Liquid Nano Curcumin OIC NEW

Wound Healing Effects of Liposomal Nanocurcumin and PL Pro Nanocurcumin on Thermal Burn and Skin Ulcer

oictrungnc — Thu, 25 Jul 2024 01:33:38 +0000

Anh Van Thi Pham1,#, Anh Quang Luong2,3,#, Dung Kim Thi Dao4, Vy Nhat Dao Nguyen4, Tam
Cong Nguyen4, Thoa Thi Dao4, Long Hai Luu5,6, Lan Hai Luu5,6, Gioi Huy Dong6, Huong Thu Thi
Bui6, Tung Thanh Tran1, Duong Thuy Dau1, Hai Van Nguyen7, Minh Hai Luu5,# and Loan Thanh
Thi Nguyen1,*
1Department of Pharmacology, Hanoi Medical University, Hanoi 10000, Vietnam
2Department of Pharmacy and Medical Equipment, National Burn Hospital, Hanoi 10000, Vietnam
3Vietnam Military Medical University, Hanoi 10000, Vietnam
4DKD International Production Joint Stock Company, Ho Chi Minh 70000, Vietnam
5Nhat Hai New Technology Joint Stock Company, Hanoi 10000, Vietnam
6Vietnam National University of Agriculture, Hanoi, Vietnam
7Hanoi University of Pharmacy, Hanoi, Vietnam

Abstract:
Background: Burn injuries and skin ulcers are important health problems resulting in physical and psychological
scars and chronic disabilities. This study investigated the wound-healing effects of liposomal nanocurcumin and PL
pro nanocurcumin on thermal burns in rats and doxorubicin-induced skin ulcers in mice and their systemic toxicity.
Methods: Having subjected to a cylindrical hot steel rod onto the dorsum, burned lesions were covered topically with
silver sulfadiazine/liposomal nanocurcumin/PL pro nanocurcumin twice a day for 21 days. Besides, the other skin
lesions which were induced by a single intradermal injection of doxorubicin on the dorsal region were topically
administered with dimethyl sulfoxide/liposomal nanocurcumin/PL pro nanocurcumin twice a day for 21 days.
Results: The results indicated that liposomal nanocurcumin and PL pro nanocurcumin significantly reduced the
wound size, increased the hydroxyproline content in animals’ skin, and improved the histopathological structure of
the affected tissues. Specifically, liposomal nanocurcumin demonstrated better healing results than PL pro
nanocurcumin on thermal burns. Furthermore, topical administration of liposomal and PL pro nanocurcumin was
deemed not to exert any systemic toxicity to the wounded animals by not influencing considerably the hematological
parameters and renal and hepatic functions and altering the histology of the liver and kidney. Additionally, liposomal
nanocurcumin and PL pro nanocurcumin with average sizes of 206 nm and 344 nm were well-dispersed in water,
accentuating that the disadvantages of limited water solubility have been overcome.
Conclusion: Thus, liposomal nanocurcumin and PL pro nanocurcumin exerted effective effects on burned wounds
and skin ulcers whilst triggering no systemic toxicity in wounded animals.
Keywords: Liposomal nanocurcumin, PL pro nanocurcumin, Burn, Skin ulcer, Healing, Wounded animals

1. INTRODUCTION
Curcumin has perennially been referred to as a
bioactive, important compound found in nature. To be
specific, this substance is isolated from Curcuma longa L.,
which belongs to the Zingiberaceae species with a
scientific name of (1e,6e)-1,7-bis(4-hydroxy-3’-methoxy
phenyl)-1,6-heptadiene-3,5-dione [1, 2]. For years,
curcumin has been profoundly embedded in the sociocultural lifestyle of different peoples, especially Asians. It
is not only considered a nature-based colorant, flavouring
agent, and food preservative in many local cuisines but is
also utilized for the sake of curing many illnesses.
Regarding the pharmacological properties, many
beneficial biological features of curcumin have been
identified, such as anti-oxidant, anti-inflammatory, antimicrobial, anti-mutagenic, anti-tumoral, anti-angiogenesis activities, and wound healing effects [3-10].
Besides the evidence for the diversity of bioactivities of
curcumin, this substance barely exhibits any toxicity at
high doses when used for clinical treatment purposes
[11-16]. Therefore, this statement does pave the way for
curcumin to be popularly studied in various research
studies relating to the dysregulation of many human
organs. In particular, when it comes to some skin
disorders and damages with many free radicals emitted,
curcumin improves the skin with its capability to eradicate
reactive oxygen species and attenuates local inflammation
by inhibiting the nuclear receptor NF-κB [17].
Furthermore, treating skin disorders with curcumin does
help to shorten the wound healing time, enhance the
deposition of collagen, and also increase the density of
fibroblasts and vasculatures, thus reinforcing the healing
of the affected tissue with different levels of severity
[18-20].
Notwithstanding those mentioned beneficial features,
curcumin does exhibit many limitations, including poor
water solubility and physicochemical instability, less
bioactive absorption, rapid metabolization, and low
penetration and targeting efficacy [21-24]. Meanwhile,
nanoformulation has been testified regarding the potential
of targeted delivery to the tissue of interest that leads to
enhanced bioavailability and bioactivity and better drug
carriage [25-28]. With the intention of taking advantage of
this compound and simultaneously solving its drawbacks,
the advent of nanocurcumin has shown to be prominent.
There are currently several methods to encapsulate
curcumin molecules at the nanoscale, and each uses a
different but suitable nanocarrier [29].
Burn injuries and skin ulcers are still considered
important health problems affecting both genders and all
age groups, resulting in physical and psychological scars
and leading to chronic disabilities [30-33]. To date,
research on burns has generated sustained interest over
the past few decades. In current burn therapy, silver
sulfadiazine has been presented as the gold standard in
topical second-degree burn treatment because of its
antibacterial activities [34, 35]. However, the effect of
silver sulfadiazine stems from the toxicity towards
keratinocytes and fibroblasts, hence decelerating the

wound healing process and probably triggering serious
cytotoxic effects on the host cells. Furthermore, there are
quite a number of articles to be reviewed on some
emerging sliver-sulfadiazine-resistant organisms [36-38].
Additionally, in the treatment of skin ulceration, dimethyl
sulfoxide (DMSO) is perennially one of the most proposed
remedies since it can easily infiltrate into the affected area
and scavenge free radicals, which is an important etiology
of serious tissue damage [39]. However, for the time
being, the accessibility of DMSO and other effective
agents for skin ulcers is still restricted. Therefore, seeking
a safer and more effective treatment approach towards
skin lesions has been critically demanded in healthcare
practice, particularly those caused by thermal or chemical
triggers.
The beneficial effects and potentials of curcumin in
different nano-based dosage forms, including liposomal
nanocurcumin and PL pro nanocurcumin, with the
assessment in terms of healing effects in both burned and
ulcerated skin lesions, as well as the systemic toxicity in
the experimental model remain unclear. In the present
study, we investigated the wound-healing effect of
liposomal nanocurcumin and PL pro nanocurcumin on
thermal burns in rats and doxorubicin-induced skin ulcers
in mice and their systemic toxicity in ulcerated
experimental animals.
2. MATERIALS AND METHODS
2.1. Preparation of Liposomal Nanocurcumin and PL
Pro Nanocurcumin Formula
2.1.1. Liposomal Nanocurcumin
Firstly, nanocurcumin was created. The dispersed
phase by dissolving curcumin in ethanol was prepared
with a volume ratio of 4/5. Then, a carrier mixture
consisting of polyethylene glycol (PEG) and ethylene glycol
by dispersing polyethylene glycol and ethylene glycol well
in water was made with a ratio of approximately 1.5/6/2
for polyethylene glycol/ethylene glycol /water, under
ultrasonic vibration for about 2 hours at room
temperature. A homogeneous mixture was made by mixing
the dispersed phase/liquid in the previous step, the carrier
mixture, and the emulsifier lecithin such that the ratio of
curcumin/PEG/lecithin in this homogenizer was 1.6/1.5/2
using an emulsifier. Nano-emulsions of curcumin were
created by allowing the mixture to homogenize overnight
and then centrifugated at room temperature at 5000 rpm
for about 10 minutes, which was repeated six times. After
obtaining curcumin nano-emulsions, nano-curcumin and
phospholipids were weighed and prepared according to
the respective ratio of 1/1. Liposomal nanocurcumin was
obtained by putting the prepared mixture into the
emulsifier and heating it at 120oC within 4 hours.
2.1.2. PL Pro Nanocurcumin
Nano curcumin was prepared using the method
described above. PL pro included 18% phosphatidylcholine, 21% cholesterol, 27% lecithin, 9.5% folic acid,
15% nano curcumin, 3% tocopherol, 3% xanthan gum, 3%

Camellia sinensis extract, and 0.5% Aloe vera extract, then
nano curcumin and PL pro were mixed according to the
corresponding volume ratio of 1/1 in the emulsifier. After
two hours, PL pro nanocurcumin was obtained.
2.2. Particle Size
Liposomal nanocurcumin and PL pro nanocurcumin
samples were tested to determine particle size. This
process was carried out utilising Malvern Mastersizer
(Malvern Instruments Ltd., United Kingdom). The
measurement was carried out by dissolving particles in
water before measuring. The system temperature was
kept at about 25°C. Hence, the solution was checked in
terms of limitations regarding solubility.
The stability of liposomal nanocurcumin and PL pro
nanocurcumin was determined through an accelerated
aging test. This test simulates the aging process over time
by subjecting the samples to high temperatures to
artificially expedite the aging process. The accelerated
aging process was conducted using an incubator (Daihan
Scientific, South Korea), maintaining a constant
temperature of 40°C for six months.
2.3. Experimental Animals
Male and female Wistar rats weighing 180 ± 20g and
seven-week-old male and female Swiss albino mice were
obtained from the National Institute of Hygiene and
Epidemiology, Hanoi, Vietnam. All experimental protocols
were in accordance with the National Guideline (reference
number: 141/QD-K2DT). This study was approved by the
Scientific Board Committee of Hanoi Medical University,
Vietnam (ref number: IRB00003121). All animals were
housed in a controlled environment (25 ± 1ºC under 65 ±
5% humidity and a 12-hour light and dark cycle) with ad
libitum to access the standard rodent diet and water. The
animals were given for at least one week to acclimate
before starting the experiments.
2.4. Healing Effect of Topical Administration of
Liposomal Nanocurcumin and PL Pro Nanocurcumin
Creams
2.4.1. Thermal Burn in Rats
We followed the previously reported model of thermal
burns on rats. A total of 50 rats were randomly divided
into five groups of ten animals. The rats were anesthetized
with a single intraperitoneal injection of 250 mg/kg
chloralhydrate (Sigma Aldrich, St. Louis, MO, USA). As
preparation, they were shaven at the dorsum with an
electric shaver and later sterilized with 70% alcohol. All
animals, except the normal control group, were subjected
to thermal burns on the back of each rat by using a
standard burning technique [40]. Burn wounds were
formed by applying a 200-gram cylindrical stainless-steel
rod (2.5 cm diameter) without any pressure, which was
pre-heated to 100°C in boiling water with the thermal
equilibrium confirmed by a monitoring thermometer, onto
the shaven skin for 35 seconds. All animals were
resuscitated immediately with Lactated Ringer’s solution
(2 ml/100 g body weight) intraperitoneally. Following the
burning, each animal was placed in a separate cage, and
the affected areas were covered with 0.3 g silver
sulfadiazine, liposomal nanocurcumin, or PL pro
nanocurcumin twice a day for 21 days. The vehicle-treated
burned rats topically received sterile distilled water (Fig.
1A).
2.4.2. Doxorubicin-induced Skin Ulcer in Mice
Fifty mice were randomly divided into five groups of
ten animals. Mice were anesthetized with an
intraperitoneal injection of 350 mg/kg chloralhydrate.
After anesthesia, the dorsal regions were shaven with an
electric shaver and sterilized with 70% alcohol. All
animals, except the normal control group, were induced
skin ulcers by a single intradermal injection of 0.2 ml
doxorubicin 1 mg/0.5 ml (Doxorubicin Ebewe, Austria)
[41]. Then, each animal was placed in a separate cage.
Seven days after the injection of doxorubicin, the vehicletreated ulcerated mice topically received sterile distilled
water. The other ulcerated mice were topically applied 0.3
ml DMSO (Sigma Aldrich, St. Louis, MO, USA) twice a day,
0.3 g liposomal nanocurcumin or PL pro nanocurcumin
twice a day for 21 days (Fig. 1B).
2.4.3. Measurement of the Wound Size
Wound sizes of animals in two experiments were
measured using a digital camera with one camera lens and
from a constant focal distance. The area of the wound was
measured in a blind manner using ImageJ basics software
ver 1.38, which was recognized as software for measuring
the area in medical experimental research by the World
Health Organization.
2.4.4. Determination of the Hydroxyproline Content
At the end of two experiments, mice and rats were
anesthetized with chloralhydrate, and skin samples were
collected from each animal. The concentration of
hydroxyproline in the skin was evaluated according to the
Stegemann H. and Stalder K method [42]. Briefly, 20 to 30
mg of skin tissues were put into hydrolytic tubes with 2
mL HCl 6N. These tubes were incubated at 115°C. After
24 hours, the hydrolyzed fluid was collected into the test
tubes. Each test tube included 0.2 mL hydrolyzed fluid of
samples, 1.8 mL distilled water, and 1 mL chloramine T.
These test tubes were shaken and kept at room
temperature for 20 minutes. Then, 2 mL pechloric acid 4M
was added, shaken well, and let stand for 5 minutes at
room temperature. 4-Dimethylaminobenzaldehyde 10%
was added, shaken well, and kept in a bain-marie at 60oC
for 15 minutes. These tubes were cooled down to room
temperature and measured the light of 560 nm wavelength
absorption (Shimadzu, Japan).
2.4.5. Histopathological Evaluation
The ulcerated skin tissue samples were collected for
histopathological examinations. Histopathological evaluation was carried out randomly in 30% of each group.
These tissue samples were fixed in 10% neutral-buffered

Fig. (1). Experimental protocols. (A) Experimental protocol for evaluating the effects of topical administration of liposomal nanocurcumin
and PL pro nanocurcumin creams on thermal burns in rats. (B) Experimental protocol for evaluating the effects of topical administration
of liposomal nanocurcumin and PL pro nanocurcumin creams on doxorubicin-induced skin necrosis in mice

formalin solution before they were embedded in paraffin
wax and cut into 5 μm-thick sections to be stained with
hematoxylin and eosin (H&E). The pathologist who
examined the slides was blind to group allocation. Under
histopathological examinations, inflammation, epithelization, neovascularization, and necrosis were evaluated.
2.5. Evaluation of systemic toxicity of topical
administration of liposomal nanocurcumin and PL
pro nanocurcumin creams in wounded animals
Blood samples were collected from each animal. The
systemic effects were quantified through general
conditions, including body weight changes in mice.
Moreover, the hematopoietic function was evaluated
through red blood cell count, hemoglobin, hematocrit,
total white blood cells, and platelet count. The liver
damage was examined through aspartate aminotransferase level (AST) and alanine aminotransferase level
(ALT), and the liver function was measured through total
bilirubin, albumin, and total cholesterol. Furthermore,
kidney function was examined through creatinine level.
Follow-up parameters were checked at the time points
before applying the products after 10 and 21 days in the
thermal burn model in rats (Fig. 1A). In the doxorubicininduced skin ulcer model in mice, blood samples were
obtained after 21 days of treatment (Fig. 1B).
At the end of the experiments, animals were
euthanized after blood collection, and the internal organs
(heart, liver, spleen, kidney, and lung) were removed and
observed for any gross lesions. The liver and kidneys of
30% of the animals in each group were preserved in a 10%
buffered formaldehyde solution for histopathological
studies using hematoxylin and eosin (H&E) staining by a
researcher blinded to the study.
2.6. Data Analysis
Sigmaplot 12.0 (SYSTA Software Inc, Richmond, CA,
USA) was used for statistical analysis. Obtained data were
expressed as the mean ± S.D and compared with either
one-way-ANOVA, followed by the post hoc StudentNewman-Keuls test for multiple comparisons or Fisher’s
Exact test for two proportions. Statistically significant
differences were considered when the p-value was less
than 0.05.
3. RESULTS
3.1. Particle Size
Liposomal nanocurcumin and PL pro nanocurcumin
with average sizes of 206 and 344 nm were well-dispersed
in water, indicating that the disadvantages of limited
water solubility have been overcome. Furthermore, the
results of the accelerated aging study revealed that after
six months of accelerated aging at 40°C, both liposomal
nanocurcumin and PL pro nanocurcumin remained stable
in particle size (Fig. S1).

3.2. Healing Effects of Liposomal Nanocurcumin and
PL Pro Nanocurcumin on Thermal Burns in Rats
3.2.1. Effect on the Wounded Area
As shown in Fig. (2), after 7 days of treatment, there
was no difference in burned area between groups. After 14
days of administration, silver sulfadiazine, liposomal
nanocurcumin, and PL pro nanocurcumin markedly
reduced the wounded area compared to the vehicletreated model group (vehicle-treated burned group vs.
silver sulfadiazine-treated burned group, p=0.003; vehicletreated burned group vs. liposomal nanocurcumin-treated
group, p<0.001; vehicle-treated burned group vs. PL pro
nanocurcumin-treated group, p=0.003). The burned area
of liposomal nanocurcumin-treated rats significantly
decreased compared with the PL pro nanocurcumintreated rats (p=0.006).
After 21 days of treatment, the burn lesions of vehicletreated rats were not completely healed. The rate of burn
wound healing in the silver sulfadiazine- and liposomal
nanocurcumin-treated groups was 50%, with a statistically
significant difference compared to the vehicle-treated
group (p=0,033; Fisher’s exact test). PL pro nanocurcumin-treated rats had a wound healing rate of 20%.
There was no markedly significant difference in the rate of
wound healing between the vehicle-treated group and the
PL pro nanocurcumin-treated group (p>0.05).
3.2.2. Effect on Hydroxyproline Content
As shown in Fig. (3), the content of hydroxyproline in
the rat skin sample of the vehicle-treated group was
significantly lower than the normal control group
(p<0.001). Compared with the vehicle-treated model
group, treatment of silver sulfadiazine, liposomal
nanocurcumin, and PL pro nanocurcumin was found to
increase the level of hydroxyproline in the skin tissue
(vehicle-treated burned group vs. silver sulfadiazinetreated burned group, p=0.002; vehicle-treated burned
group vs. liposomal nanocurcumin-treated group,
p<0.001; vehicle-treated burned group vs. PL pro
nanocurcumin-treated group, p<0.001).

3.2.3. Histopathological Examination

cells between liposomal nanocurcumin and PL pro
nanocurcumin-treated groups and normal control group

The skin biopsy of the normal control rats
demonstrated the proper and well-structured stratum
epidermis with keratinization, clear basal lamina, skin
dependent components in the dermis layer, loose
connective tissue, and small blood vessels. Thus, in the
normal control group, the skin structure of rats was found
to be normal. In the vehicle-treated group, the rat skin
tissue showed a large ulcerated area whilst the surface
was covered with the necrotic substance erythrocyte
fibrin, various inflammatory cells, neutrophils, and
macrophages. On the 21st day, burn healing was better in
silver sulfadiazine, liposomal nanocurcumin, and PL pro
nanocurcumin-treated groups than in the vehicle-treated
group (Fig. 4A-B).

(p>0.05).
3.3.2. Effect on Liver Damage, Liver Function, and
Kidney Function
Fig. (5A1-2 and 5B) demonstrate that liposomal
nanocurcumin and PL pro nanocurcumin did not cause any
statistical difference in AST, ALT levels, and creatinine
levels when comparing the treated groups to the normal
control group (p>0.05). The effect of liposomal
nanocurcumin and PL pro nanocurcumin on the total
bilirubin, albumin, and total cholesterol of the normal
control group and treated groups are presented in Table
2. No statistical difference was observed between groups
(p>0.05). In addition, there were no significant differences
in histopathological examinations of livers and kidneys

3.3. Evaluation of Systemic Toxicity of Topical
Administration of Liposomal Nanocurcumin and PL

Pro Nanocurcumin Creams in Burned Rats
During the experimental period, there was an increase
in body weight in each group of animals. No significant
differences were found as compared to that of the control
group. None of the animals in all treated groups showed
any macroscopic or gross pathological changes when
compared to the control group. No gross lesions or
changes in size were observed when evaluating all
experimental rats to a full gross necropsy, which examined
the hearts, livers, lungs, kidneys, and abdominal cavities.

(Fig. S2A).
3.4. Healing Effects of Liposomal Nanocurcumin and
PL Pro Nanocurcumin on Doxorubicin-induced Skin
Ulcer in Mice
3.4.1. Effect on Ulcerated Area
As shown in Fig. (6), no difference in the areas of skin
ulcers was found between groups (p>0.05) for the time
before treatment. After 7 and 21 days of administration,
DMSO, liposomal nanocurcumin, and PL pro
nanocurcumin significantly reduced the ulcer size

3.3.1. Effect on Hematopoietic Function
As mentioned in Table 1, there were no significant
differences in red blood cell count, hematocrit,
hemoglobin level, platelet count, and total white blood

compared to the vehicle-treated group (p<0.01).
Additionally, there were no statistical differences in terms
of reducing the skin lesions’ area between liposomal
nanocurcumin and PL pro nanocurcumin (p>0.05).

between liposomal nanocurcumin and PL pro
nanocurcumin-treated rats and the normal control group

Table 1. Effect of liposomal nanocurcumin and PL pro nanocurcumin on hematopoietic function in burned rats.

After 21 days of administration, the rate of wound
healing in vehicle-treated mice was 10%. The rate of wound
healing in the silver sulfadiazine- and the liposomal
nanocurcumin-treated group was 70% and 80%,
respectively (p=0.02 and p=0.005 compared to the vehicletreated group; Fisher’s Exact test). PL pro nanocurcumintreated mice had a wound healing rate of 60%. There was
no noticeably significant difference in the rate of wound
healing between the vehicle-treated group and the PL pro
nanocurcumin-treated group (p=0.057).

3.4.2. Effect on Hydroxyproline Content
The hydroxyproline content is presented in Fig. (7). The
hydroxyproline level in skin tissues of the vehicle-treated
group was significantly lower than the normal control group
(p<0.001). Compared with the vehicle-treated model group,
treatment of DMSO, liposomal nanocurcumin, and PL Pro
nanocurcumin significantly increased the hydroxyproline
content in the skin tissue. In addition, there were no
significant differences in the effects of liposomal
nanocurcumin and PL pro nanocurcumin on the
concentration of hydroxyproline in skin tissues (p>0.05).

3.4.3. Histopathological Examination
The skin biopsy of the normal control mice was normal,
with the proper stratum epidermis with keratinization,
clear basal lamina, skin-dependent components in the
dermis layer, loose connective tissue, and small blood
vessels. In the vehicle-treated ulcerated mice, the skin
tissue showed a large necrosis area, and the surface was
covered with necrotic substances, erythrocytes, fibrin,
many inflammatory cells, neutrophils, and macrophages.
On the 21st day, DMSO, liposomal nanocurcumin, and PL
pro nanocurcumin improved the histopathological
structure of skin tissues, which demonstrated the slight
growth of dermal papillae and epidermal ridges.
3.5. Evaluation of Systemic Toxicity of Topical
Administration of Liposomal Nanocurcumin and PL
Pro Nanocurcumin in Ulcerated Mice
During the experimental period, there was an increase
in body weight in each group of animals. No significant
differences were seen as compared to that of the control
group. None of the animals in all treated groups showed
any macroscopic or gross pathological changes when
compared to the control group. No gross lesions or changes
in size were observed when evaluating all experimental rats
to a full gross necropsy, which examined the hearts, livers,
lungs, kidneys, and abdominal cavities.
3.5.1. Effect on Hematopoietic Function
As mentioned in Table 3, there were no significant
differences in red blood cell count, hematocrit, hemoglobin
level, total white blood cell, and platelet count between
liposomal nanocurcumin and PL pro nanocurcumin-treated
groups and normal control group (p>0.05).
3.5.2. Effect on Liver Damage, Liver Function, and
Kidney Function
Fig. (8) demonstrates that liposomal nanocurcumin and
PL pro nanocurcumin did not cause any statistical
difference in AST, ALT level, and creatinine levels when
comparing the treated groups to the normal control group
(p>0.05). The effects of liposomal nanocurcumin and PL pro
nanocurcumin on the total bilirubin, albumin, and total
cholesterol of the normal control group and treated groups
are presented in Table 4. No statistical difference was
observed between groups (p>0.05).
Additionally, there were no significant differences in
histopathological examinations of livers and kidneys
between liposomal nanocurcumin and PL pro nanocurcumin-treated ulcerated and normal control mice (Fig.
S2B).

4. DISCUSSION
In this study, we not only evaluated the effect of
topical administration of liposomal nanocurcumin and PL
pro nanocurcumin on two different models of skin lesions,
which were induced, respectively, by heat and doxorubicin
but also detected any systemic toxicity of liposomal and PL
pro nanocurcumin via the ulcers in the experimental
animals. Our results showed that liposomal nanocurcumin
and PL pro nanocurcumin significantly reduced the size of
the wounded area, increased the hydroxyproline level in

skin tissues, and improved the histopathological structure
of skin tissues. Liposomal nanocurcumin showed better
effects than PL pro nanocurcumin on thermal burns in
rats. Additionally, topical administration of liposomal
nanocurcumin and PL pro nanocurcumin did not cause
systemic toxicity. Thus, liposomal nanocurcumin and PL
pro nanocurcumin have been shown to accelerate the
wound healing process without systemic toxicity in
experimental rat models.

Thermal burn injuries and skin ulcers are still
considered major health problems, resulting in physical
and psychological scars and disabilities [30]. Depending
on the lesion severity, wound healing is one of the most
complex processes, which involves several phases of
coagulation, inflammation, growth, re-epithelialization,
and remodeling [43, 44]. Research on burns has generated
sustained interest over the past few decades. However,
drugs for treating burns and skin ulcers are still limited
[36]. For the treatment of burns, silver sulfadiazine is
considered the gold standard in the topical treatment of
second-degree burns because of its antibacterial
properties. However, silver sulfadiazine is associated with
toxicity to keratinocytes and fibroblasts. So, this drug
delays the wound healing process and has some serious
cytotoxic effects on the host cells. Moreover, several
bacteria are resistant to silver sulfadiazine [36].
Additionally, for the treatment of skin ulcers, dimethyl

sulfoxide (DMSO) is a perennially proposed remedy since
it can easily infiltrate into the affected area and scavenge
free radicals [39]. However, currently, the pharmaceutical
form of DMSO is limited. Moreover, the accessibility of
DMSO in particular and other effective agents for skin
ulcers is still restricted. Considering this, there is an
emerging demand for a safer and more effective approach
to be applied in the treatment of wounds.
Curcumin possesses a powerful wound-healing effect
for the treatment of various skin disorders and damages
[5, 45-47]. In particular, curcumin attenuates the
inflammatory response and hastens wound healing by
increasing cellular proliferation and improving collagen
deposition in the wound tissues, as well as promoting
angiogenesis in chronic wounds [48-50]. Thus, curcumin
reinforces the healing of the affected tissue with different
levels of severity. Effect on inflammation, fibroblast
proliferation, granulation tissue formation, and collagen
deposition are mentioned mechanisms of the healing
potential of curcumin [51-53]. However, curcumin exhibits
several limitations in wound healing treatment, including
poor water solubility and physicochemical instability [21].
As a solution, nanoformulations should be applied in order
to deliver substance to the targets more accurately [20].
Specifically, liposomes with nano-sized phospholipid
bilayered vesicles were utilized for transport with a variety
of drugs, including wound healing agents. These are not
difficult to prepare and are highly biocompatible in nature.
This approach of nanoformulation has shown promising
results in the improvement of aqueous solubility of
curcumin and the development of a sustained and
prolonged drug-release system, thus enhancing wound
healing and closure [54]. In the present study, thermal
burn wounds in rats and doxorubicin-induced skin ulcers
in mice were used to evaluate the healing effect of topical
administration of liposomal nanocurcumin and PL pro
nanocurcumin. Liposomal nanocurcumin and PL pro
nanocurcumin significantly reduced the size of the
wounded area, increased the hydroxyproline content in
skin tissues, and improved the histopathological structure
of skin tissues. In addition to assessing the criteria for the
damaged area of skin ulcer, we also evaluated the
hydroxyproline level. According to the literature, collagen
plays a pivotal role in wound healing. Hydroxyproline is a
major component of the protein collagen, as it is a
principal component of connective tissues produced by
fibroblasts. It assists the wound in gaining tensile strength
during wound repair, hence serving as a structural
framework, strength, and milieu for the regenerating
tissue [55-68]. We determined collagen synthesis
indirectly by hydroxyproline level. Our results indicated
that liposomal nanocurcumin and PL pro nanocurcumin
increased the level of hydroxyproline in the skin tissue.
In this study, doxorubicin, a chemotherapeutic drug
belonging to the anthracyline group, was used as a skin
ulcerative agent. It is one of the most important drugs
causing skin necrosis and, ultimately, severe ulceration,
with the incidence of extravasation injury being 0.1% to
6.5% [41, 59, 60]. This agent could affect the replication

and translation process, as well as activate the gene that
is responsible for cellular apoptosis. Eventually, the ulcer
caused by doxorubicin injection was broad and deep,
indicating that the ulceration model triggered by
doxorubicin was adequately reliable in gauging the
efficiency of liposomal nanocurcumin and PL pro
nanocurcumin [61]. According to our previous study, the
development of skin necrosis reached its maximum size in
one week [62]. In order to alleviate the triggered skin
lesion, the newly formed radicals in the cytosol and
interstitial space should be eliminated by potent
antioxidants for clinical practice. Therefore, DMSO was
used as a positive control in this study. Our results
indicated that liposomal nanocurcumin and PL pro
nanocurcumin significantly reduced ulcer size. However,
there were no significant differences in the healing effect
between liposomal nanocurcumin and PL pro
nanocurcumin-treated groups. In addition, burns can be
defined as tissue lesions resulting from exposure to
thermal sources, such as flames, hot surfaces and liquids,
extreme cold, chemicals, radiation, or friction [32]. In this
study, the model of superficial second-degree burns on
rats was successfully induced. Interestingly, liposomal
nanocurcumin showed better effects than PL pro
nanocurcumin on thermal burns in rats. In addition,
liposomal nanocurcumin significantly reduced infection,
compared to the vehicle-treated group, by improving the
macroscopic and histopathological structure. Furthermore, it did not affect the number of white blood cells
when compared to the normal control group. These effects
underscore the efficacy of liposomal nanocurcumin in burn
treatment. Thus, liposomal nanocurcumin is a more potent
wound-healing agent.
We also evaluated the systemic toxicity after the
application of topical liposomal nanocurcumin and PL pro
nanocurcumin on thermal burns in rats and skin ulcers in
mice. Long-term topical application can also affect the
systemic effects, especially when applied to open wounds
[63]. Overall, the findings of this study indicated that
topical administration of liposomal nanocurcumin and PL
pro nanocurcumin caused no significant change in the
general status, haematological parameters, and renal and
hepatic functions. Additionally, they did not alter the
histology of the liver and kidneys in animals. In oral
administration, curcumin did not exert acute, subchronic,
chronic toxicity, or reproductive toxicity in animals [11,
12, 64]. To date, there have been no studies evaluating the
systemic toxicity of nanocurcumin in open wounds. Our
results indicated that liposomal nanocurcumin and PL pro
nanocurcumin did not cause systemic toxicity in burned
rats and ulcerated mice. Hence, these studies suggest the
beneficial effects of liposomal nanocurcumin and PL pro
nanocurcumin and the potential of these formulations to
be developed as a potent nontoxic agents for treating skin
disorders. Overall, liposomal nanocurcumin and PL pro
nanocurcumin are valuable in the near future for wound
healing, but additional studies are required to provide
scientists with a deeper understanding.
CONCLUSION
The current study demonstrated that the topical
application of liposomal nanocurcumin and PL pro
nanocurcumin creams exerted healing effects on burned
skin in rats and doxorubicin-induced skin ulcers in mice.
Furthermore, liposomal nanocurcumin and PL pro
nanocurcumin did not cause systemic toxicity in the
experimental model. Liposomal nanocurcumin showed
better effects than PL pro nanocurcumin on thermal burns
in rats.
AUTHORS’ CONTRIBUTIONS
It is hereby acknowledged that all authors have
accepted responsibility for the manuscript’s content and
consented to itssubmission. They have meticulously
reviewed all results and unanimously approved the final
version of the manuscript.
LIST OF ABBREVIATIONS

DMSO	= Dimethyl Sulfoxide
AST ALT	= Aspartate Aminotransferase = Alanine Aminotransferase
ETHICS	APPROVAL	AND	CONSENT	TO

PARTICIPATE
This study was approved by the Scientific Board
Committee of Hanoi Medical University, Vietnam (ref
number: IRB00003121).
HUMAN AND ANIMAL RIGHTS
All experimental protocols were in accordance with the
National Guidelines (reference number: 141/QD-K2DT).
This study adhered to internationally accepted standards
for animal research, following the 3Rs principle. The
ARRIVE guidelines were employed to report experiments
involving live animals and promote ethical research
practices.
CONSENT FOR PUBLICATION
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
The data supporting the findings of the article is
available in the Zenodo Repository at https://zenodo.org/
records/11228442.
FUNDING
None.
CONFLICT OF INTEREST
The authors declared no conflict of interest, financial
or otherwise.
ACKNOWLEDGEMENTS
Declared none.
SUPPLEMENTARY MATERIALS
Supplementary material is available on the Publisher’s
website.

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Curcumin as a Potential Treatment for COVID-19

quản trị viên — Thu, 12 Aug 2021 04:23:48 +0000

Article source: https://www.frontiersin.org/articles/10.3389/fphar.2021.675287/full?fbc…YhrM5sW8

Coronavirus disease 2019 (COVID-19) is an infectious disease that rapidly spread throughout the world leading to high mortality rates. Despite the knowledge of previous diseases caused by viruses of the same family, such as MERS and SARS-CoV, management and treatment of patients with COVID-19 is a challenge. One of the best strategies around the world to help combat the COVID-19 has been directed to drug repositioning; however, these drugs are not specific to this new virus. Additionally, the pathophysiology of COVID-19 is highly heterogeneous, and the way of SARS-CoV-2 modulates the different systems in the host remains unidentified, despite recent discoveries. This complex and multifactorial response requires a comprehensive therapeutic approach, enabling the integration and refinement of therapeutic responses of a given single compound that has several action potentials. In this context, natural compounds, such as Curcumin, have shown beneficial effects on the progression of inflammatory diseases due to its numerous action mechanisms: antiviral, anti-inflammatory, anticoagulant, antiplatelet, and cytoprotective. These and many other effects of curcumin make it a promising target in the adjuvant treatment of COVID-19. Hence, the purpose of this review is to specifically point out how curcumin could interfere at different times/points during the infection caused by SARS-CoV-2, providing a substantial contribution of curcumin as a new adjuvant therapy for the treatment of COVID-19.

Introduction

Coronavirus disease 19 (COVID-19/2019-nCoV) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestation of COVID-19 range from asymptomatic upper respiratory tract infection to critical illness and pneumonia associated with acute respiratory distress syndrome (ARDS) (Guan et al., 2020). The main risk factors associated with greater severity and mortality caused by COVID-19 include hypertension, diabetes mellitus, cardiovascular disease (CVD), advanced age, and obesity (Simonnet et al., 2020; Wu and McGoogan, 2020; Zhou et al., 2020).

SARS-CoV-2 is an enveloped β-coronavirus composed of four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins (Chen et al., 2020). Entry of the virus into the host cell occurs through the cleavage of protein S into two subunits (S1 and S2) where SARS-CoV-2 develops a multibasic site at the S1-S2 boundary, which is cleaved by furin to form protein S for processing by TMPRSS2 (Hoffmann et al., 2020). The amino-terminal S1 subunit contains a receptor-binding domain (RBD) that is responsible for binding to the cell surface receptor, angiotensin-converting enzyme 2 (ACE2) (Wrapp et al., 2020; Xia et al., 2020). The membrane-anchored S2 subunit is composed of the fusion peptide (FP), heptapeptide repeat sequences 1 and 2 (HR1/HR2), transmembrane domain (TM), and cytoplasmic domain. These components are responsible for viral fusion and cell invasion (Huang Y. et al., 2020; Xia et al., 2020). After the RBD domain is attached to ACE2, the S2 subunit changes its conformation and moves closer to the viral envelope and cell membrane for viral fusion and entry (Huang Y. et al., 2020). In the host, ACE2 is widely expressed in the lungs, heart, liver, vascular endothelium, kidneys, and gut. It is an important regulator of the renin-angiotensin-aldosterone system (RAAS), and promotes the conversion of angiotensin I (Ang I) to Ang (1–9) and Ang II to Ang (1–7) (D’ardes et al., 2020; Gheblawi et al., 2020). Ang (1–7) has an important physiological role and promotes vasodilation, including anti-hypertrophic, anti-inflammatory, anti-oxidant, anti-thrombotic, and anti-fibrotic effects (Imai et al., 2005; Kuba et al., 2005; Chung et al., 2020; D’ardes et al., 2020). The conversion of Ang II to Ang (1–7) regulates the concentration of Ang II-mediated by ACE2. When available, Ang II binds to the ATR1 receptor, thereby promoting harmful pro-inflammatory effects, such as hypertrophy, oxidative stress, and vasoconstriction (Imai et al., 2005; Kuba et al., 2005; Chung et al., 2020; D’ardes et al., 2020). Therefore, the negative regulation of ACE2, promoted by the binding of SARS-CoV-2, results in increased levels of Ang II (Imai et al., 2005; Kuba et al., 2005; D’ardes et al., 2020).

The current drugs approved by the Food and Drug Administration (FDA) for the treatment of patients with COVID-19 prior to the writing of this manuscript are: Fresenius Medical, multiFiltrate PRO System and multiBic/multiPlus Solutions (Fresenius Medical Care); Fresenius Kabi Propoven 2% (Fresenius Kabi USA, LLC.); REGIOCIT replacement solution that contains citrate for regional citrate anticoagulation (RCA) of the extracorporeal circuit (Baxter Healthcare Corporation); COVID-19 convalescent plasma (Office of the Assistant Secretary for Preparedness and Response US Department of Health and Human Services); remdesivir (Veklury) (Gilead Sciences, Inc.); bamlanivimab (Eli Lilly and Company); baricitinib (Olumiant) in combination with remdesivir (Veklury) (Eli Lilly and Company); REGEN-COV (casirivimab and imdevimab) (Regeneron Pharmaceuticals); bamlanivimab and etesevimab (Eli Lilly and Company); and Propofol-Lipuro 1% (B. Braun Melsungen AG), as obtained from the regulators database (https://www.fda.gov/).

Drug repurposing has been viewed as a promising strategy for combating COVID-19. Several factors, such as molecular recognition, binding affinity, and interactions, are calculated during computational drug design and development. Virtual screening was performed with approximately 3,410 drugs approved by the FDA. However, remdesivir was yet to be approved at the time, but has since been analyzed (Beck et al., 2020). The aforementioned and other studies suggested that remdesivir is a potential antiviral agent against SARS-CoV-2, following the demonstration of its affinity to target sites of the virus, including RNA-dependent RNA polymerase (RdRP), helicase, 3-to -5 exonuclease, 2-O-ribose methyltransferase, and endoRNAse from SARS-CoV-2 and SARS-CoV-2 main protease (Mpro, also called 3CLpro) (Beck et al., 2020; Elfiky, 2020). Following this methodology, curcumin displayed promising results, making it a strong candidate for in vitro and in vivo studies against SARS-CoV-2.

Natural compounds based on medicinal plants and traditional Chinese medicine (TCM) formulas with antiviral action against coronavirus have been investigated. These compounds presented several targets against SARS-Cov and Middle East Respiratory Syndrome (MERS), such as (1) spike (S) glycoprotein, (2) papain-like protease (PLpro), and (3) nucleocapsid (N) proteins. Among these compounds, including the specific viral targets, are ginsenoside-Rb1 (1), hirsutenone (2), tanshinones I–VII (2), with anti-SARS-CoV action, and resveratrol (3) with anti-MERS activity (Wu et al., 2004; Park et al., 2012; Park et al., 2012; Lin et al., 2017). Numerous therapeutic effects of the natural polyphenol, curcumin, have been reported, including potential chemotherapeutic, antioxidant, antiviral, antibacterial, and anti-inflammatory properties (Paciello et al., 2020). Clinical studies have demonstrated the effects of nanoencapsulated curcumin in patients with COVID-19. In the aforementioned study, a significant reduction in clinical manifestations of COVID-19 (fever, cough, and dyspnea) was observed in the group treated with nanocurcumin (patients with mild and severe disease) (Tahmasebi et al., 2020; Valizadeh et al., 2020). In addition, nanocurcumin reduced the mortality rate of these patients. However, the mortality rate of the placebo group was significantly higher than that of the two groups (patients with light and severe disease) treated with nanocurcumin (Tahmasebi et al., 2020; Valizadeh et al., 2020). Currently, another study involving patients with COVID-19 treated with nanoencapsulated curcumin is ongoing (Hassaniazad et al., 2020). Therefore, this manuscript provides a review of the biological effects of curcumin in diseases that arise following SARS-CoV-2 infection.

In Silico Models Predicting the Antiviral Effects of Curcumin Against SARS-CoV-2

The antiviral effects of curcumin have been widely explored, and the viruses to which curcumin has antiviral action are shown in Figure 1. Curcumin prevents the binding of the influenza A virus (IAV) (Chen et al., 2010; Ou et al., 2013), dengue virus (Balasubramanian et al., 2019), zika virus, and chikungunya virus (Mounce et al., 2017) to host cells. Curcumin inhibits the entry of the hepatitis C virus (HCV) (Chen et al., 2012; Anggakusuma et al., 2014), human norovirus (HuNoV) (Yang et al., 2016), viral hemorrhagic septicemia virus in fish (VHSV) (Jeong et al., 2015), and bovine herpesvirus 1 (BHV-1) (ZHU et al., 2015). Furthermore, the curcumin hinders viral genome replication and transcription of the respiratory syncytial virus (RSV) (Obata et al., 2013; Yang et al., 2016) and Japanese encephalitis virus (JEV) (Dutta et al., 2009), and interferes with the translation and assembly of the Epstein-Barr virus (EBV) (Hergenhahn et al., 2002), human cytomegalovirus (HCMV) (Lv et al., 2014a; Lv et al., 2014b), and human immunodeficiency virus (HIV) (Gupta et al., 2011; Ali and Banerjea, 2016). In vitro analyses revealed the antiviral action of curcumin against the SARS-CoV virus in Vero-E6 cells; this natural polyphenol could inhibit viral replication at concentrations of 3–10 µM (Wen et al., 2007). Based on such data regarding antiviral activity, researchers using in silico prediction models evaluated the potential of curcumin against the binding proteins of SARS-CoV-2 and its cellular receptors.FIGURE 1

FIGURE 1. Antiviral effects of curcumin. Curcumin prevents cell infection and viral replication in the SARS-CoV, influenza A virus (IAV), zika virus, chikungunya virus, hepatitis C virus (HCV), human norovirus (HuNoV), viral hemorrhagic septicemia virus in fish (VHSV), bovine herpesvirus 1 (BHV-1), respiratory syncytial virus (RSV), Japanese encephalitis virus (JEV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and human immunodeficiency virus (HIV).

The SARS-CoV-2 S glycoprotein is responsible for the interaction between the virus and the host cell, promoting fusion and internalization of the virus via the ACE2 receptor. Thus, both the S glycoprotein and ACE2 are potential targets for the treatment of COVID-19. In silico analysis showed that curcumin has a high-affinity for interaction with the S glycoprotein through the establishment of six hydrogen bonds (Maurya et al., 2020). In this study, curcumin obtained higher scores than the control compounds, such as nafamostat and hydroxychloroquine (Maurya et al., 2020). In addition, curcumin displayed an affinity for ACE2. Moreover, docking results showed that curcumin interacted with the active site of the protein, in addition to forming two hydrogen bonds (Maurya et al., 2020). Similarly, curcumin demonstrated a better affinity for ACE2 than the control compounds, such as captopril and hydroxychloroquine (Maurya et al., 2020).

The transmembrane protein serine protease 2 (TMPRSS2) facilitates the entry of SARS-CoV-2 from the spike protein (Hoffmann et al., 2020). In silico analyses focusing on TMPRSS2 showed that curcumin forms four hydrophobic interactions and an H-bond with TMPRSS2 (Motohashi et al., 2020). These findings corroborated results of in vitro studies where curcumin treatment led to the downregulation of TMPRSS2 in prostate cancer cells (Zhang et al., 2007; Thangapazham et al., 2008).

The main protease (Mpro) of SARS-CoV-2 is indispensable in maturation and viral replication, and is a promising target in the treatment of SARS-CoV-2. The proteins that are matured by Mpro include RNA-dependent RNA polymerase (RdRp, Nsp12) and helicase (Nsp13), which depend on the cleavage of Mpro (Rut et al., 2020). Inhibition of Mpro prevents viral replication; thus, compounds with inhibitory effects on Mpro have become attractive targets for the treatment of COVID-19 (Zhang S. et al., 2020; Anand et al., 2003). To identify compounds with potential binding to Mpro, an in-silico study using docking was carried out to evaluate a series of compounds, including the drugs currently used in the treatment of COVID-19. In this study, two compounds with a high affinity for Mpro were used as controls: N3 and O6K (HUYNH; WANG; LUAN, 2020). Among the compounds tested, including chloroquine, entecavir, hydroxychloroquine, and remdesivir, curcumin surprisingly formed the most stable complex with SARS-CoV-2 Mpro, and the affinity score was comparable to that of the N3 control (Huynh et al., 2020).

The entry of SARS-CoV-2 through the endosome requires an endosomal environment with an acidic pH that is promoted by the endosomal proteases, cathepsin B and L, and ion channels, particularly the vacuolar ATPase pump (V-ATPase), which is crucial in regulating endosomal pH (Aslam and Ladilov, 2020; Khan et al., 2020). Curcumin has been shown to be a potential pH controlling agent, decreasing the expression of V-ATPase, which causes an increase in pH in tumor cells (Vishvakarma et al., 2011).

In vitro results of the antiviral action of curcumin on SARS-CoV and the data from in silico analyses reinforce the hypothesis of the potential activity against SARS-CoV-2. Thus, this review aims to encourage evaluation of the effect of curcumin on cells infected by SARS-CoV-2 and the replication of the virus using in vitro and in vivo models, and in randomized clinical trials. The possible interaction sites of curcumin with SARS-CoV-2 in the host cells are shown in Figure 2.FIGURE 2

FIGURE 2. Potential curcumin targets as antiviral and anti-inflammatory in SARS-CoV-2 infection. The first antiviral effect of curcumin against SARS-CoV-2 is its potential for preventing the binding of viral S protein to the ACE2 receptor and initiate the host cell infection process (1). After penetrating the host cell via endosomes, the virus begins the replication process that requires an acid endosomal environment to initiate the proteolytic process of viral proteins and subsequent release to the external environment. Curcumin acts by inhibiting the Endosomal acidification (2) and processing of the viral proteins (Mpro), necessary for viral release (3,4). Further, the inhibition of ACE mediated by curcumin (5) prevents the increase of Ang II levels. Curcumin inhibits NF-κB (6) through the inhibition of different pathways. The binding of PAMPs, DAMPs, and cytokines that leads to IkB phosphorylation and proteasomal degradation is one of those pathways that cause NF-κB activation. Curcumin prevents both IkB phosphorylation and p65 subunit from the NF-κB (8), which consequently prevents NF-κB activation. The activation of ADAM17 by the AngII-ATR1 axis promotes the interaction between EGF and EGFR receptor, which promotes the activation of the PI3K/AKT/mTOR axis resulting in NF-κB activation. Curcumin acts as a potential inhibitor for mTOR (9), preventing the NF-κB pathway activation. ADAM17-mediated signaling also triggers the release of soluble interleukin 6-receptor, forming a complex with IL-6 (sIL-6R-IL-6) that binds to glycoprotein gp130. This complex binding (sIL-6R-IL-6+gp130) activates the signal transduction pathways responsible to induce the activators of transcription 3 (STAT3). Activation of STAT3 results in activation of NF-κB, which can be prevented by the curcumin (10). The NF-κB activation induces a protein complex formation, knowns as inflammasome, which can lead to cell death through pyroptosis, a pathway to cell death mediated by the activation of caspase-1. However, curcumin can cause the inhibition of inflammasome formation (11) by the inhibition of NF-κB. Abbreviations: TMPRSS2, transmembrane protease, serine 2; ACE1, angiotensin-converting enzyme 1; ACE2, angiotensin-converting enzyme 2; Mpro, main protease; PAMPs, pathogen-associated molecular pattern; DAMPs, damage-associated molecular patterns; ANG I, angiotensin I; Ang II, angiotensin II; ATR1, angiotensin II (AII) receptor 1; ADAM17, a disintegrin and metalloproteinase 17; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; IL-6R, interleukin 6 receptor; sIL-6R, soluble Interleukin 6 receptor; gp130, glycoprotein 130; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; STAT3, signal transducers and activators of transcription; NF-κB, factor nuclear kappa B.

Effects of Curcumin in the COVID-19-Induced Inflammatory Process

The inflammatory process of COVID-19 is complex and multifactorial. Patients with the severe form of the disease can be affected by a hyperinflammatory condition called a cytokine storm, highlighting the need for anti-inflammatory treatment to alleviate the hyperactivation of the immune response, which induces this cytokine storm. Focusing on the anti-inflammatory action of curcumin, two studies were conducted with patients with COVID-19. In the first study, the research group investigated the modulation of pro-inflammatory cytokines by nanocurcumin. Patients with COVID-19 showed high mRNA expression and secretion of cytokines, IL-1β, IL-6, TNF-α, and IL-18, but showed a significant reduction in IL-6 and IL-1β after treatment with nanocurcumin (Valizadeh et al., 2020). Subsequently, exploring the modulatory mechanisms of nanocurcumin, the researchers demonstrated that the number of Th17 cells, gene expression, and serum Th17-mediated factors level (IL-17, IL-21, IL-23, and GM-CSF) were significantly reduced in both stages of the disease in the group of patients with COVID-19 treated with nanocurcumin (Tahmasebi et al., 2020).

Despite the rapid scientific progress regarding the pathophysiology of COVID-19, the precise mechanisms that trigger the exacerbated inflammatory response observed in some of the patients have not yet been completely elucidated. However, several hypotheses attempt to explain such changes. The nuclear factor-kappa B (NF-κB) pathway is directly involved in this inflammatory process and can stimulate the production of pro-inflammatory cytokines when activated. Recent findings led to concerns regarding the overstimulation of the NF-κB pathway and its potential contribution to the emergence of cytokine storms. Studies have shown that NF-κB can be activated directly by SARS-CoV-2 from Toll-like receptors (TLRs) and RAAS system components (Mahmudpour et al., 2020). In such situations, the SARS-CoV envelope (E) and nucleocapsid (N) proteins were shown to be directly related to NF-κB activation (Liao et al., 2005; DeDiego et al., 2014). Consequently, when this protein was deleted in a genetically modified virus, a reduction in NF-κB activation was observed (DeDiego et al., 2014).

Activation of the AngII-AT1R axis causes NF-κB activation (Crowley and Rudemiller, 2017). The AngII-AT1R axis is directly involved in the pro-inflammatory response by acting on the main pathways that lead to the release of cytokines and chemokines. The increase in AngII stimulates the phosphorylation of the NF-κB p65 subunit, leading to its activation and the subsequent release of cytokines (IL-6, IL-1ß, IL-10, and TNF-α) (Ruiz-Ortega et al., 2001; Skurk et al., 2004). The AngII-AT1R axis activates disintegrin and metalloprotease 17 (ADAM17), processing the membrane form of IL-6Rα to its soluble form (sIL-6Rα) through epidermal growth factor (EGFR). The sIL-6Rα-IL-6 complex leads to gp130-mediated STAT3 activation (Eguchi et al., 2018; Murakami et al., 2019), with STAT3 being essential for the complete activation of the NF-κB pathway, in conjunction with the main pathway stimulator, IL-6 (Murakami et al., 2019). The cytokines, TNF and IL-1, also trigger signals that cause the translocation of NF-κB to the nucleus by activating genes involved in the production of inflammatory mediators (Crowley & Rudemiller, 2017). Curcumin blocks STAT3-mediated NF-κB activation, and the consequent reduction in pro-inflammatory cytokines disrupts the positive feedback between pro-inflammatory cytokines and NF-κB (Alexandrow et al., 2012; Rahardjo et al., 2014; Ma et al., 2015; Yadav et al., 2015).

NF-κB is inactive in the cell cytoplasm because of its association with the IκB protein complex. In the presence of stimuli (PAMPs, DAMPs, and cytokines), IκB undergoes phosphorylation and proteasomal degradation that dissociates the NF-κB complex, allowing NF-κB to translocate into the nucleus, leading to the expression of chemokines and pro-inflammatory cytokines (Solt and May, 2008). Curcumin acts by inhibiting the phosphorylation of IκB through inhibiting translocation and the consequent activation of NF-κB (Karunaweera et al., 2015; Wang et al., 2018; Cheemanapalli et al., 2019). Owing to NF-κB inhibition, there is a reduction in the production of inflammatory cytokines, such as IL-1α, IL-6, and TNF-α (Rahardjo et al., 2014; Ma et al., 2015; Yadav et al., 2015).

Viral infections commonly activate inflammasomes. SARS-CoV has been shown to express at least three proteins that activate the NLRP3-type inflammasome (NOD-, LRR-, and pyrin domain-containing protein 3): envelope protein (E), Open Reading Frame-3a (ORF3a), and Open Reading Frame-8b (ORF8b) (Nieto-Torres et al., 2015; Chen et al., 2019; Shi et al., 2019). Protein E and ORF3a stimulate NF-κB signaling, thereby promoting the release of pro-inflammatory cytokines, such as IL-1β, IL-8, and IL-18, and priminf NLRP3 expression to reach the functional level (Kanzawa et al., 2006; DeDiego et al., 2014; Siu et al., 2019). The amino acid sequence of protein E is 94.7% conserved in SARS-CoV and SARS-CoV-2, indicating the possibility of inflammasome activation in patients with COVID-19 (Chan et al., 2020; Lu et al., 2020). A recent study demonstrated that active caspase-1 (Casp1p20), IL-1β, IL-18, IL-6, and lactate dehydrogenase (LDH) were increased in the serum of patients with COVID-19, and that Casp1p20 and IL-18 are products derived from inflammasomes (Rodrigues et al., 2021). The researchers also found active inflammasome NLRP3 in peripheral blood mononuclear cells (PBMCs) and in the tissues of deceased patients at autopsy. The levels of IL-18 and Casp1p20 were higher in patients who had severe disease, indicating a worse prognosis (Rodrigues et al., 2021). Therefore, the regulation of NF-κB by curcumin inhibits the formation of inflammasomes, specifically NLRP3, decreasing the secretion of IL-1β and IL-18 (Yin et al., 2018).

Another regulator of NF-κB is the mammalian target of rapamycin (mTOR) pathway. mTOR is comprised of two complexes, mTORC1, which is sensitive to rapamycin inhibition through the Raptor protein that is associated with mTORC1, and mTORC2, which is associated with Rictor protein, and has low sensitivity to rapamycin (Saxton and Sabatini, 2017). In lipopolysaccharide sepsis models, the inhibition of mTOR by rapamycin resulted in decreased phosphorylation of the p65 subunit of NF-κB, with a consequent reduction in cytokines and pro-inflammatory chemokines, such as IL-1β, IL-18, IL-6, TNF-α, MCP-1, and led to the reduced expression of the NLRP3 inflammasome (Temiz-Resitoglu et al., 2017; Jia et al., 2019). Although rapamycin is already used as an immunosuppressant in the treatment of transplant patients, it has numerous adverse effects and is associated with a high cost. Curcumin is a potential target inhibitor of the mTOR pathway and can promote the inhibition of both the mTORC1 and mTORC2 complexes (Beevers et al., 2009). Curcumin at low doses was found to suppress the mTORC1-Raptor interaction, leading to inhibition of the mTORC1 complex. Curcumin also promoted interruption of the mTORC2-Rictor interaction at higher doses, thereby inhibiting mTORC2 (Beevers et al., 2006; Beevers et al., 2009; Johnson et al., 2009).

The anti-inflammatory mechanisms of curcumin have been extensively investigated in clinical studies of several inflammatory diseases, such as Crohn’s disease, ulcerative proctitis, ulcerative colitis, irritable bowel syndrome, rheumatoid arthritis, postoperative inflammation, gastric ulcer, Helicobacter pylori infection, and idiopathic inflammatory orbital pseudotumor (Gupta et al., 2013). Evaluating the mechanisms of action of curcumin already described in both experimental and clinical trials, which can potentially benefit patients with dysregulated immune responses in COVID-19, seems to be an innovative strategy. The mechanisms of action of curcumin and its potential effects on COVID-19 are showed in Figure 2.

Curcumin in Hemostatic Disorders

A growing number of studies have reported thromboembolic events in patients hospitalized due to COVID-19. High D-dimer levels are considered to be a common marker for increased thrombotic propensity and poor prognosis (Paliogiannis et al., 2020; Zhou et al., 2020). Increased platelet activation and viral RNA detectable in the blood are associated with platelet hyperactivity, leading to abnormal blood clotting. These causes have been associated with thromboembolic prognosis in patients with COVID-19 (Zhang L. et al., 2020). The following signs of hypercoagulability have been observed in these patients: prolonged prothrombin time (PT), activated partial thromboplastin time (APTT), and elevated levels of D-dimer and other fibrin degradation products (FDP) (Tang et al., 2020). In such cases, antithrombin (AT) activity has been reported to be lower than normal (Tang et al., 2020). Human platelets express ACE2 and TMPRSS2 receptors. SARS-CoV-2 binds to these receptors and promotes platelet activation (Zhang L. et al., 2020).

Endothelial cells express the necessary receptors for SARS-CoV-2 to bind and infect cells, causing cell damage and apoptosis. Damage to the vascular endothelium exposes pro-coagulating factors, such as collagen and von Willebrand factor (vWF), and stimulates the release of tissue factor (TF) (Grobler et al., 2020; Iba et al., 2020). Platelets express specific receptors for these molecules, including glycoprotein VI (GPVI) which binds to sub-endothelial collagen, and glycoprotein (GP) Ib-IX-V which binds to vWF (Falati et al., 1999; Grobler et al., 2020). In addition, activated platelets express P-selectin, which binds to monocytes and circulating neutrophils via the PSGL-1 receptor, causing activated monocytes to express TF and activated neutrophils (McFadyen et al., 2020). Curcumin exerts a critical antiplatelet effect, preventing platelet adhesion to the vascular endothelium and subendothelium, in addition to reducing the expression of P-selectin and GP VI (Zhang et al., 2008; Mayanglambam et al., 2010).

Activated neutrophils release extracellular neutrophil traps (NETs). This process is accompanied by cell death (NETosis) and can exacerbate the inflammatory response (Schönrich and Raftery, 2016; Bonaventura et al., 2018). NETs can contribute to the formation of clots and thrombi via platelet-dependent or independent pathways. The latter can cause total blood vessel occlusion, resulting in organ damage (Jiménez-Alcázar et al., 2017; Gómez-Moreno et al., 2018). Studies have shown that defects in NET degradation cause partial or total obstruction of blood vessels in the lungs (Jiménez-Alcázar et al., 2017). Furthermore, analyses of lung tissue collected at autopsy from patients with acute respiratory distress syndrome and sepsis revealed the presence of NET components in the observed clots (chromatin and myeloperoxidase), indicating that NETs can form intravascular clots in humans (Jiménez-Alcázar et al., 2017). The products released from NETs can also be cytotoxic to endothelial cells, leading to the recruitment of more NETs, which contributes to a thrombo-inflammatory response (Gómez-Moreno et al., 2018). Curcumin treatment, both in vitro and in vivo, was demonstrated to inhibit the function of NETs and reduce neutrophilic infiltration in a murine air pouch model induced by LPS (Antoine et al., 2013). In addition, the reduction in expression of P-selectin promoted by curcumin may be a key mechanism in the reduction of NETS; this is because platelets use P-selectin to bind to neutrophils, thereby promoting neutrophilic activation (Zhang et al., 2008; McFadyen et al., 2020).

In endothelial cells associated with the airways, the increased concentration of Ang II causes TF to be upregulated, with consequent activation of the pro-coagulant response (Nishimura et al., 1997). TF is expressed after vascular injury or activation of endothelial cells. Inflammatory mediators, such as TNF-α and IL-1β, are important inducers of TF in endothelial cells (Pendurthi et al., 1997). When expressed, TF serves as a receptor for factor VIIa, and the binding of factor VIIa to TF initiates the coagulation cascade. This leads to thrombin generation and sequential clot formation with the deposition of fibrin protofibrils (Hergenhahn et al., 2002; Butenas et al., 2008; D’Alessandro et al., 2018; Sathler, 2020).

Treatment of human endothelial cells with curcumin inhibited the expression of TF induced by TNF-α, LPS, and thrombin (Pendurthi et al., 1997). Curcumin was also found to inhibit platelet aggregation induced by arachidonic acid, adrenaline, and collagen (Srivastava et al., 1995). These findings corroborate those of another study that revealed the inhibition of platelet agonists, viz. epinephrine-induced platelet aggregation, platelet-activating factor (PAF), and arachidonic acid, with curcumin (Shah et al., 1999). Furthermore, curcumin has been shown to inhibit the formation of thromboxane A2 (TXA2) by platelets (Shah et al., 1999). Platelet aggregation is stimulated by TXA2 produced by active platelets, and promotes the activation of other platelets. Pretreatment of platelets with curcumin inhibited platelet aggregation induced by the calcium ionophore A-23187, following curcumin interfering with the mobilization of intracellular Ca²⁺, which is essential for platelet aggregation (Shah et al., 1999). Curcumin has also been shown to decrease the levels of D-dimers, circulating platelets, and inhibit diesel exhaust particles (DEP) (Nemmar et al., 2012).

Curcumin administration in an in vivo model of disseminated intravascular coagulation (DIC) reduced the circulating levels of TNF-α, preventing the consumption of peripheral platelets and plasma fibrinogen (Chen et al., 2007). Curcumin also reduced the deposition of fibrin in the renal glomeruli, a characteristic finding of DIC with curcumin (Chen et al., 2007). In a clinical study, a 10 mg curcumin injection administered for 15 days was sufficient to reduce plasma fibrinogen levels (Ramirez Boscá et al., 2000).

Procoagulant and pro-thrombotic events are recurrent in patients with COVID-19 and can cause significant damage. Curcumin, a well-tolerated natural compound, is a promising candidate for studies in the context of COVID-19 disorder hemostatic. In fact, several in vitro and in vivo studies have reported its anticoagulant and antithrombotic effects. Therefore, the mechanisms described in the management of other diseases can be reused for new studies regarding hemostatic disorders induced by SARS-CoV-2 deserving further investigation. The molecular mechanisms underlying the targets of curcumin involved thrombotic and coagulant disorders caused by COVID-19 are illustrated in Figure 3.FIGURE 3

FIGURE 3. Curcumin as a Potential antithrombotic in hemostatic disorders induced by SARS-CoV-2. Pro-inflammatory cytokines and Ang II elevated levels can induce the production of tissue factor (TF) by the endothelial cells, initiating the coagulation cascade. Curcumin decreases pro-inflammatory cytokines (1) and inhibits TF expression (2) in the vascular endothelium, avoiding the activation of the coagulation cascade. The affinity of curcumin by the SARS-CoV-2 protein S and ACE2 binding can prevent the infection and activation of endothelial cells (3). During the activation of the coagulation cascade, fibrinolysis can occur, generating D-dimers. Curcumin treatment decreases fibrin deposition and D-dimer levels formation (4). Lesions of the endothelial cells can expose the subendothelial collagen, which can be recognized by the platelet’s receptor (GP-VI), leading to platelet cell activation. Curcumin can inhibit the GP-VI receptor, reducing and/or abolishing the platelet activation by binding to collagen (5). The interaction of platelets with monocytes through binding the P-selectin-PSGL-1 receptor promotes monocyte activation, causing an increase of TF expression. Curcumin inhibits this interaction by inhibiting P-selectin in platelets (6). The mobilization of intracellular calcium mediates platelet aggregation. Curcumin prevents calcium-mediated platelet aggregation (7). Besides, curcumin inhibits the thromboxane A2 (TXA2) generation (9) released by activated platelets to stimulate other platelet activation. Thus, curcumin inhibits platelet aggregation (10). Abbreviations: TNF-α, tumor necrosis factor alpha; IL-1β, interleukin 1 beta; Ang II, angiotensin II; GPVI, glycoprotein VI; vWF, Von Willebrand factor; GPIb-IX-V, glycoprotein (GP) Ib-IX-V; PSGL-1, P-selectin glycoprotein ligand-1; AA, arachidonic acid; TXA2, thromboxane A2; TP, thromboxane receptor.

Curcumin as a Potential Agent Against Pulmonary Impairment

Alveolar type II (ATII) cells are the primary target of SARS-CoV-2 infection, triggering the apoptotic death of target cells and subsequent infection of adjacent ATII alveolar cells (Mason, 2020). The inflammatory process, together with cellular damage, results in the appearance of multinucleated giant cells and a fibrin-rich hyaline membrane, which causes diffuse alveolar damage that can progress to acute respiratory distress syndrome (ARDS) (Dushianthan et al., 2011). In a model of lung injury induced by benzo (a) pyrene (BaP), curcumin reduced the death of ATII cells and decreased the levels of pro-inflammatory cytokines (TNF-α, IL-6, and C-reactive protein) in serum (Almatroodi et al., 2020).

In more severe cases, patients with COVID-19 may require mechanical ventilation (MV) (Fan et al., 2020). However, inadequate MV can worsen pulmonary pathology. Ventilator-induced lung injury (VILI) causes lung expansion conversion into biochemical signals, resulting in increased activation of inflammatory cells (Silva et al., 2015). Experimentally, it has been shown that curcumin reverses the damage caused by VILI, reducing edema and lung injury. This effect was found to be mediated by the inhibition of NF-κB and the reestablishment of the redox balance from recovery of total antioxidative capacity (Wang et al., 2018).

High levels of circulating NETs have been detected in intubated patients with COVID-19 (Middleton et al., 2020). A correlation between severity and NETs has been established, suggesting that NETs contribute to COVID-19-related lung injury. In addition, platelet colocalization with citrullinated histone H3⁺ and NETs indicated the presence of NETosis in pulmonary microthrombi of patients who died of COVID-19 (Middleton et al., 2020). In the lungs, NETs have a cytotoxic effect on epithelial cells, endothelial cells, and connective tissue, which can aggravate pulmonary pathology (Saffarzadeh et al., 2012). In sepsis and ARDS, NETs cause cell damage and microthrombi, potentially resulting in multiple organ dysfunction and death (Czaikoski et al., 2016; Lefrançais et al., 2018; Papayannopoulos, 2018). In experimental studies involving ARDS due to polymicrobial sepsis (CLP), curcumin decreased the apoptosis of lung cells and attenuated the severity of lung injury. IL-17A acts on ATII cells causing them to release CXCL-1, in turn inducing neutrophil aggregation. Curcumin treatment reduced the levels of IL-17A and neutrophils in the lungs (Chai et al., 2020).

Regulatory T cells (Tregs) are essential regulators of the inflammatory process and generate an adequate immune microenvironment through their anti-inflammatory and anti-apoptotic functions (Lin et al., 2018). Curcumin induces the differentiation of naïve CD4⁺ T cells to Tregs by regulating the expression of IL-10 (Chai et al., 2020). IL-10 is an anti-inflammatory cytokine that promotes macrophage reprogramming from an inflammatory profile (M1) to a repeating profile (M2) by suppressing the mTORC1 complex. M2 macrophages decrease the inflammatory process and stimulate tissue repair in sepsis-induced LPA (Ip et al., 2017). Macrophages with the M1 phenotype are essential for controlling viral replication. However, limiting immunopathological reactions through the M2 phenotype is essential (Sang et al., 2015). In a COVID-19 study, severely ill patients showed a higher frequency of type M1 macrophages than patients with moderate infection or healthy control subjects who presented higher frequencies of type M2 macrophages (Liao et al., 2020). Curcumin promotes a decrease in M1 and an increase in M2 macrophages in septic lungs, indicating its potential effect on macrophage polarization (Chai et al., 2020).

In an in vivo model of lung injury mediated by cyclophosphamide, treatment with curcumin reduced lung injury and restored the oxidant-antioxidant balance by reducing lipid peroxidation (Ashry et al., 2013). In LPS-induced acute lung injury (ALI), treatment with curcumin decreased pulmonary edema, increased PaO₂, and improved lung function (Cheng et al., 2018). ALI can be a consequence of hemorrhagic shock and resuscitation (HSR). Animals subjected to HSR and treated with curcumin showed a reduction in the levels of reactive oxygen species, TNF-α, and neutrophilic infiltrates. Such finding indicates that the treatment provided a protective pulmonary barrier function (Yu-Wung Yeh and Wang, 2020). ALI and ARDS studies in animals with sepsis showed that treatment with curcumin attenuated lung damage and decreased proinflammatory cytokine levels (Xiao et al., 2012; Xu et al., 2013; Liu et al., 2017).

Although clinical studies have not reported the direct effects of curcumin on respiratory impairment, the decrease in clinical manifestations (fever, cough, and dyspnea) in patients with COVID-19 is a promising indicator that encourages further investigations (Tahmasebi et al., 2020; Valizadeh et al., 2020). Many clinical trials have established the therapeutic potential of curcumin, either as a single agent or in combination with other drugs in various diseases, owing to its effect on diverse cell signaling pathways. The possible curcumin action sites that can be targeted after SARS-CoV-2-induced changes in the lungs are illustrated in Figure 4.FIGURE 4

FIGURE 4. Potential curcumin in cell damage caused by SARS-CoV-2 in the lung and heart. Curcumin promotes differentiation from naïve CD4+T-cell to Tregs through the modulation of IL-10 (1). The cytoprotective role of curcumin decreases the death of type II alveolar cells (ATII) with a consequent decrease in the release of DAMPs (2). Curcumin also mediates macrophages’ polarization, decreasing the population of inflammatory macrophages M1 to macrophages M2 that participate in the resolving and reparative process (3). The presence of Th17 cells promotes the activation of ATII cells through IL-17. In turn, activated ATII cells release a chemoattractant for neutrophils that causes neutrophil aggregation. Curcumin decreases IL-17 levels with a consequent decrease in neutrophil aggregates. The anticoagulant and antithrombotic effects of curcumin can have protective effects on the heart, decreasing the heart attack risk (5). The anti-inflammatory action of curcumin can prevent damage to cardiomyocytes caused by an excess of inflammatory mediators, known as a cytokine storm (6). Its affinity for protein S and ACE2 can prevent the direct infection of cardiomyocytes by SARS-CoV-2 (7). Abbreviations: ATII, alveolar type II cells; Tregs, regulatory T cells; Th17, T helper 17 cells; CXCL-1, chemokine ligand 1; NET, neutrophil extracellular traps.

Cardioprotective Effects of Curcumin

Clinical reports involving some of the first patients with COVID-19 from the Wuhan province of China showed that 5 of the 41 patients had changes in levels of highly sensitive cardiac troponin I (hs-cTnI), indicating myocardial injury (Huang C. et al., 2020). Interestingly, some patients sought medical assistance after cardiac symptoms (palpitations and chest tightness) rather than the classic symptoms of COVID-19 (fever and cough) (Deng et al., 2020; Stefanini et al., 2020). In children, COVID-19 can cause a hyperinflammatory syndrome similar to Kawasaki disease (Riphagen et al., 2020).

Underlying CVD significantly increases the mortality rate of patients with COVID-19. One study showed that patients with COVID-19, CVD, and increased troponin T levels had a mortality rate of 69.4%; however, the mortality rate of patients with COVID-19 with increased levels of troponin T without CVD was 37.5% (Guo et al., 2020).

The cardiac events reportedly caused by COVID-19 include acute myocardial injury, heart failure, acute coronary syndrome, infarction, and arrhythmia (Lang et al., 2020; Amirfakhryan and Safari, 2021). The hypotheses surrounding cardiovascular involvement in COVID-19 involve direct infection of cardiac cells by SARS-CoV-2, injury mediated by the inflammatory process, reduced oxygen supply, hypoxia, microthrombi, and stress cardiomyopathy (Lang et al., 2020; Amirfakhryan and Safari, 2021). Histopathological analysis of the heart of a patient with COVID-19 revealed cardiac tissue with a fibrin thrombus in a perforating vein associated with myocardial infarction, myocardial necrosis (transmural), and neutrophilic infiltrates (Rapkiewicz et al., 2020).

In experimental models of sepsis, curcumin proved to be effective at improving the survival parameters, reducing hypovolemia levels observed in the late phase of sepsis, suppression of hyperglycemia in the acute phase, and attenuation of hypoglycemia in the late stage (Silva et al., 2017). Curcumin also attenuated heart damage induced by sepsis; improved cardiac function and body temperature (Yang et al., 2013); and reduced troponin I levels and the product of lipid peroxidation, suggesting its reduction of oxidative damage (Yang et al., 2013).

The restoration of blood flow in the ischemic myocardium can exacerbate tissue injury and result in a poorly adaptive tissue process (Vinten-Johansen et al., 2005; Prasad et al., 2009). First, oxidative stress activates metalloproteinases (MMPs) that promote degradation of the extracellular matrix (ECM). This results in the progressive expansion of the infarction, thinning of the ventricular wall, and dilation of the chamber (Wang et al., 2012). The cure for the infarction involves deposition of collagen, forming a fibrotic and non-functional scar. In an experimental model of ischemia and reperfusion, treatment with curcumin reduced ECM degradation by MMPs and increased the synthesis of collagen and the accumulation of myofibroblasts (Wang et al., 2012). Consequently, there was an improvement in cardiac function, reduced left ventricle dilation, and increased wall thickness (Wang et al., 2012).

An increased number of studies evaluating post-COVID-19 sequelae warns of cardiovascular symptoms, such as chest pain and palpitations (Schneider, 2020; Carvalho-Schneider et al., 2021; Halpin et al., 2021; Huang et al., 2021; Vallejo et al., 2021). The cumulative incidence of thrombosis (2.5% at 30 days after discharge), including segmental pulmonary embolism, intracardiac thrombus, thrombosed arteriovenous fistula, and ischemic stroke, were reported in a single-center study in the United States with 163 patients (Patell et al., 2020). The 6-month post-evaluation of COVID-19 showed that patients suffer from long-term sequelae of the disease, including venous thromboembolic diseases (cardiovascular and cerebrovascular events) (Huang et al., 2021). Currently, there are no reports of curcumin in cardiac changes resulted from COVID-19. However, based on data published on other diseases and cardiac disorders, we hypothesize that curcumin may be a promising agent in preventing cardiovascular damage caused by SARS-CoV-2 infection, as summarized in Figure 4.

Conclusion

Due to the uncountable mechanisms of action addressed in this and other reviews, it has been reinforced that curcumin could serve as an adjuvant drug in COVID-19 treatment (Babaei et al., 2020; Manoharan et al., 2020; Roy et al., 2020; Soni et al., 2020; Zahedipour et al., 2020; Saeedi-Boroujeni et al., 2021; Thimmulappa et al., 2021). The multiplicity of pathophysiological responses induced by SARS-CoV-2 highlights the need for a combination of different drugs as a treatment strategy (i.e., there is no single “magic pill” for the cure of COVID-19). Curcumin is a well-tolerated natural compound in humans, even at high concentrations (Dhillon et al., 2008; Kanai et al., 2011; Gupta et al., 2013). Thus, its combination with drugs that are already approved for use appears logical. Curcumin is a well-tolerated natural compound in humans, even at high concentrations (Dhillon et al., 2008; Kanai et al., 2011; Gupta et al., 2013). Thus, its combination with drugs that are already approved for use appears logical. The first results from the studies regarding the effect of curcumin in patients with COVID-19 are promising. However, several questions need to be answered: 1) Does curcumin prevent SARS-CoV-2 infection of the host cells? 2) Does curcumin treatment attenuate respiratory and cardiovascular system commitment? 3) Is the curcumin able to reestablish hemostatic homeostasis?

Despite the absence of specific studies addressing the mechanism of action of curcumin in the treatment of COVID-19, currently, the world is experiencing an uncommon situation, which has led researchers and physicians to evaluate the available knowledge to the other diseases, in an attempt to design more promising pathways against SARS-CoV-2. In conclusion, this review strategically contributes to the relentless search for therapies that can act on combat of COVID-19, in addition to providing targets for future studies using the curcumin as an adjuvant treatment to COVID-19.

Author Contributions

BR: Conceptualization, Writing—original draft, author of illustrations. SR: Conceptualization, Writing—review and editing, Funding acquisition. MC: Conceptualization, Writing—review and editing, Funding acquisition, Supervision.

Funding

This work was supported by grants from the Fundação de Amparo a Pesquisa do Estado de Goiás (FAPEG/BRAZIL) (2017/1026700006-8) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil) (88882.378587/2019-01).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The authors acknowledge the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil) [88882.378587/2019-01] and Fundação de Amparo a Pesquisa do Estado de Goiás (FAPEG/BRAZIL) [2017/1026700006-8] for supporting funds. The authors also acknowledge the BioRender for making it possible to create the illustrations.

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Nano Fucolive – New formula for chemotherapy people

quản trị viên — Thu, 12 Aug 2021 03:20:48 +0000

Recently, Nhat Hai New Technology Joint Stock Company has just launched a Nano product to help limit oxidative damage. Products used for people exposed to oxidizing factors due to chemicals and radiation, causing reduced resistance.

With the main ingredient is Fucoidan – a precious herb that has been proven to support people who have to undergo chemotherapy and radiation therapy.

Fucoidan – origin and medicinal properties

Fucoidan is a mucilage found in brown algae (brown seaweed) such as Kombu, Wakame, and Mozuku. According to science, Fucoidan is a high molecular chain polysaccharide composed of many monosaccharides called Fucose. It can be said that fucoidan is an active ingredient with natural ingredients, easily found in brown seaweed and most popular in Japan.

Based on the report of the Japan Anti-Cancer Society in 1996, Fucoidan is effective in supporting cancer prevention by various mechanisms. Fucoidan has been shown to have the ability to stimulate the immune system, induce Apoptosis (a process of cyclical suicide) on selected foreign cells, preventing their formation and growth.

Nano Fucolive OIC – New formula for chemotherapy people

Nano Fucolive is a new technology product line of OIC NEW that specializes in supporting people with poor resistance, people exposed to chemicals and radiation that cause oxidation. Fucoidan contained in Nano Fuclive product is Olifuco line – low molecular weight 500-1500 dalton has many times more absorption and bioavailability. This is also a line that has clinical trials on humans and is effective in supporting people new to chemotherapy and radiation.

The uses of Olifuco series Fucoidan have been proven:

– Supports reduction, inhibits no progression, inhibits the supply of oxygen and nutrients to the tumor.

– Helps reduce the side effects of chemotherapy and radiation

OIC’s Nano Fucolive with exclusive formula:

– Fucoidan: 490mg. With high purity brings benign, safe for users. The high content of Fucoidan in each capsule helps to improve bioavailability with a small dose, thereby saving costs.

– Combined with the ingredient Nano Resveratrol. Resveratrol (extracted from red grape skin) has the ability to support strong antioxidants, neutralize free radicals, stimulate the activity of antioxidant enzymes, stimulate immune cells… Strong anti-aging, regenerate new blood cells…

Uses:

– Support to enhance antioxidant capacity, enhance resistance

– Helps limit the harmful effects of oxidation

Users:

– People with low resistance

– People exposed to oxidizing factors due to chemicals and radiation cause reduced resistance

Advertising license No. 823/2021/XNQC-ATTP

* This food is not a medicine, it is not a substitute for medicine!

OIC NEW – 4 years after raising 5 billion from Shark Tank Vietnam

quản trị viên — Mon, 28 Jun 2021 03:07:26 +0000

Shark Tank Vietnam is not too strange for Vietnamese startups. Because this is a place where many young businesses with new products and business models seek investment and development opportunities.

Impressive deals are expected to flourish in the future thanks to the investments and cooperation of the Sharks. Nhat Hai New Technology Joint Stock Company (OIC NEW) is one of the science and technology enterprises that received an investment of up to 5 billion VND in the first season.

Receiving investment means receiving opportunities

At the end of 2017, OIC NEW with Nano Curcumin product participated in calling for investment in the business to receive VND 5 billion in exchange for 15% of shares and a commitment of 30% profit per year, with mortgage conditions. home. It was the enthusiasm of founder Luu Hai Minh – the determination to “plug in” that attracted the investment of Shark Phu as well as the attention of viewers.

Ông Lưu Hải Minh tại Sharktank Việt Nam.

After more than 4 years, OIC NEW has established itself a strong position in the health food market. No longer struggling to find solutions to sell products to the market, now OIC NEW has built a network of agents from large hospital pharmacies to drug retailers nationwide. Products are also available on e-commerce platforms, reputable websites of distributors as well as enterprises’ own. Now mentioning Nano is referring to OIC NEW with wide coverage. In addition, according to founder Luu Hai Minh, not only domestic units, many distributors in the US, German and Japanese markets also propose to distribute products exclusively in these markets.

Continuous research and development

In 2017, OIC NEW brought to Shank Tank Vietnam only 1 new product to help overcome stomach disease to raise capital, but so far OIC NEW has researched and launched more than 5 other Nano products to support symptom relief. many chronic diseases such as liver, vestibular disorders, hemorrhoids, diabetes, blood fat,…

Liquid Nano Curcumin in Sharktank.

The diversification in products helps OIC reach many customers, creating a biomedical Nano value chain – something that few medical and pharmaceutical businesses can do. With a lot of Nano research and products on the market, OIC NEW is proud to be the pioneer and leader in this technology and is recognized by the state as a Vietnamese science and technology enterprise.

Do not stop at the domestic but have to reach the international level

Not only the domestic market, OIC NEW directly competes in foreign markets such as the US, Japan, Singapore… Foreign partners choose to trust and import OIC NEW’s finished products. Despite difficulties in many import-export procedures in difficult markets, OIC NEW is confident with product quality that meets international standards to satisfy distributors as well as consumers. The presence in foreign markets is OIC’s first steps in entering a new market.

Nano Curcumin OIC product on Amazon (USA).

Catching up with the global e-commerce trend (Global Selling), OIC NEW quickly put products on e-commerce platforms such as Amazon, Alibaba… From here, OIC can easily contact and cooperate with many retailers other international distribution. The large orders placed through e-commerce platforms are increasingly proving that the attraction of the product in the global market is very high and competitive on the new playing field.

Accompany – cooperate – develop together

In our country, in recent years, the field of health foods has been increasingly interested by consumers because of the trend of “prevention is better than cure”. This is a stepping stone for the development of the health food industry. OIC NEW inherits the values of science and technology brought, is increasingly researching and developing more new products, helping Vietnamese health.

After more than 4 years, after raising capital from Shark Tank, OIC NEW is considered as one of the enterprises with outstanding strides. Going up from researchers, now the crystallization of science is well received by consumers as a great success of the business. By the quality of those scientific crystals, OIC NEW is not only interested by investors but also receives the trust and love of customers. It can be said that the “blood” of founder Luu Hai Minh has now forged valuable “gold bars” for businesses. Shark Tank is like a launch pad, but how high and how long it can fly is still based on the relentless efforts of the business.

OIC NEW and 11-year journey from pioneer to leader

quản trị viên — Wed, 26 May 2021 09:39:39 +0000

Established in 2009 with the name Nhat Hai New Technology Joint Stock Company, OIC NEW has spent 7 years in-depth research on Nano technology. And after 11 years of dedication to this path, OIC NEW has more than 60 researches and 10 Nano patents granted by the National Office of Intellectual Property.

Why Nano and the Story of Capturing Technology

“Why Nano?” – This question is often asked to Mr. Luu Hai Minh – Chairman and Director of Research and Development of OIC NEW. And without hesitation, he replied: “Nanotechnology is the foundational technology for the 4.0 technology revolution. In the past years, from the time of its establishment in 2009, people mentioned Nano very recently because of the nano in activated carbon, nano in water purifier, nano silver…. but no one has mentioned Nano in biomedical and pharmaceutical chemistry”.

Similar to the story of putting pebbles in a jar, ordinary medicinal herbs are likened to pebbles, the size of these pebbles is too big to fill the gaps. But for nano-medicine, at the size of 20-30 nm, it will easily penetrate through the cells and go deep into the body, increasing its absorption into the blood and helping the medicinal herbs to promote optimally. its use. Many people worry that the use of Nano technology will lose the properties of medicinal herbs. However, with OIC NEW’s technology, the essences of medicinal herbs are always preserved in use and benefits for users.

Doing science is synonymous with research and development

In 2016, OIC NEW launched the first product, Nano Curcumin in liquid form. This is considered a new breakthrough in the preparation of nano curcumin, when the market for nano curcumin products to support the stomach emerged as a fever. Not following the path, OIC NEW chose the quality solution as the top priority and the OIC Nano Curcumin Solution was born after 7 years of research. Then, continuously from 2016 -2020, OIC NEW created a Nano wave with more than 50 researches and launched many products extracted from nature to help overcome many current diseases such as: liver, gallbladder, bone. joints, blood fat, cerebral circulatory insufficiency, cardiovascular, male physiology, female physiology, fat loss, diabetes, …

OIC NEW received the title of the main industrial product of Hanoi city

With a series of massive research projects, OIC NEW has been awarded Enterprise Awards for many years by the Association of Science and Technology, Hanoi People’s Committee. Not only that, Nano OIC products are also highly appreciated by experts and are distributed at major agents, hospitals, and pharmacies across most of the provinces. The belief that OIC NEW brings to customers is the real value of “no color and no enhancement” scientific research.

OIC NEW always carries with it the mission of a scientific enterprise. Therefore, after grasping biomedical Nano technology, OIC NEW focuses its resources on research and product development. Inventor Luu Hai Minh once shared that “in the future, it is possible to make Vietnamese herbs and medicinal herbs help overcome many chronic and malignant diseases”. In addition to products with materials imported from abroad, OIC NEW always appreciates Vietnamese medicinal herbs, familiar plants of Vietnamese people in traditional medicine. Changing the view of traditional medicinal herbs with low or slow effects of Vietnamese people. When applying Nano technology to these products, OIC confidently turns Vietnamese plants into typical products in the world health care market. As proof of that, OIC NEW has been successful with Nano health care products from natural herbs branded Made in Vietnam and reached international level with major partners in the US, Japan, Singapore, Malaysia, Greece, ….

New journey – new mission

After more than 11 years of asserting itself in the market and receiving the trust of customers for its products, OIC NEW continues its research and development journey, constantly striving to produce “golden” products for customers. health. Not only in the field of Biomedical Sciences, OIC NEW has been implementing other Nano application researches in beauty, agriculture, environment, etc. to create greater value, to thoroughly exploit the stronger uses of Nano.

OIC NEW’s vision is from the core Nano technology, which can create an ecosystem, a network that connects individuals and businesses from product development to commercialization to the market. Because OIC NEW’s desire is that more and more customers can choose for themselves high-value, effective and reputable products.

“OIC’s responsibility is the responsibility of a new age scientist.”

Nhat Hai New Technology Joint Stock Company

Tel.: 1900 63 69 13

Address: 66 Trung Hoa, Cau Giay, Ha Noi

Website: https://oic.com.vn/

Inventor Luu Hai Minh and his big dream named Nano

quản trị viên — Wed, 26 May 2021 09:35:08 +0000

Once considered an outsider in the biomedical industry, for more than 11 years, the inventor, Dr. Luu Hai Minh, has persistently written the story of the massive Nano with his relentless research.

7 years of research and definition of success – failure.

OIC NEW was established in 2009 but only launched the first product in 2016 which is Liquid Nano Curcumin OIC. That 7-year process is a huge financial and material investment, non-stop efforts, and thousands of failures. Do not follow the path, do not follow the old method, put technology and quality factors first, the journey that Dr. Luu Hai Minh’s choice seems to be a foretold success journey.

Inventor Luu Hai Minh once shared: “When I give up, it is a FAILURE and SUCCESS is when I make a product that is recognized by everyone”.

During those 7 years, Luu Hai Minh continuously received words of encouragement from family and friends and sometimes he was “praised” for the two words “paranoid”. But with his own ideals and determination as hard as iron, Minh asserted that only if he didn’t give up, nothing was a failure. Claiming to be a “bloody” person, steadfast in his ideals, but within 7 years for a pharmaceutical nanotechnology research company that has not yet launched a product, it is inevitable that people around as well will be attacked. like himself, he also feels depressed, disappointed in himself and always feels “tricked” even though “no one cheated on me” – Mr. Minh shared wittily.

Solve the problem of balancing Technology and Marketing

After launching the product Nano Curcumin solution, Dr. Luu Hai Minh continued to face difficulties when finding ways to market the product to consumers. Previously, he was a successful businessman with different professions such as computer technology, software and also quartz import and export, but for this doctor, pharmaceuticals is a complete field. totally different. Pharmaceuticals must take customer value as the center, the mission of the business is to protect the health of consumers. OIC NEW’s Nano technology is an advanced technology, the foundation technology for Industry 4.0 with many outstanding advantages compared to conventional pharmaceutical products. So how do customers know that? And what do people understand about Nano? Frequently asked questions in OIC NEW team meetings.

People mentioned Luu Minh Hai more through the program Shank Tank Vietnam with the title “Pledge the house in exchange for 5 billion investment”. It is an interesting story in the stage of bringing the product to the consumer. “House mortgage” – shows that his determination is so great that it is hard for anyone to match. He once shared, for that decision, he himself felt reckless because “mortgaging the house” affected not only him but also his wife and children. But he himself feels confident with his technology, confident in the value it brings to consumers. And not to disappoint him, not only received investment, but he was also known by more people and many people learned about Nano, learned about his products and contacted him for help.

“I want to help those who want to research my Nano science and technology in the future to turn Vietnamese herbs and herbs to treat a wide range of chronic and malignant diseases.”

After mastering Nano technology and his products are trusted by customers, Mr. Minh has a new dream for himself. “If you don’t wish, then wish is big” – His dream is that when it comes to Nano products, he must mention OIC NEW, when he mentions OIC NEW, he must immediately think of the symbol of the pioneering industry. innovation and application of advanced technology not only in Vietnam but also internationally. In the pharmaceutical market, not only OIC NEW makes Nano, but when it comes to product quantity to quality, OIC NEW is both a pioneer flag and confidently leads the industry. Focusing most of his resources on product research and development, Mr. Minh defines himself as doing more science than commerce and product quality must come first. Not only present in the country, the products have been distributed by many foreign partners and are eager to transfer technology.

And the scientific research results so far are the pride of the inventor Luu Hai Minh as well as the OIC NEW team: with more than 60 nano-research from natural medicinal herbs, not only in the field of health care but also also in the field of beauty, agriculture. Up to now, OIC NEW has 6 self-commercialized products under the OIC NEW brand and 10 products distributed by domestic and foreign pharmaceutical partners. With the objective and fair assessment of the Science and Technology Council, inventor Luu Hai Minh has owned 10 patents granted by the National Office of Intellectual Property. He shared: “I hope that within 10 years, I will have 50 inventions myself. I don’t dare compare myself to Thomas Edison, but I hope to be 1/30th with the desire to make a practical contribution to public health” – a belief that can be considered feasible when looking at the research practice of OIC NEW.

In 2021, OIC NEW officially has more than 12 years in the field of research and development of health protection products based on Nano technology. What inventor Luu Hai Minh is proud of is not the number of products sold or the profit of the business, but that he himself did the right role of a pharmacist. The mission is to protect the health of every home and spread Nano technology to those who need it.

Nhat Hai New Technology Joint Stock Company

Tel.: 1900 63 69 13

Address: 66 Trung Hoa, Cau Giay, Ha Noi

Website: https://oic.com.vn/

Sản phẩm Nano chất lượng cao của Việt Nam vươn ra thế giới

quản trị viên — Wed, 26 May 2021 09:28:17 +0000

Inventor Luu Hai Minh is currently the Chairman of Nhat Hai New Technology Joint Stock Company and Vice Chairman of the Hanoi Association of Small and Medium Enterprises, which has brought high-quality Vietnamese Nano products to the world.

Vietnam’s high-quality Nano products reach out to the world

Nhat Hai New Technology Joint Stock Company was established in 2009 (formerly known as Information Technology Research Center) and is a leading science and technology enterprise in Vietnam that successfully applied Nanotechnology in the biomedical field. With a team of good, experienced engineers and leading experts in the field of Nano, OIC NEW’s vision is to bring Vietnam’s high-quality Nano products to the world.

With special self-research and exclusive production machines, OIC NEW is proud to be the first and only unit to successfully prepare nanoparticles from natural compounds with the smallest size on the market today. 5-30nm), with USP&EP international pharmacopoeia standard ingredients – and the know-how of formulas, Nano products are perfectly absorbed into cells, bioavailability is hundreds of times higher than conventional products. Usually, it is both effective and safe for the body.

All Nano products from natural medicinal plants of OIC NEW are granted a Patent or a Utility Solution Patent by the National Office of Intellectual Property for the Preparation Process – a clear demonstration of the research potential. research, development and output quality for products. In addition to the Patents and Utility Solutions, Inventor Luu Hai Minh and his collaborators at the OIC R&D center also have international articles published in specialized journals on Nanotechnology in the UK as well as articles about the application of Nano OIC products in supporting cancer treatment published in the Journal of Practical Medicine.

Inventor Luu Hai Minh is the author of 35 registered patent applications and has been granted 2 invention patents and 5 utility solution patents by the National Office of Intellectual Property. The raw materials for the production of products are mainly imported from countries around the world such as the US, Europe, Japan and especially the natural materials of Vietnam.

Target 100 patents on natural compounds

The first direction with nanotechnology is in the fields of agriculture and industry, but now, OIC NEW has been and is one of the pioneers in the nanotechnology of natural medicinal plants with immense potential. big. With a strategic vision and a scientific and bold organizational method, the inventor Luu Hai Minh – Chairman of the Board of Directors of Nhat Hai New Technology Joint Stock Company has built the OIC NEW brand with the following products: The first Nano product line in the market and the world.

Up to the present time, OIC NEW has more than 50 researches on Nano products being commercialized in the market. From standard herbal ingredients, with scientific evidence of effectiveness, OIC NEW is the first unit in Vietnam and in the world to make nano preparations with the smallest particle size on the market to support the treatment of diseases. treatment of common chronic and malignant diseases today.

Inventor Luu Hai Minh’s goal is that by 2030, his company will launch 100 patents on natural compounds that have the effect of improving health and preventing disease. “Due to many problems, Vietnamese products have not been exported to the world. I hope with the wisdom of Vietnam and my collaborators to launch 100 patents to be able to apply Vietnamese natural products for export,” said Inventor Luu Hai Minh.

Digital transformation – General trend of international business

According to Inventor Luu Hai Minh, digital transformation is a business model transformation that requires a product transformation, which is very suitable for OIC. Grasping the future, since 2009, Inventor Luu Hai Minh has transformed his business model from information technology to focus on researching Nano technology products.

In the early stages of transformation, the company faced many difficulties because the direction was not yet available, the technology was unknown, but with the determination of the leaders, currently, OIC has 25 products sold in the market. America, Amazon, Alibaba, Vietnam,…

“This is the general trend of international business, as an alumnus of Foreign Trade University, I understand what needs to be done for the company to grow and be strong,” said Inventor Luu Hai Minh. .

Before starting a business, Mr. Hai Minh was an IT, when he decided to start a business he was opposed by his family and friends. Although his friends invest in real estate and securities, he chooses his own path by investing completely both capital and knowledge in the field of Nano technology. Because of too much investment, he is determined not to give up, also because of that he has made remarkable achievements. After more than 10 years choosing the path of Nano Technology.

OIC achievements are certified by consumers

With the principle of “Prestige – Internationally equivalent quality”, Nano OIC products always have to go through extremely strict evaluation stages, from controlling input materials to meet quality standards, the ingredients must meet the USP/EP international pharmacopoeia standards of the US and EU; to testing the product quality criteria of the National Institute of Food Hygiene and Safety. Therefore, OIC NEW’s products are trusted and used by customers, domestic and foreign partners and successfully present in 63 provinces and cities in Vietnam and major markets in the world such as: USA , Germany, Japan, Cambodia, Singapore, Angola, etc. The company has received the certificate of exporting goods to the US market by FDA organization.

Continuously from 2016 up to now, Nhat Hai New Technology Joint Stock Company has received the Certificate of Merit and the Rotary Flag from the Chairman of the Hanoi People’s Committee for its excellent performance in production and business activities, contributing to the development of Vietnam. socioeconomic of the City. Awarded by the Ministry of Science and Technology for great achievements and works in Science and Technology activities. OIC NEW’s products have been certified as Vietnamese Goods loved by consumers for many consecutive years and are in the Top Top Key Industrial Products in Hanoi.

“Don’t expect investors’ money, but protect investors’ money. If you want to work towards success, never give up,” said Inventor Luu Hai Minh.

Inventor Luu Hai Minh: Aspiration to bring nanotechnology and Vietnamese medicinal herbs to the world

quản trị viên — Wed, 26 May 2021 09:24:09 +0000

Succeeding in the information technology market, but with a passion for research and invention, Dr. Luu Hai Minh has ventured into the field of nanotechnology. He has helped elevate the value of dozens of valuable Vietnamese medicinal herbs into world-class products.

Dr. Luu Hai Minh, Chairman of the Board of Directors of Nhat Hai New Technology Joint Stock Company is considered as a model of a passionate scientist and a businessman with business acumen. With what he has done, it has helped Vietnamese intelligence raise new heights in the international arena.

Certain successes in the field of informatics

Although currently inventor Luu Hai Minh is known as the leader in nanotechnology in Vietnam, few people know that he has also been very successful in the field of information technology. He graduated as a Mechanical Engineer majoring in Automotive – Hanoi University of Transport and Majoring in IT at Hanoi University of Science and Technology.

Also while studying, he established Nhat Hai Company Limited (OIC). With continuous development, OIC dominated the retail market of computers and informatics equipment at that time and became a Senior partner for Cisco – USA, IBM – USA and Gold Partner of Microsoft – USA. Not only that, OIC has also developed the market for software solutions and has provided hardware packages for a number of hospitals such as Institute 105, Institute 109 of the Ministry of Defense.

Inventor Luu Hai Minh is always spend his mind on his passions

OIC also participates in both the foreign outsourcing market and online game development. OIC’s products and solutions also won the Sao Khue Award of the Vietnam Software and IT Services Association in 2006 and 2009. In addition, OIC also won the Vietnam Gold Star Award for 5 consecutive years, 2008,2009,2010,2011, 2013. And OIC was honored to receive the Certificate of Merit from the Prime Minister in 2010 and the Third Class Labor Medal awarded by the President in 2012 for outstanding achievements in the IT field.

However, inventor Luu Hai Minh understands that he needs to have a success of his own, not just for OIC to be a distributor of foreign companies. So he entered the field of nanotechnology.

Aspiration to bring nanotechnology and Vietnamese medicinal herbs to international level

Earning a decent capital back, in 2009 OIC entered the nanotechnology market. Starting with the study of nano-extracted turmeric (scientific name is curcumin), Mr. Minh and his team found that even though it only accounts for 3% of turmeric’s composition, after ultrasonic emulsification under high pressure, it distilled that precious essence. Curcumin after being emulsified reaches a smaller size than human cells, so it easily penetrates diseased cells to heal wounds.

After about a year of doing nearly 2,000 experiments and spending a large amount of money, businessman Luu Hai Minh and his colleagues have selected 10 samples that are equivalent to German nano curcumin products for testing at the National Institute of Control. national experience. In 2016, the process of preparing curcumin nanoemulsion system of the inventor Luu Hai Minh was granted an exclusive patent by the National Office of Intellectual Property (Ministry of Science and Technology).

Inventor Luu Hai Minh and his colleagues have produced many useful studies

In order to specialize in the field of Nanotechnology research and development, on May 13, 2018, Nhat Hai New Technology Joint Stock Company established the Research Center for Natural Compound Nanotechnology – OIC NanoTech R&D with the aim of nanochemical products made from precious medicinal herbs of Vietnam such as cassava, cinnamon, red grape skin, milk thistle, flowers. The main task of OIC NanoTech R&D is to research and develop new products and produce raw materials for natural nanocomposite products to supply to the global market.

After many years of development, until now, OIC NanoTech R&D has been granted many useful patents. The products have also been brought to market. However, inventor Luu Hai Minh has always raised the desire to bring nanotechnology and Vietnamese medicinal herbs to the international level.

LIST OF PATENT

1. Patent No. 16095 on Process for preparing curcumin nanoemulsion system

2. Patent No. 24070 on Process for preparation of lutein nanoemulsion system

3. Patent No. 2490 on Process for preparation of rutin nanoemulsion system

4. Patent No. 2489 on Process for preparation of silymarin nanoemulsion system

5. Patent No. 2492 on Process for preparation of ginkgo biloba nanoemulsion system

6. Patent No. 2491 on Process for preparation of melatonin nanoemulsion system

7. Patent No. 2321 on Process for preparation of berberin nanoemulsion system

And more than 30 studies on natural medicinal herbs and other nanotechnology applications have been completed and are under patent registration

Looking back on the journey of the controversial deal that committed a profit of 30%/year and mortgaged the house to receive an investment of 5 billion VND

quản trị viên — Wed, 26 May 2021 09:15:59 +0000

The story at Sharktank Vietnam is the first season with the billion-dollar deal of Nhat Hai New Technology Joint Stock Company with Shark Phu.

Nhat Hai New Technology Joint Stock Company, after 4 years of joining Sharktank, is now the leading S&T Enterprise in Vietnam successfully applying Nanotechnology in the field of Biomedical, specializing in research and production of Nano products from nanotechnology. Vietnamese natural medicine for health care. Currently, OIC NEW has 6 product lines of health foods, in addition to Nano Curcumin solution brought to Sharktank, 1 research and development laboratory, exclusive partners nationwide and successfully exported to Amazon. (USA), Singapore, Greece,…

Appearing at Shark Tank season 1 episode 4, Mr. Minh nodded to Shark Phu’s “solid” investment, namely VND 5 billion in exchange for 15% of shares, with a commitment to profit 30% minimum and with mortgage conditions. While many viewers debated the reasonableness of the agreements in this deal, even saying that Shark Phu was more like a “creditor” than a venture capitalist, the main character – Mr. Luu Hai Minh completely different thinking.

Below is our live interview with Mr. Luu Hai Minh after the program was broadcast.

* Hello Mr. Minh. Can you tell us after the show aired, did your business change?

After only 2 days since Shark Tank aired, I received calls from 10 investors, proposing to invest with more favorable conditions than Shark Phu offered. For example, no need to mortgage a house, invest more money, committed profit rate less than 20%, etc., but I have not responded to an investor yet, because I respect what I signed with Shark Tank Vietnam.

In addition, we were proposed to become distributors by some overseas units in new markets such as Germany, USA, and Japan. Some domestic units have proposed to be new agents, but they want to buy it to mix in bran for shrimp and fish while my product is a health food for humans. I think maybe my product can bring some benefit to the seafood industry and this is the motivation for us to develop new products.

* Many people think that the conditions Mr. Phu gave him turned the form of investment into a loan, because there was a requirement to mortgage the property. What do you think about this issue?

I think Shark Phu’s thinking is completely correct. There’s nothing wrong with securing your financial interests against an emerging company that has just launched a product. From the time of filming until now, I don’t think Mr. Phu is a “borrower” as commented on the internet, but a professional investor who has a “hot heart” and a “cold head”. Benjamin Franklin once said, “If you want to know the value of money, go out and try to borrow some.”

* With assets worth 15 billion dong, 2 billion dong in cash, and owning a house, why don’t you take a bank loan instead of accepting this somewhat “lost” investment?

Mr. Phu and I are still in the process of negotiating, so I would like to answer this question after a while, when we have finished negotiating.

* Can you tell us a little bit about the content of the negotiation?

From the day of filming until now, there have been meetings between the two sides and we are coming to higher terms of negotiation between the leaders. But above all, we respect what has been committed with Shark Tank Vietnam.

Mr. Phu’s three conditions: VND 5 billion for 15% of the shares, a commitment to a minimum profit margin of 30%, and a house mortgage is just a necessary condition of the deal. In my opinion, 4-5 more conditions are needed for the deal to be successful. And these conditions we are negotiating, so we have not disclosed.

* Many people think that he is on air just to do media, so what do you think?

I’m not on TV because of my face, it’s not necessary. The important thing is that I want to get the product to people who need it, people with stomach problems, liver enzymes, colon problems. Many broadcasters don’t even know what strengths and weaknesses their products have for Shark to invest in. I am someone who has been eating and sleeping with the product for many years to successfully research the product. I and my colleagues are still using Liquid Nano Curcumin every day for health care.

* Do you ever regret the decision you made?

I never regret any of my decisions, including the one on Shark Tank. In my opinion “I never give up”.

You can watch the video detailing this shocking deal here

List of Health Supplement Nano OIC.

OIC Nano Curcumin at Sharktank “If you fail, live on the street”

quản trị viên — Wed, 26 May 2021 09:00:18 +0000

Considered in international cooperation, associating with reputable domestic enterprises to create useful products is the aspiration of Dr. Luu Hai Minh after he aired Shark Tank Vietnam.

Technology-based business model

In order to specialize in the field of Nanotechnology research and development, Nhat Hai New Technology Joint Stock Company established the Research Center for Natural Compound Nanotechnology – OIC NanoTech R&D with the aim of nanotechnology of products made. from precious medicinal herbs of Vietnam such as cassava, cinnamon, red grape skin, milk thistle, rose flower. The main task of OIC NanoTech R&D is to research and develop new products and produce raw materials for natural nanocomposite products to supply to the global market.

“For example, from milk thistle (milkweed), we can extract silymarin, a substance capable of treating liver diseases, sage contains rutin – an anti-stroke agent, cinnamon bark contains Cinnamaldehyde – a substances that help increase blood circulation” – Dr. Luu Hai Minh explained.

In addition to establishing a Research Center according to international standards, OIC NanoTech R&D also recruits many scientists who have studied in Japan, Australia, Germany, and Russia. They used to have very good jobs with extremely high salaries, but decided to join Nhat Hai so that they could contribute to Vietnam’s Nano field. Those are the people that businesses cannot offer high salaries to offer. They are talented people who want to contribute to the Vietnamese technology industry and they see that Nhat Hai has been creating a good environment in which to contribute.

But what is more special is that these outstanding scientists are willing to spend their remuneration to sponsor students, creating conditions for them to study with them.

“Their actions mean a lot, making us feel that we have to improve our social responsibility,” said Dr. Luu Hai Minh.

According to Dr. Luu Hai Minh, the social responsibility of businesses should come from the sense of responsibility for their products and services, the product must be really valuable to the community and, importantly, the level of trust. from the public to the business.

Aspiration to reach international level

A professional company in pharmaceutical chemistry technology in Italy has come to Nhat Hai. The two sides are in the process of negotiating to cooperate on research at the international level.

“That company also bought our Liquid Nano Curcumin OIC product for research and testing in Europe,” said Dr. Luu Hai Minh.

“Our research results have appeared in articles in prestigious Science and Technology journals around the world,” said Dr. Luu Hai Minh.

At Nhat Hai, a degree is not an important factor for the human resources department and Dr. Luu Hai Minh is ready to give the responsibility to very young people if they have passion and desire to learn.

“Because there is no emphasis on degrees, many PhDs and researchers with the desire to accompany in creating new products using Nano technology have come to our company to work,” he said. .

Liquid Nano Curcumin of Nhat Hai company supports antioxidant, protects and heals gastric mucosal damage, supports fast wound healing, fades dark spots and many other effects.

“Because there is no emphasis on degrees, many PhDs and researchers with the desire to accompany in creating new products using Nano technology have come to our company to work,” he said. .

Currently, Nhat Hai’s nano products are sold on two major international commercial products, Amazon and Alibaba, and have cooperated with many partners in Greece, Singapore, Japan,… Inventor Luu Hai Minh international cooperation must be a top priority. For him, this is a mandatory orientation if the company wants to go far with Nano technology.

“Someone might think that Nano technology is just something to promote a brand. But Nhat Hai will not use the word Nano just to polish the image. All Nhat Hai products will be born from Nano technology to support the treatment of chronic diseases. We also combine nano products with other products to create functional foods and new drugs that can increase the effectiveness of the treatment process,” said the doctor of economics but passionate about technology. Nano confided.

New discovery: Rutin in Nano form has an inhibitory effect on lung and colon cancer cells

quản trị viên — Mon, 01 Mar 2021 07:01:38 +0000

Research by a group of scientists from Nhat Hai New Technology Joint Stock Company (OIC NEW) was published in the Hindawi Science and Technology Journal, specializing in Nanomaterials.

Rutin

Rutin is a flavonol, found in abundance in typical plants such as daffodils, passionflowers, buckwheat, black tea, and apples. Rutin has diverse biological activities and many pharmacological applications such as: antioxidant, anti-inflammatory, anti-viral and low toxicity with potential clinical applications, including anti-cancer effects. letter of this active substance.

Reports have shown that, at a dose of 120 mg/kg, Rutin has the ability to inhibit the growth of human leukemia tumors in an in-vivo mouse xenograft model. Rutin affects cell arrest and apoptosis, reducing the number of metastatic nodules and cytotoxicity. In addition to leukocytes, rutin also showed effects on many other cancer cell lines such as CRC colorectal cancer cells, B16F10 lung cancer cells, HTC liver cancer cells.

Chemical structure of rutin

However, rutin is a natural active ingredient that is poorly soluble in water (only 0.8 mg/mL) so it is only slightly absorbed from the gastrointestinal tract. Therefore, the oral bioavailability of rutin is only 20%, which is quite low compared to the target.

To solve this problem, a group of scientists from OIC NEW Company, represented by Inventor Luu Hai Minh, has chosen a nanoparticle-based drug delivery system approach. The advantage of nanoparticle-based drug delivery systems is that nanoparticle drugs can be engineered to achieve longer circulation times, better stability, improved concentration and internal drug accumulation, and increased drug availability. better ability to reduce toxicity to normal tissues.

The prenanoemulsion nanoparticle-based drug delivery system contains surfactants, surfactants and pharmaceutics, which can form nanoemulsions under conditions of digestive juices and intestinal motility after oral administration. The formation of rutin in the form of a nanoemulsion with a particle size of less than 100 nm can enhance drug solubility and absorption in the gastrointestinal tract. In addition, thanks to its stability, long circulation time and the ability to increase drug accumulation in cancer cells, Tween-80 and PEG-600 were selected as excipients to prepare rutin pre-emulsions in this study. . The requirement here is that the system should not be toxic to normal cells.

Rutin nanoemulsion system

To date, there have been few studies on the formulation of rutin in the pre-emulsion system and its cytotoxicity against lung and colon cancer. The research of inventor Luu Hai Minh and a group of scientists is considered a new invention for modern medicine. Inventor Luu Hai Minh said that, with a small size of 20-50 nm, the created rutin nanosystem has the potential to penetrate into cancer organizations. Then, under the influence of the environment, temperature, enzymes, etc., the shell will release, releasing nutrients without being destroyed or eliminated along the way.

The results of the particle size analysis showed that the rutin nanoparticles have a spherical shape with a smooth surface, which helps to have better mobility in blood vessels compared to other shaped nanoparticles.

The rutin particles have uniform size and shape, evenly distributed in the water emulsion. The average size of rutin nanoparticles is about 15 nm, which is very optimal and suitable for drug delivery into the body, thereby accumulating toxic compounds in cancer cells to weaken. Nanoparticles larger than 10 nm in size will not leak into the capillaries and are not eliminated by the one-time renal clearance process, thereby improving blood circulation time. At the same time, it is not captured by macrophages in the mononuclear phagocyte system and easily penetrates into human organs, especially tumors.

HR-TEN image of nano rutin after dissolving the pre-emulsion in water. Particle size is small, spherical and uniform

With these advantages, the process of preparing rutin nanoemulsions of Nhat Hai New Technology Joint Stock Company has been granted the Patent Utility Solution Patent No. 2490 by the National Office of Intellectual Property on 13/10/ 2020.

The team also conducted in-vitro tests on lung cancer cells, colon cancer cells and human fibroblast cells. By means of IC50 analysis, the research team determined that, within 72 hours, to inhibit over 50% of cancer cells, the concentration of rutin is: 154.8 μM for lung cancer cells and 154.8 μM for lung cancer cells, respectively. 251.5 μM with colon cancer cells.

Testing the water solubility of nano rutin vs rutin via the Tyndall effect

With the success of this study, the OIC NEW team of scientists will open a new direction in the application of rutin by nanotechnology to treat cancer. At the same time, it creates a premise for the development of new research on Nano technology based on this first published process.

Currently, the OIC R&D team and Inventor Luu Hai Minh are taking the final steps to announce Nano NO+ to help promote cardiovascular health; Reduce high blood pressure, prevent cardiovascular diseases such as atherosclerosis, stroke.

The study “Evaluation of cytotoxic effects of Rutin Prenanoemulsion in lung and colon cancer cell lines” was published in the Hindawi Journal of Science and Technology. Readers can watch it in full here.

Nhat Hai New Technology Joint Stock Company

Tel.: 1900 63 69 13

Address: 66 Trung Hoa, Cau Giay, Ha Noi

Website: https://oic.com.vn/

NEW OIC and 11-year journey from pioneer to leader

quản trị viên — Wed, 20 Jan 2021 09:59:51 +0000

Why Nano and the Story of Capturing Technology

Doing science is synonymous with research and development

OIC NEW received the title of the main industrial product of Hanoi city

New journey – new mission

“OIC’s responsibility is the responsibility of a new age scientist.”

Nhat Hai New Technology Joint Stock Company

Tel.: 1900 63 69 13

Address: 66 Trung Hoa, Cau Giay, Ha Noi

Website: https://oic.com.vn/