF-7 and Hep3B.
The galactose binded lectin isolated from the mulberry leaves has
cytotoxic activity on the human breast cancer with IC50-8.5 \selectlanguage{greek}μ\selectlanguage{english}g and also
on colon cancer cell with IC50-16 \selectlanguage{greek}μ\selectlanguage{english}g. {[}49{]}. Many phenolic compounds
are present in mulberry leaves which induces anticancer activity in
hepatoma cells by cell cycle captured at G2-M phase and inhibition of
topo-isomerase II activity. The anthocyanins are also a phenolic
compound present in mulberry leaves and has beneficial effects in
decreasing the risk of cancer because of its high chemopreventive
properties {[}50{]}. Another flavonoid present in mulberry leaves is
Quercetin which is capable of reducing the progress of human \selectlanguage{greek}β \selectlanguage{english}leukemia
{[}51{]}.Many other clinical trials revealed the therapeutic potential
of mulberry leaves against cytotoxicity as a cheap and easily available
source for the treatment of cancer and reduces the invasiveness of
cancer cells. The flavonoids and quercetins present also exhibited
selective cytotoxicity against human ovarian cancer and gastric cancer
{[}52{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image10/image10}

\end{center}
\end{figure}

\textbf{Fig.10.} Mechanism of mulberry leaves as anti-cancer agents

\textbf{3.3 Antidiabetic Activity}

Recent studies revealed that the total flavonoid in mulberry leaves
exhibit excellent hypoglycemia properties. Mulberry leaves contains
several iminosugars which includes 1-deoxynojirimycin and to inhibit
\selectlanguage{greek}α-\selectlanguage{english}amilase and galactosidase{[}53-55{]}.The most effective are
nojirimycin derivatives among all the iminosugars. The oral antidiabetic
drug used in Europe is a synthetic derivative of 1-Deoxynojirimycin.

The flavonoids and their related constitution present in mulberry leaves
are also have anit-diabetic related effects and the mechanism of
anti-diabetic activity is shown in figure 11. The mulberry leaves of the
South-American mulberry species were found to contain some benzofurane
derivatives and are active on STZ induced diabetic rats {[}56{]}. Some
of the purified flavone fractions of mulberry was found to activate
\selectlanguage{greek}α-\selectlanguage{english}glucosidase enzymes which in turn increase the blood glucose level
{[}57{]}.The polysaccharides present in leaves of mulberry have strong
potential for the inhibition of \selectlanguage{greek}α-\selectlanguage{english}glucosidase.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image11/image11}

\end{center}
\end{figure}

\textbf{Fig.11.} Mechanism of anti-diabetic activity of mulberry leaves

\textbf{3.4 Antimicrobial activity}

Fresh fruits and vegetables are living tissues which continue their
metabolic activities thereafter harvested. Antimicrobials helps in
protection against the microbial organisms which in turn used for the
production antibiotics. Mulberry leaves contained Kuwanon C,
Mulberrofuran G and albanol B with strong antibacterial activity with
MIC's ranging from 5-30 mg/ml {[}58{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image12/image12}

\end{center}
\end{figure}

\textbf{Fig.12.} Antimicrobial activity of flavonoids

The mulberry leaves extract in ethanol shows moderate antibacterial
activity whereas in aqueous it was little {[}59{]}. Some microbes
like\emph{E. Coli, Salmonella typhimurium, Staphylococcus epidermis, S.
aureus, Candida albicans} and \emph{Saccharomyces cerevisiae} can be
inhibited by the flavonoids present in mulberry leaves {[}60{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image13/image13}

\end{center}
\end{figure}

\textbf{Fig.13.} Mechanism of antimicrobial activity

\textbf{3.5 Cardiovascular activity}

In many eastern countries used mulberry leaves to treat cardiovascular
diseases. In china people use mulberry for decreasing blood pressure
which is the main reason for the cardiovascular disorder. The mulberry
leaves also helps to reduce the serum cholesterol, hypertension and to
prevent artherosclerosis {[}61{]}. The cardiovascular diseases basically
related to heart or blood vessels. High concentration of iron present in
mulberry leaves which helps in better distribution of oxygen by boosting
the production of RBCs. Reveratrol is a flavonoid present in the
mulberry leaves helps in increasing the formation of nitric oxide (NO)
which acts as a vasodilator. This will relaxes blood vessels and reduces
the chances of blood clot formation and subsequent heart diseases like
heart strokes. The resveratrol helps to remove the restrictions in blood
vessels which in turn reduces the chance of heart failure {[}62{]}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image14/image14}

\end{center}
\end{figure}

\textbf{Fig. 14.} Cardiovascular mechanism of flavonoids

\textbf{3.6 Neuroprotective activity}

The neuroprotection activity is related to prevent the disease
progression and other injuries due to the loss of neurons and halting.
The cognitive disorders and many other neuronal dysfunctions are treated
with the use of medicinal plants and mulberry is most prominent among
all. Recent studies reports that the phenolic compounds, anthocyanins
and flavonoids possess neuroprotective effects {[}63,64{]}. The
polyphenols and alkaloids present in mulberry leaves can improve the
cognitive function and also suspend the neural-degeneration {[}65{]}.The
isolated compounds from mulberry leaves can be used as neuroprotective
agents for neurodegenerative diseases treatment {[}66{]}. One of the
most common diseases with neurodegenerative disorder is Alzheimer's
diseases. The extract of mulberry leaves reduces the risk of Alzheimer's
disease. The leaf extract inhibit the amyloid \selectlanguage{greek}β-\selectlanguage{english}peptide (1-42) fibril
formation and attenuation of amyloid \selectlanguage{greek}β-\selectlanguage{english}peptide (1-42) induced
neurotoxicity {[}67{]}. The mechanism of neuroprotective activity is
shown in figure 15.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image15/image15}

\end{center}
\end{figure}

\textbf{Fig. 15.} Mechanism of Neuroprotective activity

\textbf{Future perspectives and challenges}

Glycosylation is one of the most important physiological and biochemical
reactions in nature given its crucial role in a multitude of essential
processes. This intrinsic importance has attracted long-standing and
wide research attention on the characteristics of GTs to facilitate
their application in glycosylation reactions for the metabolic
engineering of natural product biosynthesis. Although several GTs have
been found to be suitable for altering glycosylation patterns, low
catalytic activity and stringent substrate specificity remain limiting
factors in the diversification of PNPs for industrial fermentation
systems.

Many enzymes and genes are involved in flavonoid pathways and have been
characterized. However, many aspects of flavonoid biology remain
unidentified. The expression patterns and activity of some transcription
factors that regulate this branched pathway have not yet been
identified. Very little evidence exists for protein-protein interactions
that form metabolic channels and increase the efficiency of this
pathway. These problems can be solved by achieving efficient engineering
of flavonoid pathways in plants. The great biodiversity of plants that
arose during evolution has generated a concomitant variety of flavonoid
structures known to date, many of which are yet to be discovered.
Further analysis of different plant species will allow the discovery of
novel structures and possibly new metabolic pathways. Future studies
will also contribute to the improvement of floricultural, food,
pharmaceutical, and chemical industries. Moreover, evidence of beneficial
functions of flavonoids in human health and the use of natural compounds
for the prevention and treatment of different pathologies are
continuously increasing worldwide, and interest will continue to grow
among researchers in the coming years.

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\end{enumerate}

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