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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5698_Библиотеки_им_академика_М_И_Перельмана
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second group, and the third group administered with curcumin and diclofenac simulta-
neously. The study result found that the group administered with curcumin showed prom-
ising antiinflammatory activity in RA patients without significant serious side effects [38].
It inhibits oxidative stress in inflammatory situations by increasing antioxidan t enzyme ac-
tivity and activating the Nrf2-Keap1 pathway [39]. It increases serum antioxidant activity
(e.g., SOD and GSH) as well as the scavenging of ROS and RNS [40e42], and also iNOS,
5-LOX, COX-1, and COX-2 enzymes are all inhibited by curcumin.
6. Quercetin
Quercetin is a type of plant flavonoid that is present in a variety of fruits like lemon, or-
ange, apple, and grape and also present in some vegetables like onions and tea [43,44]. It sup-
presses the enzyme cyclooxygenase-2 and iNOS with macrophages and PBMCs block NF-kB
translocation, and adversely controls LPS-induced TLR-4 signaling [45,46]. The antiinflam-
matory effects of quercetin are prolonged in both animal and human models. The suppres-
sion of inflammatory factor-producing enzymes like cyclooxygenase and lipoxygenase is
what gives quercetin its antiinflammatory properties. It also retards the production of
lipopolysaccharide-generated TNF-a and IL8.
Besides antiinflammatory property, quercetin also has antioxidant and analgesic proper-
ties. It was reported that quercetin suppressed the NLRP3 inflammasomes which are respon-
sible for severe inflammation in case of COVID-19 virus infection (Fig. 18.3)[47].
Six quercetin derivatives have an antiinflammatory effect: quercetin-3-O-glucuronide, tam-
arixetin, isorhamnetin, isorhamnetin-3-O-glucoside, quercetin-3,4
0
-di-O-glucoside, and quer-
cetin-3,5,7,3
0
,4
0
-pentamethylene. All of these were compared for antiinflammatory activity
with some standard antiinflammatory drugs such as aspirin. The natural onion extract was
used as a source of quercetin and its derivatives. After administration, the concentration of
quercetin was found in systemic circulation and showed antiinflammato ry and antioxidant
effects (Fig. 18.4)[48].
7. Genistein
An iso flavonoid is found in red clover, legumes, and soy-based diets [49]. Suppressing
IL-6, ICAM-1, and NF-kB diminishes endothelial inflammatory damage [50]. By preventing
FIGURE 18.3 Quercetin.
18. Role of phytop harmaceuticals in inflammatory disorders438
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NF-kB expression and the activation of ERK1/2 and p-38, it reduces atherosclerotic inflam-
mation caused by angiotensin II (Fig. 18.5)[51]. It blocks the formation of TLR4 dimers, elim-
inates MyD88- or TRIF-dependent pathways, and deactivates NF-kB, which suppresses the
production of proinflammatory cytokines. It triggers the Nrf2 pathway, which explains
how it has antioxidant properties [52].
8. Butyrate
Butyrate has a role in colonic homeostasis and is a vital source of energy for intestinal
epithelial cells. The use of butyrate enemas as ulcerative colitis (UC) treatment has been stud-
ied (Fig. 18.6). Butyrate used topically has been found in certain trials to help reduce colon
inflammation. Nancey et al. [53] hypothesized that TNF may inhibit butyrate oxidation at
quantities observed in inflamed human mucosa, which might explain the lower oxidation
in UC patients.
Several in vitro and in vivo studies by Segain et al. and Song and Xia [54,55] have
confirmed the antiinflammatory effect of butyrate via NF-B inhibition, which results in
decreased concentrations of myeloperoxidase, cyclo-oxygenase-2, adhesion molecules, and
FIGURE 18.4 Working of
quercetin.
FIGURE 18.5 Genistein.
8. Butyrate 439
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various cytokine levels. According to Kato et al. [56], the intestinal mucosa of people with
active UC demonstrated a decreased capacity to oxidize butyrate.
9. Licorice
The natural drug licorice is used extensively in Indian systems of medicine to treat a va-
riety of diseases and discomforts. Additionally, licorice has adaptogenic and immunological
modulatory capabilities, both of which are essential for the growth of ulcer colitis. Many
active compounds, including glycyrrhizin, are thought to be responsible for its biological
effect (Fig. 18.7). A refined licorice extract called Diammonium glycyrrhizinate may be help-
ful in the treatment of UC [57]. Kudo et al. [57] and Yuan et al. found that Diammonium
glycyrrhizinate may inhibit the expression of NF-B, TNF-, and ICAM-1 in rats’ inflamed
mucosa [58].
10. Proanthocyanidins (PAC)
For the treatment of recurrent UC in rats, the therapeutic efficacy and mechanism of PAC
were determined for grape seed extract. Reduced colonic weight/length ratio, as well as
microscopic and macroscopic damage scores, was an indicator of how well the pathologic al-
terations in the colon responded to the grape seed treatment after the development of recur-
rent colitis [59]. This was confirmed by Li et al. [60], who found that grape seed reduces
FIGURE 18.6 Butyrate.
FIGURE 18.7 Glycyrrhizin.
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inflammation in the case of acute ulcerative colitis in a rat model. It preve nts cell signaling
during inflammation and can reduce oxidative stress. It has the property to repair cell dam-
age and minimize oxidative stress and increase the biosynthesis of antiinflammatory cyto-
kines (Fig. 18.8).
11. Bromelain
The antiinflammatory drug bromelain has also been used as a digestive aid, blood thinner,
and treatment for edema, sinusitis, and sports injuries. Specifically, ulcerative colitis brome-
lain can be used as a supplement for IBD. According to a recent study, bromelain, an “active”
component of pineapple, may aid in reducing the inflammation connected to UC (Fig. 18.9).
Most of its antiinflammatory activities are attributable to currently unidentified mechanisms.
FIGURE 18.8 Proanthocyanidins.
FIGURE 18.9 Bromelain.
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Proteolytic activity is very necessary for bromelain’s anti-inflammatory effects on T-cell cyto-
kine production in murine models bearing IBD [61 ,62]. Although research indicates that
bromelain also has immunomodulatory and hormone-like qualities that function through
intracellular signaling pathways, it appears that its primary method of action is proteolytic.
It has been discover ed that bromelain blocks cell surface receptors [63].
12. Naringenin
Citrus fruit flavonoid naringenin (NAR), which possesses antiviral and antiinflammatory
characteristics, such as lowering cytokine production and viral multiplication, has been stud-
ied. Tutunchi et al. and Clementi et al. proposed the hypothesis that NAR indicates an
approaching antiinflammatory effect in COVID-19-linked risk factors and SARS-CoV-2 infec-
tion ( Fig. 18.10)[64e67].
Secondary metabolites from plants may hold promise as a source of compounds with anti-
inflammatory characteristics that inhibit COVID-19 replication and cytokine production.
Hossam M. Abdallah [68] used a systematic computer-aided virtual screening technique to
find prospective natural product inhibitors of SARS-CoV-2 primary protease using commer-
cially accessible natural products discovered on the Zinc Database in addition to an in-house
compound library (M Pro). The screening’s top 18 hits were chosen for in vitro testing against
the viral protease (SARS-CoV-2 M Pro). The viral protein was highly actively inhibited by five
substances: naringenin, 2,30,4,50,6-pentahydroxybenzophenone, apigenin-7-O-glucoside,
sennoside B, and acetoside. Acteoside had comparable action to that of the GC376 positive
control.
Only naringenin demonstrated substantial anti-SARS-CoV-2 action at noncytotoxic micro-
molar concentrations in vitro with a significant selectivity index (CC50/IC50 ¼ 178.748/
28.347 ¼ 6.3) when the most effective drugs were tested in vitro on the SARS-CoV-2 Egyptian
strain. Additionally, a common feature pharmacophore model was developed to explain the
conditions in which this heterogeneous set of active ligands can inhibit an enzyme. These
findings open the door to the future creation and repurposing of natural compounds to
help fight COVID-19 [68].
Ahmed Kandeil [69] published a report to compare the SARS-CoV-2 in vitro antiviral
properties of curcumin, hesperidin, and quercetin to hydroxychloroquine and figure out
how they work. These substances greatly slowed down viral replication in Vero E6 cells, prin-
cipally acting as virucidal agents and suggesting that they may be active in the early stages of
viral infection. Molecular docking experiments were performed against the SARS-C oV-2
FIGURE 18.10 Naringenin.
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spike (S) and major protease (M Pro) receptors to better understand the investigated drugs’
mode of action. As a whole, the results from in vitro and in silico research indicate that the
compounds may be effective SARS-CoV-2 Mopar inhibitors because of their well-estab lished
antiinflammatory effects [69].
13. Naringin
A plant flavonoid known as naringin has significant medical use in the healthcare system.
The phenylpropanoid pathway uses seven enzyme-catalyzed steps to produce it, starting
with phenylalanine and ending with pruni n. An essential water-soluble flavo noid known
as naringin has been discovered in citrus fruits. Its chemical formula is C
27
H
23
O
14
, and its mo-
lecular weight is 580.4 g/mol. Naringin appeared to have a variety of functions, including
those for antioxidants, antiinflammatories, hepatoprotective, kidney protective, cardiovascu-
lar tonic, expectorant, protective effect against neurotoxicity, antidiabetics, and hypolipi-
demic (Fig. 18.11). It has also been shown to increase bone formation and to be anticancer
and antiapoptotic.
The important flavanone naringenin, also known as 2, 3-dihydro-5, 7-dihydroxy-2-(4
hydroxyphenyl)-4 H-1-benzopyran-4-one, has a molecular weight of 27.226 Da. Both the
glycoside and aglycone variants of naringenin can be found in nature. Both vegetables and
fruits contain naringenin and its derivatives, which are mostly synthesized through the phe-
nylpropanoid pathway. Naringenin has extensive biological impacts on human health,
including anticancer, antiproliferative, antiinflammatory, antiatherogenic, and antiviral prop-
erties. Naringenin has been found to repair DNA damage, reduce ROS, improve glucose
metabolism, affect the immune system, and cause intracellular signaling reactions. In an acute
model of induced colitis in mice, Ribeiro et al. [70] investigated the antiinflammatory effects
of citrus fruit constituents such as naringin and naringenin. To do this, they used the enzyme
immobilization approach to create microstructured particles. They employed a central com-
posite design to evaluate how naringin and naringinase affected the system. Colitis was
induced in mice by administering 7% dextran sodium sulfate (DSS) dissolved in water for
5 days. Additionally examined were the ratio of gut dry to wet weight, tissue nitrate/nitrite
levels, and tissue malondialdehyde levels, markers of lipid peroxidation. In this mouse model
of colitis, they found that naringin and naringe nin therapy significantly reduced the growth
of intestinal edema, indicating an antiinflammatory activity.
FIGURE 18.11 Naringin.
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Naringenin’s anti-inflammatory prop erties in rats with carrageenan-induced paw edema
were evaluated by Chung et al. [71]. The oral dose of naringenin (100 or 200 mg/kg) signif-
icantly decreased the time it took for mice to respond to heat stimulation from a hot plate and
a tail-flick device. Additionally, it reduced mice’s tendency to writhe after being exposed to
acetic acid. Additionally, naringenin’s antiinflammatory capa bilities were demonstrated by
the fact that it significantl y lessened the edema developed by carrageenan in the paw region
of the rats. They came to the conclusion that naringenin showed antinociceptive and antiin-
flammatory properties, which can be again subjugated to produce drugs fo r conditions linked
to inflammation and pain. Ribeiro et al. [72] prepared and used immobilized naringinase to
hydrolyze naringin into naringenin and evaluated their antiinflammatory properties. A rat
paw edema model of acute local inflammation that was developed by using carrageenan
was utilized to assess the antioxidant action as well as its antiinflammatory effect. It was
found that grape juice is generally digested by the enzyme naringinase, which was adminis-
tered after immobilizing it in the beads of 2.0% w/v k-carrageenan. Activity of 19.5 mg/mL/
min of grape juice was utilized to produce 215 mg/L of naringenin. It was found that the
immobilized naringinase (1000 mg/L) was able to convert naringin by 95% in grapefruit
juice. To analyze the data, an ANOVA was utilized along with Dunnett’s posttest. According
to the results, 6 h after carrageenan injection, rats (n ¼ 9) which are administered with narin-
gin and naringenin in the form of solution (in concentrations equivalent to grapefruit juice),
and rats (n ¼ 9) were pretreated with a naringenin and naringin solution all displayed a sig-
nificant decrease in edema formation. Rats pretreated with naringenin solution had just 8%
paw edema, demonstrating the substance’s substantial in vivo antiinflammatory activity
(P .001). Grapefruit juice’s antiinflammatory properties were shown to be unaltered by enzy-
matic processing in comparison studies on rats given the juice (pre- and postprocessing)
orally.
14. Chrysin
Chrysin, a flavonoid with a 15-carbon structure, is a naturally occurring polyphenolic sub-
stance. Its chemical name is 5,7-dihydroxy-2-phenyl-4H-chromen-4-one. The main natural
sources of chrysin include propolis, honey, and passion fruit (Passiflora species). It can be
found in forest honey up to 5.3 mg/k g. The molecular structure of chrysin consists of a het-
erocyclic ring attached between two benzene rings. It does not have a 3-carbon hydro xyl
group, but it does contain a carbonyl group attached to the fourth carbon and has two to
three double-bond carbons (Fig. 18.12). Additionally, it has eOH groups at the fifth and
FIGURE 18.12 Chrysin.
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seventh carbon atoms. Chrysin, however, does not share oxygenation with any other flavo-
noids in the Ring-B. The majority of the diversity in the ring is made up of various chrysin
derivatives, such as wogonin, baicalein, and pyroxylin A.
Because there is no oxygen in the B and C rings, chrysin has biological characteristics that
range from antiinflammatory to antitoxic. Additionally, it has bee n proposed that the variety
of these chemical compounds’ structures is what supports the antioxidant action of different
flavones. Chrysin’s carbonyl group on carbon atom number four and the double bond be-
tween carbon atoms two and three are what primarily affect its antioxidant action (30, 40 hy-
droxylation). According to health claims, chrysin has hepatoprotective, neuroprotective,
antiinflammatory, anticancer, antidiabetic, antiallergic, antioxidant, and cardiovascular ef-
fects. Using rats with secondary osteoporosis (OP) brought on by retinoic acid (13cRA),
Nada et al. [73] sought to investigate the effects of the flavonoids naringenin and chrysin
on oxidative stress inflammation and bone deterioration. Changes in body and uterine
weight, biochemical bone parameters (bone mineral density (BMD), bone mineral content
(BMC), markers of bone turnover), bone geometry parameters, bone histology parameters,
oxidative stress parameters, biochemical and hematological parameters, and levels of inflam-
matory cytokines were all evaluated. They noticed decreased bone calcium and phosphorus
levels, BMD and BMC, as well as the expression of markers for bone turnover, in osteoporotic
rats. They also noticed elevated serum levels of the enzymes lactate dehydrogenase and alka-
line phosphatase (ALP) (LDH). While glutathione (GSH) levels and antioxidant enzyme ac-
tivities were lowered, the inflammatory mediators TNF-, IL-1, IL-6, and RANTES
chemokine (regulated on activation normal T cell generated and secreted) were released
into the bloodstream at increased rates in the liver, kidney, and ovary. Therapy with natural
antioxidants such as chrysin or naringenin enhanced bone quality, decreased bone resorption,
and increased bone mineral deposition, but more ineffectively than alendronate, indicating
their considerable potential for slowing bone loss and preventing osteoporosis. Flavonoid de-
rivatives, such as chrysin 5,7-dihydroxy-8-(pyridine-4yl) flavone, showed antiinflammatory
effects on PE2 production from LPS-treated RAW 264.7 in Lim et al. [74] study (C721).
They showed that the C-721 was superior to chrysin at suppressing PGE2 and generating
NO in LPS-treated RAW cells. Analysis revealed that this compound decreased PGE2 synthe-
sis by inhibiting COX-2 and downregulating COX-2, whereas C-721 mainly decreased NO
via decreasing the expression of inducible nitric oxide (iNOS). C-721 was able to reduce
IL-6 and TNF-a production in addition to avoiding edema in mice with carrageenan-
induced inflammation. Overall, CMI-mediated inflammatory reactions like mice’s collagen-
induced arthritis can be significantly reduced by flavonoid medications like chrysin and its
analogs. Alipour et al. [75] stated that the infection and inflammation must be eliminated us-
ing the appropriate endodontic material to set the stage for pulp tissue regeneration, healing,
and biomineralization. In this regard, they highly favored chrysin, which has potent antiin-
flammatory and antibacterial properties and also has mineralization effects on dental pulp
stem cells (DPSCs). Chrysin-loaded scaffolds were successfully synthesized and analyzed us-
ing SEM, FTIR, and TGA tests. C-721 was able to reduce IL-6 and TNF-a production in addi-
tion to avoiding edema in mice with carrageenan-induced inflammation. In conclusion,
flavonoid medications like chrysin and its analogs can significantly lower other CMI. The
antibacterial activity of the synthesized scaffold against Acinetobacter baumannii, Pseudomonas
aeruginosa, Staphylococcus aureus, and Enterococcus faecalis was assessed using the agar
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diffusion test and live/dead assay. The proliferative rate of DPSCs on various scaffolds was
evaluated using the MTT assay, DAPI labeling, and DNA extraction. Additionally, the anti-
oxidant and antiinflammatory effects of chrysin-loaded scaffolds on inflamed DPSCs were
evaluated. Alkaline phosphatase activity and Alizarin Red S stain assays were carried out
to evaluate the mineralization of DPSCs seeded on these scaffolds. Chrysin-loaded scaffolds
showed antibacterial action toward the investigated bacterial strains. There was a significant
increase in the number of DPSCs that could proliferate on these scaffolds (P .05). Inflamed
DPSCs had considerably lower levels of TNF and DCF when scaffolds loaded with chrysin
were present (P 0.05). These scaffolds significantly increased the formation of mineralized
nodules and ALP activity in DPSCs when compared to the control group (P .05). According
to their research, the traditional medicinal component chrysin may speed up the repair of
damaged pulp tissue and serve as a safe alternative to regenerative endodontic procedures.
15. Mangiferin
Mangiferin, a 1, 3, 6, and 7-tetrahydroxyxanthone-C2-D-glucoside, is a naturally occurring
compound in several species. Mangiferin has an anhydrous melting point of 271
C, a molec-
ular weight of 422.35, and the chemical formula C
19
H
18
O
11
. It dissolves poorly in the majority
of solvents but is easily soluble in DMSO and DMF and soluble in aqueous ethanol at a 60%
concentration. It displays a wide range of biological behaviors and, in certain instances, is the
cause of the trad itional exploitation of its natural resources. It has been demonstrated to
display a variety of pharmacological properties, and as a result, there are numerous potential
uses in clinical research. It is a well-known phytomedicinal compound that the Indian med-
ical system recommends using to treat a variety of illnesses. Plants that contain mangiferin
have a wide range of traditional uses in traditional medicine. Applied scientific experiments
have verified some of these therapeutic effects. Following its separation from medicinal
plants based on folklore, new pharmacological actions of mangiferin have also been found.
Pan et al. [76] investigated how mangiferin protects the liver from acute injury caused by
D-galactosamine and lipopolysaccharide (LPS). Mangiferin, a glucosyl xanthone from the
Mangifera indica plant, may have antiinflammatory properties. Even though the specific
mechanisms and effects of mangiferin are still unknown, it may prevent liver damage
(Fig. 18.13). They want to figure out how mangiferin protects the liver from acute damage
caused by
D-galactosamine (D-GalN) and lipop olysaccharide (LPS). LPS and D-GalN were
administered following the administration of LPS. Their findings showed that mangiferin
decreased serum ALT, AST, IL-1, TNF-, MCP-1, and RANTES levels as well as liver
FIGURE 18.13 Mangiferin.
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malondialdehyde (MDA) and ROS levels. Mangiferin also significantly decreased the amount
of IL-1 and TNF generated by primary hepatocytes activated by LPS. Mangiferin was found
to upregulate Nrf2 and HO-1 expression in a dose-dependent manner. In the liver, LPS/d-
GalN-induced expression of NLRP3, ASC, caspase-1, IL-1, and TNF was also decreased by
mangiferin. Mangiferin hence provided protection.
For the first time, Mangiferin’s antiinflammatory effects in an animal model of allergic
rhinitis (AR) were studied by Wang et al. [77]. Mangiferin is a xanthone found in higher
plants and mangoes that have anticancer, antioxidant, antimutagenic, antidiabetic, antibacte-
rial, and antiinflammatory properties. Sneezing and rubbing of the nose were reduced in AR
after mangiferin administration. Additionally, the MDA created by giving allergens was
greatly decreased by mangiferin therapy. Mangiferin also prevented the NF-Bp65 and
STAT3 signaling pathways from being activated in the cytosol, which increased the levels
of antiinflammatory cytokines and decreased the levels of proinflammatory cytokines. Man-
giferin also decreased the AR model’ s ciliary loss, vascular lamina congestion, goblet cell
elevation, and eosinophil filtration symptoms. Thus, their results imply that mangiferin is
a potential immunotherapy strategy for AR illness.
Bulugonda et al. [78] studied the molecular mechanism of Pueraria tuberosa’s (PT-
Mangiferin) powerful antiinflammatory properties using a carrageenan-induced air pouch
model. Normal cells were not poisoned by PT-Mangiferin, but it was toxic to cancerous cells
and had an apoptotic effect. It significantly reduced the generation of proinflammatory me-
diators in LPS-stimulated RAW 264.7 cells (COX-2, iNOS, and TNF-). It has also reduced the
ROS generated and prevented the LPS-induced translocation of NF-kB in these cells. Addi-
tionally, it limits cytokine production and inhibits neutrophil and monocyte invasion. These
effects were mediated by the suppression of the NLRP3 inflammasome complex and its
downstream signaling molecules.
16. Conclusion
In a nutshell, this research looks at how a variety of plant-derived compounds influence
inflammation in a variety of immune cells and chemical messengers. While some of these
pathways are shared by other natural compounds and contribute to their antiinflammatory
actions, others are pleiotropic and target many sites in the TLR4 pathway. By inhibiting
TLR4 receptor expression and NF-kB transcription factor activation, the plant secondary me-
tabolites in this scenario block the upregulation of inflammatory reactions by inhibiting the
production of cytokines and free radicals. The final section of the review covered how phy-
tochemicals and nutraceuticals can be used to reduce COVID-19 risk by modulating inflam-
matory markers.
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