TAF Articol Rich-Lipid Diet 02.03

The effect of gold nanoparticles synthesized with Cornus mas L.
on high fat
diet mice -experimental study
Diana Dalina Zugravu (Pop), Stefan Lucian Popa, Andrei-Vasile Pop, Remus Moldovan, Flaviu
Tăbăran, Simona Clichici
A diet characterized by a high lipid content establishes a correlation between elevated cholesterol
levels in the bloodstream and the advancement of liver disease, specifically hepatocellular
carcinoma. Despite extensive epidemiological investigations delving into the relationship between a
lipid-rich diet and the progression of liver disease, the exact mechanism underlying hepatotoxicity
resulting from such dietary patterns remains elusive (1)
Liver disease
Chronic liver disease is mainly cause by numerous factors as: (2)
Infections Immune system Cancers and Genetic Other causes

problems tumors conditions
Hepatitis A Autoimmune Liver cancer Alpha-1 Alcohol abuse
hepatitis antitrypsin
deficiency
Hepatitis B Primary biliary Bile duct cancer Hemochromatosis Drug overdose
Cholangitis
Hepatitis C Primary Liver cell Hyperoxaluria Nonalcoholic
sclerosing adenoma fatty liver disease
cholangitis (NAFLD)
Hepatitis D Wilson’s disease
Hepatitis E
To protect liver health and prevent disease advancement, it is advisable to adhere to various
preventive measures. These measures encompass minimizing exposure to hepatotoxic agents,
refraining from alcohol consumption, implementing antiviral treatments as appropriate, and
adhering to a balanced diet (3).
Recent research underscores the heightened susceptibility of hepatic liver diseases, including
hepatocellular carcinoma, to progression in individuals experiencing overnutrition, obesity, and the
consumption of a diet rich in lipids (4).
High fat diet

Studies indicate that experimental animals are often subjected to a high-fat diet to induce hepatic
steatosis, characterized by mononuclear inflammation and aberrant mitochondrial function. This
dietary regimen also results in insulin resistance, obesity, and disturbances in serum blood
parameters, including elevated cholesterol levels, abnormal aminotransferase levels, increased
triglycerides, hyperglycemia, and heightened insulin levels. Histopathological examinations following
the administration of a lipid-rich diet reveal liver tissue changes such as steatosis, mitochondrial
abnormalities, necroinflammation, pericentral fibrosis, and hepatocyte apoptosis (5).
The onset of hepatic steatosis is influenced by dietary factors, lipid composition, and quantity
delivered to hepatocytes, potentially serving as risk factors for insulin resistance, obesity, and
diabetes. Studies on animal models have revealed that certain saturated fatty acids trigger
lipotoxicity, while others, like n-3 polyunsaturated fatty acids (PUFAs), can be beneficial. Research
conducted on mice has demonstrated that a high lipid diet induces inflammation, significant
steatosis, and liver fibrosis (6).
Comprehending the mechanisms triggered by particular lipids could assist in the prevention of
hepatocellular carcinoma (1).
Cholesterol serves as a fundamental component in the human body owing to its pivotal roles in
cellular and systemic functions. Maintaining optimal functionality necessitates the maintenance of a
dynamic equilibrium among processes including uptake, biosynthesis, export, and esterification (7).
Cholesterol is synthesized through a series of enzymatic reactions within the mevalonate pathway
(8). This pathway holds significant importance in numerous cellular processes by facilitating the
synthesis of sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, including isopentenyl
tRNA, dolichol, heme-A, and ubiquinone (9).
Within the human body, cholesterol levels are governed by two distinct pathways: firstly, the hepatic
synthesis originating from acetyl-CoA through the regulation of hydroxymethylglutaryl-CoA (HMG-
CoA) reductase, and secondly, absorption from ingested food within the intestines. In cases of
excessive lipid intake, both the de novo cholesterogenesis by hepatocytes and cholesterol absorption
by enterocytes are restrained to uphold homeostasis (10).
Prior to 2015, dietary guidelines advised a consumption of up to 300 milligrams (mg) of dietary
cholesterol daily for individuals deemed healthy, and 200mg for those identified as being at high risk
of heart disease. However, as of 2015, these guidelines underwent revision, and presently, there are
no explicit recommended limits for cholesterol intake. Nonetheless, it is emphasized that there
should be constraints on the consumption of saturated and trans fats (11).
Nevertheless, determining daily cholesterol intake through the use of frequency questionnaires may
not consistently align with actual dietary consumption, and the precise mechanism underlying the
hepatotoxic effects of a lipid-rich diet remains elusive.
Gold nanoparticles
Gold nanoparticles have attracted considerable interest owing to their exceptional optical
characteristics, biocompatibility, and capacity for surface modification through the attachment of
diverse ligands (12). Recognized for their anti-inflammatory properties, gold nanoparticles are
presently under investigation in the context of patients with rheumatoid arthritis (13).
Cornus mas
Regarding Cornus mas L., it is the fruit of Cornelian cherry belonging to the Cornaceae family, with
anti-inflammatory effects, especially due to iridoids. Cornuside, a secoiridoid isolated from Cornelian
cherry, is known to reduce the mRNA of iNOS and COX-2, inhibit LPS-induced production of PGE2,
NO, IL-1β, IL-6, and TNF-α. Glycosides isolated from Cornus mas inhibit the secretion of IL-6 and IL-1,
PGE2 in rat plasma, TNF-α in peritoneal macrophages, and edema (14).
Oxidative stress
Oxidative stress is acknowledged as a unified pathological mechanism that plays a role in the onset
and advancement of liver injury. Numerous risk factors, encompassing alcohol consumption,
pharmaceutical substances, environmental contaminants, have the potential to induce oxidative
stress in the liver. This, in turn, leads to the development of serious liver conditions, including
alcoholic liver disease and non-alcoholic steatohepatitis. The utilization of antioxidants represents a
convincing therapeutic approach aimed at preventing and treating liver diseases associated with
oxidative stress (15).
Glutathione (GSH), a tripeptide primarily found in high concentrations within the liver, serves as a
pivotal thiol reducing agent crucially engaged in the regulation of redox mechanisms. Furthermore,
research has elucidated that GSH not only functions as a conventional free radical scavenger but also
actively contributes to the intricate network dictating the balance between cellular survival, necrosis,
and apoptosis (15).
The ratio between reduced glutathione (GSH) and oxidized glutathione (GSSG) serves as an indicator
of cellular healthiness (16). The extent of oxidative stress can be evaluated by measuring the levels of
malondialdehyde (MDA).
Aim
The aim of our study was to investigate the histological changes occurring shortly after the
administration of a high-fat diet compared to a control group fed a normal diet.
Subsequently, we selected several oxidative stress markers and analyzed how they are
altered following the administration of solutions containing Cornus mas and, respectively,
solutions of gold nanoparticles phytoreduced with Cornus mas, in comparison to the control
group. Simultaneously, we aimed to elucidate any potential differences between the two
types of solutions and to examine whether gold nanoparticles have a potentiating or
inhibitory effect on the Cornus mas solution, or if there is any significant difference between
them.
Methods
For our experiment we used Sprague Female rats that were fed for a period of 9 moths with high fat
diet (HFD).
We selected randomly 4 groups of animals :
1. HFD group received -> saline solution
2. HFD+ Cornus mas (CM) group received –> CM solution
3. HFD + AuNPsCM group received –AuNPsCM solution
4. Control group – standard diet- saline solution by oral gavage

High fat diet
Throughout the entirety of the experimental duration, a standardized lipid-rich diet of 20g/100g
body weight per day via gavage administration was employed, providing a supplemental energy
increase of 45%. Adherence to the manufacturer's specifications ensured the constituents of the diet,
encompassing L-cysteine, casein, maltodextrin, corn starch, lard, salt, cellulose, a vitamin-mineral
premix, soybean oil, calcium carbonate, choline, dye, monocalcium phosphate, and butylated
hydroxytoluene (BHT), were meticulously followed.
The caloric value of the diet was 4.75 kcal/g and consisted of 24.3% crude protein, 21.2% crude fat,
11.75% crude fiber. The diet was produced by Cantacuzino National Medico-Military Institute for
Research and Development, Bucharest, Romania, with the identification number ROB0001.
Experimental Design
We used 32 rats for randomizing divided into four groups, each group being formed of 8 rats (n=8).
The high fat diet was administrated for 32 weeks, and after that the treatment was induced for a
period of 4 weeks, according to the rats group. Our experiment ended after week 36. The treatment
was administrated to overweight rats at the beginning of week 33 due to the plan:
1. HFD received from week 33 by oral gavage for 4 weeks normal saline 0,9%
2. HFD+CM received from week 33 by oral gavage for 4 weeks cornus mas extract solution
3. HFD+ AuNPsCM received from week 33 by oral gavage for 4 weeks gold nanoparticles
phytoreduced with bioactive compounds from Cornus mas L. extract.
4. The control group received standard diet for 32 weeks, and from week 33 by oral gavage
normal saline 0.9%
Medication was administrated between 7 a.m. and 8 a.m. in an amount of 0,5mL/day by gastric tube
gavage. The amount of Cornus mas L. extract administrated was 0.158mg/ml polyohenols ) and the
amount of gold nanoparticles functionalized with bioactive compounds from Cornus mas L extract
(260 µg Au /kg/day). We also took samples of blood with K3EDTA tubes from the retrooribital plexus
of rats under mild anesthesia. Anesthesia was performed with 2.5 mg/100gbw ketamine 10% and 50
mg/100gbw of xylazine hydroxichloride 2%. The blood was centrifuged at 6,500 rmp for 10 minutes
and kept at -80 ͦ until further biochemical analysis.
In the end, we induced deep anesthesia in rats, using ketamine 10% (5mg/100gbw) and xylazine
hidroxichoride 2% ( 100mg/100gbw) to collect the liver.
Material and methods

The harvested hepatic tissues were fixed by immersion in 10% neutral-buffered formalin (NBF). After
complete fixation, the samples were trimmed and embedded in paraffin wax following a routine
protocol (Prophet et al. 1992). The paraffin blocks were sectioned (2 µm) using the rotary microtome
and stained using hematoxylin–eosin (H&E). Histopathological slides were examined under an
Olympus BX51 microscope and micrographs were obtained using an Olympus SP350 digital camera
and finally processed using the Olympus cellSens dedicated software.
Results
fel?
Control group: There are no significant findings. H&E stain, ob x 20 (left) and x 40 (right)
HFD group :There is minimal diffuse hepatocyte glycogenosis. There are no significant findings within
the portal spaces. H&E stain, ob x 20 (left) and x 40 (right)
HFD+ AuNPsCM: There is minimal zonal (mainly mod-zonal and centrilobular) glycogenosis (minimal).
There are no significant findings within the portal spaces. H&E stain, ob x 20 (left) and x 40 (right)
HFD +CM: There is minimal zonal (mainly mod-zonal) glycogenosis (minimal). There are no significant
findings within the portal spaces. H&E stain, ob x 20 (left) and x 40 (right)
Fig 1.
Fig. 2 Fig. 3
Tab. 2
The data underwent analysis via one-way ANOVA, subsequently followed by Tukey's multiple
comparisons posttest utilizing GraphPad Prism 9.3.1 software (GraphPad, San Diego, USA). Results
were presented as means with standard deviation (±S.D.); significance levels were denoted as
*p<0.05, **p<0.01, and ***p<0.001 compared to the control group.
If we compare the MDA levels in the test group (DBL/HFD) with the HFD + CM group, we will obtain
statistical significance (***p<0,001). Similarly, comparing the MDA levels in the test group (DBL) with
the HFD + AuNPsCM group will yield statistical significance (***p<0,001). Moreover, comparing the
MDA levels in the HFD + CM group with the control group results in statistical significance (**p<0,01).
Likewise, comparing the MDA levels in the HFD + AuGNPsCM group with the control group will yield
statistical significance (**p<0,01). By comparing the MDA value in the test group (DBL) with the
Control group, statistical significance was observed between the two groups (*p<0,05). However,
comparing the MDA levels between the two groups, HFD + CM and HFD + AuGNPsCM, does not yield
statistical significance.
Elevated levels of malondialdehyde (MDA) were noted (*p<0.05, **p<0.01, and ***p<0.001) in the
groups subjected to a high-fat diet (HFD/DBL), HFD+CM, and HFD+ AuNPsCM, in comparison to the
control group. Upon comparing MDA levels between the HFD+CM and HFD+ AuNPsCM groups, no
statistically significant differences were detected. In the groups where CM or AuGNPsCM were
administered, the MDA levels exhibited a significant decrease compared to the test group.
Tab. 3
*p<0.05, **p<0.01, ***p<0.001 ****p< 0,0001 compared to the control group.
If we compare the TNF alpha (tumor necrosis factor) value between the test group DBL and the
HFD+CM group, statistical significance will be observed (****p<0.0001). However, if we compare the
TNF alpha value between the test group DBL and the HFD+AuNPsCM group, no statistical significance
will be evident between the two groups. Moreover, comparing the test group DBL with the control
group yields a p-value of <0.0001, indicating statistical significance between these two groups.
Furthermore, if we compare the control group with both the HFD+CM group and the HFD+AuNPsCM
group, statistical significance (****p<0,0001) will be evident regarding each individual comparison
with the control group. However, when comparing them with each other, HFD+CM and
HFD+AuNPsCM, no statistical significance will be observed regarding the TNF alpha value between
the two groups. TNF alfa was surprisingly increased in study compared to control.
Fig. 4 Fig. 5
Tab 4.
Regarding IL-1 alpha (Interleukin-1 alpha), there were no statistically significant differences observed
when comparing the test group with the control group, as well as when comparing the test group
with the HFD+CM group. However, a statistically significant difference was noted (*p<0.05) when
comparing the test group (DBL) with the HFD+AuNPsCM group. Furthermore, no statistical
significance was found when comparing the IL-1 alpha value in the control group with the HFD+CM
group. Conversely, statistical significance (*p<0,05) was obtained when comparing the IL-1 alpha
value in the control group with the HFD+AuNPsCM group. Additionally, a slight statistical significance
(*p<0.05) was observed when comparing the IL-1 alpha value in the two groups, HFD+CM and
HFD+AuNPsCM.
Tab. 5
When comparing the toll-like receptor 4 (TLR4) value between the test group (DBL) and the control
groups, HFD+CM, as well as with the HFD+AuNPsCM group, a statistically significant difference of
considerable magnitude was observed between the test group and each of the three groups
(***p<0.001). Comparing the TLR4 value between the control group and the HFD+CM group revealed
a strong statistical significance (***p<0.001). The most robust statistical significance was observed
between the control group and the HFD+AuNPsCM group (****p<0.0001) concerning the TLR4 value.
Additionally, a slight statistical significance was observed between the HFD+CM group and the
HFD+AuNPsCM group regarding the TLR4 value (*p<0.05).
Fig. 6 Fig. 7
Tab. 6
When comparing the value of reduced glutathione and its ratio with oxidized glutathione (GSH/GSSG)
between the test group (DBL) and HFD + CM, as well as between the test group (DBL) and HFD+
AuNPsCM, a slight statistical significance was observed (*p<0.05). Regarding the control group, only a
slight statistical significance was obtained (*p<0.05) when compared to the test group (DBL)
concerning the value of GSH/GSSG. No statistical significance was observed between the control
group and the other groups: HFD+CM and HFD + AuNPsCM.
Tab. 7
When comparing the value of glutathione peroxidase (GPX) between the test group (DBL) and HFD +
CM, no statistical significance was observed; however, a slight statistical significance (*p<0.05) was
noted between the test group (DBL) and HFD+ AuNPsCM. Regarding the control group, only a slight
statistical significance (*p<0.05) was obtained when compared to the test group (DBL) concerning the
value of GPX. No statistical significance was observed for the value of GPX between the control group
and the other groups: HFD+CM and HFD + AuNPsCM.
Fig. 8 Fig. 9
Tab. 8
When comparing the studied groups, no statistical significance was obtained regarding the value of
catalase.
Tab. 9
When comparing the value of hyaluronic acid between the test group (DBL) and the HFD+CM group,
as well as between DBL and HFD+AuNPsCM, no statistically significant difference was observed.
However, a slight statistical significance (*p<0.05) was obtained when comparing the value of
hyaluronic acid in the test group (DBL) with the control group. Comparing the value of hyaluronic
acid in the control group with both the HFD+CM group and the HFD+AuNPsCM group yielded a
strong statistical significance (***p<0.001). No statistical significance was found between the
HFD+CM and HFD+AuNPsCM groups regarding the value of hyaluronic acid.
Discussion
In our study, we endeavored to examine the hepatic alterations resulting from a high-lipid diet
compared to a control group receiving a standard diet. Moreover, we sought to investigate whether
the administration of Cornus mas solution and AuGNPsCM solution yielded any hepatic
improvements in the rats to which they were administered. Despite the relatively brief duration of
administration of the CM and AuGNPSCM solutions in our experiment, subtle enhancements in
hepatic structure, particularly centrolobular, were discernible.
It can be observed that, compared to other studies in the literature (17), the group administered a
high-fat diet (HFD) exhibited the presence of hepatic steatosis (18).
In a study conducted by Romestaig et al. in 2007, it was found that a high-fat diet failed to induce
NASH or liver steatosis in experimental animals. This observation was attributed to the presence of
hepatic mitochondria expressing energy dissipation, which potentially mitigates steatosis and
oxidative stress (19).
Furthermore, another study suggests that NASH/NAFLD resulting from a lipid-rich diet is often
characterized by high instability and, at times, mild manifestations. The severity of this condition
appears to be strongly influenced by various factors including the duration and composition of the
high-fat diet, as well as the species, age, strain, and gender of the animals (5).
In their study, Nishikawa et al. observed that middle-aged C57BL/6 mice demonstrated elevated
hepatic lipid accumulation and a higher fat body weight ratio compared to their younger
counterparts. Moreover, a comparison between two mouse strains revealed that C57BL/6J male
mice exhibited lower liver lipid accumulation than BALB/c male mice (20).
On the contrary, a study conducted by Lieber et al. in 2004 investigated the effects of administering a
high-fat liquid diet to Sprague Dawley rats. Their findings revealed that after 3 weeks of dietary
intervention, the rats exhibited mild steatosis compared to those on a standard diet, with the liver
returning to a normal state post-experimentation. Additionally, the high-fat diet induced
mononuclear inflammation, abnormal mitochondrial morphology, and elevated levels of hepatic
tumor necrosis factor-alpha, collagen type 1, and oxidative stress markers, including heightened
levels of 4-hydroxynonenal (21).
The initiation of intracellular oxidative stress by oxidized low-density lipoprotein, via lipid
peroxidation products, triggers enhanced synthesis of the p53 protein and subsequent activation of
the tumor suppressor p53. These cellular responses likely stem from the cytotoxic effects of oxidized
low-density lipoprotein, as p53 activation elicits necrotic and apoptotic outcomes (22).
In a study conducted in 2018, Hui Chen et al. explored the utilization of gold nanoparticles for their
anti-inflammatory properties in mitigating weight gain in mice subjected to a high-fat diet. Their
findings indicated a shift in adipose macrophages from the M1 to M2 phenotype, potentially
contributing to weight reduction. Although the hypothesis remained unproven, the researchers
concluded that mice treated with gold nanoparticles while on a high-fat diet exhibited protection
against glucose intolerance and hyperlipidemia (13).
Recent research has highlighted the hepatoprotective effects of anthocyanins derived from cornelian
cherry fruit extract in animal experimental models, suggesting a potential impact on non-alcoholic
fatty liver disease (NAFLD) (23). An additional study highlighted the antioxidant properties of Cornus
mas L., attributed to its antioxidant constituents. These components have been shown to restore
aberrant biochemical profiles and promote membrane stabilization when subjected to CCl4
exposure, thereby demonstrating its therapeutic potential in the management of liver disorders (24).
Oxidative stress arises from an inequality between the generation of free oxygen radicals and their
neutralization by the antioxidant defense system. This imbalance has the potential to inflict damage
on various cellular and extracellular components (25). Oxidative stress is recognized as a collective
pathological mechanism that plays a role in both the onset and progression of liver injury (26).
Malondialdehyde (MDA) serves as a biomarker for assessing oxidative stress levels in diverse
biological samples (27).
Comparing our MDA values with the literature (28) we obtained similar results in our study, the MDA
value increases following the administration of HFD compared to the control group, while after the
administration of solutions with Cornus mas or solutions with gold nanoparticles functionalized with
Cornus mas, its value begins to decrease compared to the control group.
Conclusion
Our investigation highlights the incidence and progression of histological alterations observed in an
experimental model involving the administration of a high-fat diet to rats. Furthermore, we elucidate
the evolution of these histological changes subsequent to the administration of Cornus mas solution
and AuNpsCM solution. In our study, we monitored the evolution of oxidative stress markers and
arrived at the following conclusions: The MDA value significantly decreased in groups with HFD
administered with CM and AuNPsCM solutions, with no statistically significant difference between
the two. The TNF-alpha value markedly increased in groups with HFD administered with CM solution
and AuNPsCM solution, without statistically significant evidence between the two solutions. The IL1-
alpha value showed a slight statistically significant increase in the HFD group administered with CM
solution and in the HFD group administered with AuNPsCM solution, with a slight statistically
significant difference between the two solutions, indicating a slight superiority of the CM solution.
Regarding the TLR4 value, there was a significant increase with the administration of CM and
AuNPsCM solutions in the HFD group, with a slight statistical significance between the two solutions,
with the AuNPsCM solution being slightly more statistically significant. We also tested the GSH/GSSG
ratio, where no statistically significant differences were found between the control group and the
HFD groups administered with CM and AuNPsCM solutions. The only slightly statistically significant
differences were obtained when administering the solutions to the test group (DBL), with a slight
statistical significance observed between the GSH/GSSG ratio values of the test group and the control
group. Similar results to those observed for the GSH/GSSG ratio were obtained for GPX as well.
Regarding catalase, in the case of our groups, statistically significant values were not obtained. We
obtained statistically significant results regarding the value of hyaluronic acid. Comparing the control
group with the HFD groups administered either CM or AuNPsCM solutions, there was a significant
increase in both cases, with no statistically significant difference between the two solutions in our
results.
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The effect of gold nanoparticles synthesized with Cornus mas L.

Infections Immune system Cancers and Genetic Other causes

High fat diet

We selected randomly 4 groups of animals :

1. HFD group received -> saline solution

2. HFD+ Cornus mas (CM) group received –> CM solution

3. HFD + AuNPsCM group received –AuNPsCM solution

4. Control group – standard diet- saline solution by oral gavage

Material and methods

1. Wang X, Tanaka N, Hu X, Kimura T, Lu Y, Jia F, et al. A high-cholesterol diet promotes steatohepatitis

11. Dietary_Guidelines_for_Americans_2020-2025 [Internet]. Available from:

23. Sangsefidi ZS, Hosseinzadeh M, Ranjbar AM, Akhondi-Meybodi M, Fallahzadeh H, Mozaffari-Khosravi

27. Cordiano R, Di Gioacchino M, Mangifesta R, Panzera C, Gangemi S, Minciullo PL. Malondialdehyde as

28. Khoubnasabjafari M, Ansarin K, Jouyban A. Reliability of malondialdehyde as a biomarker of oxidative

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