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Received: 3 December 2019    Revised: 8 March 2020    Accepted: 10 March 2020

DOI: 10.1111/jfbc.13219

FULL ARTICLE

Immunomodulatory effect of curcumin on hepatic cirrhosis in

experimental rats

Mabrouk A. Abo-Zaid1  | Emad S. Shaheen2 | Ahmed H. Ismail1

1
Department of Biology, Faculty of Science,
Jazan University, Jazan, Saudi Arabia Abstract
2
Medical Research Centre, Jazan University, Cirrhosis is a chronic liver disease. The present work aimed to evaluate the regula-
Jazan, Saudi Arabia
tory immune effect of curcumin in hepatic cirrhosis induced by carbon tetrachloride
Correspondence (CCl4) injections in experimental rats’ model. Chronic liver fibrosis was induced in ex-
Mabrouk A. Abo-Zaid and Ahmed H. Ismail,
periment animals by recurrent injections of CCl4 for more than 5 weeks. They were
Department of Biology, Faculty of Science,
Jazan University, Jazan, Saudi Arabia. divided into five groups: first group was injected with normal saline, second group
Email: mabrouk_ss@yahoo.com (M. A. A.-Z.)
with CCl4, third, fourth, and fifth groups were injected with CCl4 (intraperitoneal
and ahanafy12@gmail.com (A. H. I.)
injection) at dose 3 ml/kg, two times weekly for 6 weeks supplemented with the ad-
ministration of curcumin with concentrations 250, 200, and 150 mg/kg. Immune re-
sponse was analyzed to different treatments. Interleukin 10 (IL-10), pro-inflammatory
cytokines TNF-α, TGF-1β, and liver histopathological examinations were conducted.
The results showed that estimations of IL-10 concentrations were significantly in-
creased in curcumin groups compared with CCl4 group, whereas TNF-α and TGF-1β
levels were significantly decreased comparing with CCl4 group. The histopathologi-
cal examinations for liver tissues showed that curcumin treated groups have almost
retained the normal structure of liver tissues. In conclusion, curcumin inhibited he-
patic fibrosis and liver fibrogenesis with regulation of the immune system mechanism
against invader chemical toxicity.
Practical applications
Curcumin is well documented for its medicinal properties, commonly used as a spice.
Our work has thus demonstrated its effectiveness as an immunomodulatory agent.
Practically, clinical studies have suggested that curcumin displays a diverse and powerful
array of pharmacological effects in nearly all of the human body's major organ systems.
These are: antidiabetes, anti-inflammatory, anticancer, antiaging, antioxidant, antibacte-
rial infection, hepatoprotective, neurodegenerative, and cardiovascular effects.

KEYWORDS

curcumin, cytokines, hepatic cirrhosis, immunomodulatory

1 |  I NTRO D U C TI O N of liver diseases are infectious diseases mainly from viruses and para-
sites as in Africa and Asia (Buonomo et al., 2019). Liver fibrosis occurs
Liver diseases are considered as an important diagnostic sign for body as a result of chronic liver diseases, in which excessive accumulation of
health. In such countries that suffers from obesity and alcohol abuse; some extracellular proteins such as collagen are presented. Information
liver diseases obviously occur, while in poor localities, the main cause about the cellular and molecular mechanisms of liver fibrosis has been

J Food Biochem. 2020;00:e13219. wileyonlinelibrary.com/journal/jfbc |

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greatly modified. The diseased liver cells markedly develops collagen Numerous purposes have been attributed to cytokines, compris-
producing cells like hepatic stellate cells, portal fibroblasts, and myofi- ing stimulation of (TGF) β1, (TNF)-α, and (IL)-6. Transforming growth
broblasts. These cells are stimulated by some cytokines like TGF-β1, an- factor β1 is related to the stimulation of perisinusoidal cells. Also,
giotensin II, and leptin (Komolkriengkrai, Nopparat, Vongvatcharanon, TNF-α and IL-6 are considered a main hepatotoxicity mediators in
Anupunpisit, & Khimmaktong, 2019). several experimental models of liver disease (Seki & Schwabe, 2015).
While some studies have also shown ability for regeneration or So, we targeted to study curcumin immunomodulatory effect in
healing of the liver itself, the liver usually does not heal once liver dam- experimental rats with CCl4-induced hepatic cirrhosis.
age is done in humans. However, changes in medicines and lifestyle can
help prevent fibrosis from getting worse. There are many factors that
cause chronic liver damage, such as alcohol, medications, toxins, viral 2 | M ATE R I A L S A N D M E TH O DS
hepatitis, and autoimmune diseases (Koyama & Brenner, 2015). Liver
cirrhosis, hepatocellular carcinoma, and even death may be occurred if 2.1 | Animals and experimental design
hepatic fibrosis left without treatment (Jung & Yim, 2017).
Transforming growth factor-β1 is an active profibrotic cytokine Sixty male Rattus rattus L. rats were brought from Medical Research
with multifunctional functions in cell proliferation, cell differentiation, Center, Jazan University, Jazan, Saudi Arabia. They were reared in
wound healing, angiogenesis, and immune response (Mishra, Derynck, our facilities and maintained in a 12 hr light/12 hr dark cycle under a
& Mishra, 2005; Rahimi & Leof, 2007). TGF-β1 mediated signaling is a suitable temperature (20 ± 4°C) and relative humidity (55% ± 10%).
key trigger for collagen manufacturing (Xu et al., 2002) and excessive The animals had free access to regular food and water for one week
development of collagen contributions to fibrosis of the human body for adaptation, and then, divided into five groups. All groups were
or mice (Dooley & Ten Dijke, 2012; Trautwein, Friedman, Schuppan, & injected intraperitoneally with (3 ml/kg) CCl4 two times weekly for
Pinzani, 2015). Perisinusoidal cells are the major types of cells that can 6 weeks except the control group was inoculated with saline (3 ml/
become collagen producing myofibroblasts in the liver and contribute kg). The second group received CCl4 alone, 3  ml/kg) two times
to pathological fibrosis (Friedman, 2008; Mederacke et al., 2013). weekly for 6  weeks without treatment. Third, fourth, and fifth
Carbon tetrachloride (CCl4) is a liver toxin that destroying liver groups received CCl4, 3 ml/kg accompanied with orally curcumin at
architecture causing liver necrosis, fibrosis, and cirrhosis, when ap- doses of 150, 200, and 250 mg/kg. The animal model was conducted
plied periodically. Hepatotoxicity composed of two phases (Basu, according to Proctor and Chatamra (1982).
2003). The first phase showed metabolization of CCl4 by cyto-
chrome P450 resulting in a highly reactive trichloromethyl radicals
companied with some inflammatory responses, which considered as 2.2 | Chemicals
an important factor in liver hepatotoxicity (Zhang et al., 2004). Later,
in the second stage, some liver cells, such as Kupffer cells, perisinu- Curcumin was purchased from Sigma-Aldrich Company Ltd. (1386,
soidal cells, and sinusoidal endothelial cells, are excited to generate Sigma Aldrich, St. Louis, Mo, USA). All other reagents and chemicals
cytokines that promote liver fibrogenesis (Zhang et al., 2004). used were of diagnostic and analytical grade.
Recently plant extract medications occurred as effective liver
cirrhosis therapies (Kim et al., 2014). For example, Han et al. (2013)
and Hong, Kim, and Yoon (2011) used extracts from Artemisia cap- 2.3 | Preparation method of curcumin extract
illaris Thunb in liver treatment that resulted in fibrinogen secretion
shrinkage and a specific portion inhibited proliferation of fibroblast. Curcumin was prepared in a small amount of dimethyl sulfoxide
Curcumin is extracted from Curcuma longa Linn, rhizome a member (DMSO, equal to <1% of the final volume). Dimethyl sulfoxide cur-
of the Zingiberaceae family. This pigment showed an antioxidant, cumin solution was filtered using filter paper (0.22 μm). Aliquots
anti-inflammatory, and anticarcinogenic effects (Qiu et al., 2017). were kept at (20°C) away from light.
Previous investigations indicated that its mode of action could be ei-
ther directly interfering with molecular targeting or altering the gene
expression and signaling pathway. Cai et al. (2017) demonstrated 2.4 | Biochemical study
that curcumin prevents liver cirrhosis by inhibiting the pathway of
NF-κB and decrease oxidative stress. Therefore, curcumin has effec- 2.4.1 | AST and ALT determination was estimated
tive role as a treatment for hepatic diseases. according to Wilkinson, Baron, Moss, and Walker
Curcumin immunomodulatory effects have been described (1972).
previously indicating its modulatory and activating functions of
T-lymphocytes, B-lymphocytes, NK cells, and phagocytic cells 2.4.2 | Enzyme-linked immunosorbent assay
(Jagetia & Aggarwal, 2007). Moreover, curcumin proved a downregu-
latory effect on the expression of many pro-inflammatory cytokines, The collected sera were used to evaluate some immunological pa-
such as interleukins IL-1, IL-2, IL-6, IL-8, and IL-12 and tumor necrosis rameters by enzyme-linked immunosorbent assay (ELISA).
factor-α (TNF-α) by deactivation of NF-κB (Bruck et al., 2007). IL-10 using Rat Coated ELISA Kit Cat. No.; BMS629.
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F I G U R E 1   Histograms for ALT and AST in the different animal groups

TNF-α using Tumor Necrosis factor alpha (Rat) ELISA Kit groups were evaluated. Data were presented as mean ± SD. Tukey
(CUSABIO) Catalog No.; CSB-E11987r. test was used for comparisons between groups. Statistical signifi-
TGF-β1 using Transforming Growth Factor β1 (Rat) ELISA Kit cance was considered at p < .05.
(CUSABIO) Catalog No.; CSB-E04727r.

3 | R E S U LT S
2.5 | Histological investigation
3.1 | Biochemical criteria
The liver tissues from different groups were collected and fixed in
formalin solution (10%), soaked in paraffin wax, and sectioned by Figure  1 demonstrates aminotransferases levels in rats with CCl4-
microtome. Then, sections were stained by hematoxylin and eosin induced hepatic fibrosis. The data obtained in Figure 1 indicate that
(H&E) stain and examined by light compound microscope. ALT levels were significantly decreased in groups (3, 4, and 5), re-
spectively (−39.21, −36.1, and −32.36% change, p < .05), as compared
to group (2) CCl4 group. While, AST level in groups treated with cur-
2.6 | Statistical analysis cumin at doses 250 (G3), 200 (G4), and 150 (G5) mg/kg showed a
significant decrease in AST levels, reached (−39.5%, −35.45%, and
ANOVA tests were conducted to analyze obtained data using the −41.23% change) as compared to CCl4 group (G2). On the contrary,
SPSS 17 software package for Windows. The dissimilarities between the data in Figure 1 showed a significant increase in serum ALT and
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AST levels in CCl4 group (G2), percentage change recorded (87.58% and G5 showed a significant reduction (p < .05) as the percentage
& 89.4%) as compared with control negative (G1). changes recorded −61.0%, −53.65%, and −50.0%, respectively, com-
pared to the CCl4 group (G2).

3.2 | Immunological criteria
3.3 | Histopathological criteria
3.2.1 | IL-10
Figure 3a represents a photomicrograph of liver of control rat
The data obtained in Table  1 and Figure  2 revealed a significant showing the normal rat liver and the arrangement of the liver cells
decrease in serum IL-0 level in the CCl4 alone (G2) amounted to (hepatocytes) in the form of strands extending from the central vein,
−18.95% as compared to control group. In contrast, groups (G3, G4, the hepatic strands separated by sinusoids with an endothelial lin-
and G5) received CCl4 and treated with curcumin at doses 250, 200, ing including kupffer (K) cells. The peripheral cells are larger in size
and 150 mg/kg, respectively, showed a significant increase (p < .05) than those pericentrally located; these cells are bordered by defined
as the percentage changes recorded (75.58% & 116.64%), (53.93% boundaries, having a slightly granulated cytoplasm with one or two
& 89.92%), and (61.94% & 99.81%), respectively, in comparison with nuclei. Liver section of rat received CCl4 alone showed infiltration of
the control group (G1) and CCl4 group (G2). lymphocytes, degeneration of liver tissue, fibrous tumor, whereas in
other parts, the tumor consisted of finger-like strands of cells epithe-
lial tumor was formed. Pattern of hepatocellular carcinoma in these
3.2.2 | TNF-α parts was also observed (Figure 3b). On the contrary, section of rat
liver tissue from rats received CCl4 and treated with curcumin at
The data obtained in Table 1 and Figure 2 revealed a significant eleva- 150 mg/kg showed droplet fat scattered between hepatocytes cells
tion in serum TNF-α concentration in the CCl4 group (G2) amounted to and appeared also in central vein accompanied by some pyknotic
69.04% change as compared to control group. In contrast, rats received nuclei at beneath of central vein (Figure 3c). The rats received CCl4
CCl4 and treated with curcumin in G3, G4, and G5 showed a significant and injected with curcumin at 200 and 250 mg/kg showed winded
reduction (p < .05) as the percent changes recorded −50.58%, −48.14%, and elongated blood vessels with dilated sinusoids with activated
and −42.73%, respectively, compared to the CCl4 group (G2). kupffer cells appeared as normal structure, sinusoids returned to
the normal size, also whole structure appeared as normal with some
droplet fat beside slight dilation of sinusoids (Figure 3d and e).
3.2.3 | TGF-1β

The data obtained in Table  1 and Figure  2 indicated a significant 4 | D I S CU S S I O N

elevation in serum TGF-1β concentration in the CCl4 group (G2)
amounted 86.24% (p  <  .05) as compared to control group. In con- This study is presented to evaluate the effect of curcumin extract
trast, rats received CCl4 and treated with curcumin in G3, G4, against hepatic fibrosis in rats. In this study, the hepatic fibrosis

TA B L E 1   Effect of curcumin therapy on level of immune response in rat's hepatic fibrosis induced by CCl4

ANOVA

  G1 G2 G3 G4 G5 F P
a,b a,b a,b
IL-10 (pg/ml) 222.5 ± 19.14 180.33 ± 14.96 390.67   ± 24.8 342.5   ± 37.35 360.33   ± 23.04 81.4 p < .05
Percentage of −18.95* 75.58* & 116.64** 53.93* & 89.92** 61.94* & 99.81**
change
TNF-α (pg/ml) 340.5 ± 18.11 560.17a  ± 69.04 275.17a,b  ± 23.54 290.5b  ± 13.53 320.83b  ± 15.22 66.77
Percentage of 64.51* −19.19* & −50.88** −14.68* & −48.14** −5.78* & −42.73**
change
TGF-1β (pg/ml) 220.5 ± 15.62 410.67a  ± 119.46 160.17b  ± 18.78 190.33b  ± 10.44 205.17b  ± 14.47 19.52
Percentage of 86.24* −27.36* & −61** −13.68* & −53.65** −6.95* & −50**
change

Note: G1, Control; G2, CCl4 group; G3, CCl4 with curcumin 250 mg/kg; G4, CCl4 with curcumin 200 mg/kg; G5, CCl4 with curcumin 150 mg/kg.
a
Significant comparing to control negative;
b
Significant comparing to CCl4 group.
*Percentage of change comparing to control negative; **Percentage of change comparing to CCl4 group.
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F I G U R E 2   Histogram for plasma cytokines in the different animal groups

was induced by administration of CCl4. Several methods have been and AST levels were reduced significantly in rats treated with CCl4
used to cause liver fibrosis in animals. The most widely used hepa- and treated with curcumin at different doses, 250, 200, and 150 mg/
totoxic drugs-induced cirrhosis models are CCl4-induced cirrho- kg body. The data revealed dose-dependent difference observed be-
sis (Basu, 2003; Mohammed & Abu-Deif, 2018). Chronic irregular tween these three groups. These result are similar to the result of
administration of CCl4 convinced fibrotic changes, after a marked Sundari et al. (2018) who reported that after treatment with water
infiltration of inflammatory cells, especially in lymphocytes and extract of Phaleria macrocarpa (Proliverenol) against CCl4-Induced
monocytes. liver fibrosis in experimental rats, ALT and AST were significantly de-
The results of the present study revealed that CCl4 induced he- creased. Also Chinnala et al. (2018) found that serum ALT, AST, and
patic fibrosis. The rats received CCl4 alone without treatment re- ALP levels were significantly decreased by administration of ethano-
corded a highly significant increase in ALT and AST levels percent lic extract of Allium sativum (EEAS) on thioacetamide (TAA)-induced
change, reached 90.4% and 91.2% as compared with CCl4 group. hepatotoxicity in rats at 200 and 400 mg/kg. These results displayed
These findings agreed with Sundari, Soetikno, Louisa, Wardhani, and that curcumin protect the liver from fibrosis and also suppressed in-
Tjandrawinata (2018) who revealed that water extract of Phaleria flammation caused by CCl4.
macrocarpa and N-acetylcysteine (NAC) significantly protected Also, our results demonstrate that the curcumin enhanced IL-10
CCl4-induced liver injury in male Sprague-Dawley rats as established secretion which agrees with Mollazadeh et al. (2019). The level of
by decreased AST, ALT, ALP, and percentage of fibrosis as compared IL-10 in groups treated by curcumin at doses 250, 200, and 150 mg/
to the CCl4-only group. On the contrary, our study revealed that ALT kg body weight, recorded a highly significant increase at percent
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F I G U R E 3   (a): Normal liver tissue showing central vein (CV) with cords of normal liver cells radiating from it (arrow) and kupffer cells
(KC). (H & E, X100), (b): Liver tissue from rats exposed to CCl4 alone showed fibrous tumor (arrow), in other parts, the tumor consisted of
finger-like strands of cells, epithelial tumor was formed which produced the pattern of hepatocellular carcinoma in these parts sinus dilation
(SD) marked with (arrow) lined with endothelial cells (EC) and congestion of the portal blood vessels (H & E, X100), (c): Liver tissue from
rats exposed to CCl4 and treated with curcumin at 150 mg/kg showed droplet fat (arrow head) scattered between hepatocytes cells, and
appeared also in central vein accompanied by some pyknotic nuclei (arrow) at beneath of central vein. (H & E, X100), (d): Liver tissue from
rats exposed to CCl4 and treated with curcumin at 200 mg/kg showed winded and elongated blood vessels with dilated sinusoids (S) with
activated kupffer cells (KC) (Arrows) appeared as normal structure, sinusoids (S) returned to the normal size.(H & E, X250), (e): Liver tissue
from rats exposed to CCl4 and treated with curcumin at 250 mg/kg showing normal hepatic cells with slight congestion of sinusoids, portal
vein appeared in normal structure with slight dilation, with few droplet fat (H&E, X100)

change 73.3%, 52.5%, and 60.7%, respectively. On the contrary, Inflammation is commonly linked with hepatic fibrogenesis
IL-10 recorded significant decrease in rats injected by CCl4 alone at throughout chronic liver diseases (Seki & Schwabe, 2015). Underlying
percent change (−20.2%). Many studies indicate that IL-10 act as an- the mechanisms of protecting effects for curcumin, we suggested
tifibrotic agent, anti-inflammatory, and immunomodulatory effects that curcumin could safeguard the liver against CCl4-induced dam-
and can decrease and regulate manufacture of pro-inflammatory age by inhibiting inflammation in the liver and enhancement of IL-10
cytokines, like IL-1, INF-γ, and IL-2 from T-lymphocytes. These re- secretion. Sudo, Yamada, Moriwaki, Saito, and Seishima (2005)
sults confirm the result of Kohli, Ali, Ansari, and Raheman (2005) reported that the serum concentrations of TNF-α, INF-γ, and IL-6
who reported that IL-10 might have antifibrogenic properties by in CCl4 induced hepatic fibrosis in rats were significantly reduced
downregulate production of profibrogenic cytokines, such as TGF- under treatment with curcumin.
β1 and TNF-α. Also Shi et al. (2014) found that IL-10 apparently The data of the present study revealed a significant elevation
inhibits fibrosis by activating AKT and signal transducers and stimu- in serum TNF-α concentration in the CCl4 group amounted 64.7%
lators of transcription (STAT) 3 phosphorylation downstream of IL-10 comparing with control group. Also in this study, we observed in-
receptor. filtration of inflammatory cells in liver throughout the CCl4. This
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result confirms the result of Ezz, Hamdy, and Abd El Atti (2011) who activity (Chen, Brenner, & Kisseleva, 2019). Also liver fibrosis is
reported that concentrations of TNF-α is remarkably elevated by induced by increase secretion and decomposition of insoluble col-
CCl4 in the liver tissue. CCl4 activated Kupffer cells to produce as- lagen and extracellular matrix constituents following continuous
sortment of cytokines, such as TNF-α. All these molecules act as chronic damage in the liver. Kupffer–Browicz cells in Chemokine
inflammatory cytokines. Cytokines also can have a detrimental role, (C-X3-C motif) ligand 1 (CX3CR1)-deficient mice after CCl4 treat-
however, when secreted in enormous amounts, enhancing the im- ment revealed excessive expression of tumor necrosis factor alpha
mune response into double speed as a result stimulating the devel- and transforming growth factor beta and decreased expression
opment of liver cirrhosis (Li, Zhang, Chen, Huang, & Wang 2001). of the anti-inflammatory markers IL-10 and arginase-1 (Aoyama,
TNF-α is an inflammatory cytokine participating in liver inflam- Inokuchi, Brenner, & Seki 2010). Liver injury caused by increase
mation and continuous liver inflammation results in liver fibrosis. transforming growth factor beta (TGF-β) excite an increase in ex-
Yang and Seki (2015). On the contrary, our study revealed that rats pression levels of numerous cytokines involved in fibrogenesis,
which received CCl4 and treated with curcumin at doses 250 and including platelet-derived growth factor (PDGF), connective tis-
200  mg/kg showed a significant decrease in serum TNF-α as the sue growth factor (CCN2), and interleukins such as (IL-1α, IL-β, and
percent changes recorded −19.3% and −14.7%, respectively, in com- IL-6 and TNF-α) (Brigstock, 2010; Chen et al., 2019). curcumin re-
parison with the control group. Such results are in agreement with duces the inflammatory cells and liver fibrogenesis throughout the
Chainani-Wu (2003), who elucidated the basic immune defensive suppression of pro-inflammatory cytokines (Farzaei et al., 2018).
mechanisms of curcumin in inhibiting hepatic fibrogenesis in the ex- Curcumin not only inhibits pro-inflammatory cytokines, but also
perimental rats. Furthermore, curcumin was found to be capable to inhibits apoptosis and transformation of fibrogenic cells. These
reduce the level of TNF-α expression in vitro CCl4 injury rat models. results were confirmed with result of El-Houseini, El-Agoza, Sakr,
Curcumin not only prevents the stimulation of nitric oxide synthase and El-Malky (2017), who reported that oral administration of
in stimulated macrophages, but also inhibits the pro-inflammatory curcumin suspension (100 mg/kg) can inhibit the hepatic fibrosis
cytokines such as TNF-α, IL-6, and IL-2 and has been shown to be and have defensive effect against hepatocarcinogenesis in a rat
a potent scavenger of free radicals like nitric oxide (Park, Jeon, Ko, model of DENA-induced HCC. Several investigations were made
Kim, and Sohn, 2000). to evaluate the bioactivity and health benefits of curcumin, such
TGF-β1 is a vital pro-inflammatory and fibrogenic cytokine in liver as antioxidant, anti-inflammatory, immune regulatory, anticancer,
fibrosis Fan et al. (2013). Stimulation of hepatic stellate cells by trans- antidiabetic, neuro-protective, cardiovascular protective, and
forming growth factor (TGF)-β1 is a pivotal step in hepatic fibrosis hepatoprotective effects (Cao, Wang, & Wang, 2018; Wang, Li,
(Yu et al., 2018), the data of the present study revealed a significant Zhao, Li, & Yin, 2018). Likewise, preceding studies improved the
increase in serum TGF-1β in the group, which received CCl4 alone capability of curcumin to suppress the production of numerous
these results are in agreement with Hafez et al. (2017). The CCl4 have cancer cells in vitro and inhibit cancer propagation in rats Xu et al.
a crucial role in initiating necrosis of hepatocytes. The CCl4 enhanced (2018).
the production of profibrogenic factors as TGF-1β and TNF-α. Also,
our study revealed that curcumin significantly reduced the levels of
TGF-1β at doses 250 and 200  mg/kg body weight in serum of the 5 | CO N C LU S I O N
CCl4 rat model. Chang et al. (2007) and Jiang et al. (2004) stated
that the activation of transforming growth factor-β1 (TGF-β1) was The current work evaluated the protective role of curcumin against
elevated in experimental rats administered by a single dose of CCl4 liver injury and hepatic cirrhosis induced by CCl4 in rat model. We
(20%) in olive oil, and this rise was restored by a low-dose of herbal found that,
extract. Gaedeke, Noble, and Border (2004) reported that curcumin
inhibits the profibrotic activity of (TGF-b1) on renal fibroblasts via 1. Curcumin at dose of 250  mg/kg gave the best results in pro-
control of T beta RII, and via limited suppression of c-jun activity. tecting liver.
Liver histological changes (Figure  3) induced by CCl4 that 2. It enhanced the immune system response against fibrogenesis by
infiltrated enormous number of inflammatory cells in intralobu- suppressing pro-inflammatory cytokines such as TNF-α, IL-6, and
lar or interlobular regions, and a large number of fibrous tissues TGF-β.
was formed with irritation in hepatic fibrogenesis. Sudo et al. 3. It decreased the concentrations of serum GOT and GPT and im-
(2005) demonstrated that the CCl4 increased inflammatory cells proved the histological structure of the hepatic tissues.
and release of pro-inflammatory cytokines. Consequently, he-
patic stellate cells are transformed into myofibroblast cells to To conclude, Curcumin enhanced the immune system and sus-
produce more proteoglycans and collagen, increase accumula- tained the liver architecture against chemical toxicity.
tion and changed arrangement of extracellular matrix in hepatic
cells Tomita et al. (2006). Resolve of cirrhosis needs a decline of AC K N OW L E D G M E N T S
fibrogenic and pro-inflammatory cytokines, a reduction in extra- The facilities provided by the Faculty of Science at Jazan University,
cellular matrix protein production, an proliferation in collagenase Saudi Arabia are greatly acknowledged and appreciated.
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C O N FL I C T O F I N T E R E S T El-Houseini, M. E., El-Agoza, I. A., Sakr, M. M., & El-Malky, G. M. (2017).

Novel protective role of curcumin and taurine combination against
The authors declare that they have no conflict of interest.
experimental hepatocarcinogenesis. Experimental and Therapeutic
Medicine, 13, 29–36.
AU T H O R C O N T R I B U T I O N S Ezz, M. K., Hamdy, G. M., & Abd El Atti, R. (2011). The synergistic hepa-
Mabrouk A. Abo-Zaid and Ahmed H. Ismail researched data and toprotective effect of curcumin and ginger against carbon tetra-
chloride induced-liver fibrosis in rats. Australian Journal of Basic and
contributed to discussion and wrote the manuscript draft. Emad S.
Applied Sciences. 5, 1962–1971.
shaheen contributed to the statistical analysis and participated in Fan, X., Zhang, Q., Li, S., Lv, Y., Su, H., Jiang, H., & Hao, Z. (2013).
researched data and manuscript draft. Mabrouk A. Abo-Zaid and Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating
Ahmed H. Ismail reviewed the final manuscript and followed pub- against TGF-β1. PLoS ONE, 8, e82190.
lication process. Farzaei, M., Zobeiri, M., Parvizi, F., El-Senduny, F., Marmouzi, I., Coy-
Barrera, E., … Abdollahi, M. (2018). Curcumin in liver diseases: A
systematic review of the cellular mechanisms of oxidative stress and
E T H I C A L S TAT E M E N T clinical perspective. Nutrients, 10, 855.
All the experiments were performed in agreement with the regula- Friedman, S. L. (2008). Hepatic stellate cells: Protean, multifunctional,
tions of the institutional animal ethics committee of Jazan University, and enigmatic cells of the liver. Physiological Reviews, 88, 125–172.
Gaedeke, J., Noble, N. A., & Border, W. A. (2004). Curcumin blocks
Jazan, Saudi Arabia kingdom.
multiple sites of the TGF-β signaling cascade in renal cells. Kidney
International, 66, 112–120.
ORCID Hafez, M. M., Hamed, S. S., El-Khadragy, M. F., Hassan, Z. K., Al Rejaie,
Mabrouk A. Abo-Zaid  https://orcid.org/0000-0003-4267-8787 S. S., Sayed-Ahmed, M. M., … Alsharari, S. D. (2017). Effect of gin-
seng extract on the TGF-β1 signaling pathway in CCl 4-induced
Ahmed H. Ismail  https://orcid.org/0000-0002-4793-210X
liver fibrosis in rats. BMC Complementary and Alternative Medicine,
17, 45.
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