Geraniol prevents CCl4-induced hepatotoxicity via suppression of hepatic oxidative stress, pro-inflammation and apoptosis in rats

Abdulmohsen I Algefare; Manal Alfwuaires; Ademola C Famurewa; Hany Elsawy; Azza Sedky

doi:10.1016/j.toxrep.2024.01.007

. 2024 Jan 13;12:128–134. doi: 10.1016/j.toxrep.2024.01.007

Geraniol prevents CCl₄-induced hepatotoxicity via suppression of hepatic oxidative stress, pro-inflammation and apoptosis in rats

Abdulmohsen I Algefare ^a, Manal Alfwuaires ^a, Ademola C Famurewa ^b,^c,^⁎,¹, Hany Elsawy ^d, Azza Sedky ^a,^e,^⁎⁎

PMCID: PMC10831491 PMID: 38304701

Abstract

Carbon tetrachloride (CCl₄) is a classic chemical hepatotoxicant that triggers liver damage through hepatic exacerbation of oxidative stress. Geraniol (GRL) is a natural bioactive acyclic monoterpene with several pharmacological effects. We thus explored whether GRL could prevent CCl₄-triggered hepatic toxicity. Rats were divided and administered GRL (100 mg/kg) and/or CCl₄ (1 ml/kg of 1:1 v/v CCl₄: olive oil) in Control group, GRL group, CCl₄ group, GRL + CCl₄ groups 2 times per week for 4 consecutive weeks. CCl₄ caused significantly (p < 0.05) elevated serum activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TB), whereas the albumin (ALB) and total protein (TP) levels were significantly (p < 0.05) reduced relative to the control group. The liver activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) decreased significantly (p < 0.05), while malondialdehyde (MDA) level evidently elevated in comparison to the control group. The CCl₄ exposure caused significant increases in proinflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), apoptotic caspase-3 and caspase-9 levels, whereas the anti-inflammatory interleukin-4 (IL-4) and interleukin-10 (IL-10) were reduced in consistent with histopathological changes compared to the control. On the contrary, the GRL administration prevented the hepatic toxicity and lesions through restoration of liver status markers, antioxidant enzyme activities, MDA, cytokines and apoptosis in comparison to the CCl₄ group. Altogether, the findings reveal that GRL could abrogate CCl₄-provoked hepatic toxicity via inhibition of hepatic oxidative stress, inflammation and apoptosis in rats.

Keywords: Geraniol, Oxidative stress, Hepatotoxicant, Apoptosis, Hepatotoxicity

Graphical Abstract

ga1 — Schematic representation of experimental design and analyses.

Highlights

•
CCl4 induced hepatic toxicity via oxidative inflammation and apoptosis in rats.
•
The caspase signaling and hepatic dysfunction were upregulated in the CCl4-injected rats.
•
Geraniol exerted protective mechanism against oxidative inflammation and apoptosis in the liver of rats.
•
Geraniol improved liver enzyme activities and markers against CCl4 injury.

1. Introduction

Carbon tetrachloride is an industrial chemical and a classic hepatotoxicant. Carbon tetrachloride (CCl₄) is still found as a component of insecticides, fire extinguishers and grains exposed to fumigation [22]. Human exposure to CCl₄ is well recognised to cause liver fibrosis and injury to the liver organ; hence, it is an established experimental agent for development of hepatotoxicity model [29]. The target organ of CCl₄ metabolism is the liver, where it is metabolised by cytochrome P450-enzymes. The hepatic metabolism produces toxic oxidant metabolites like trichloromethyl peroxyl (•OOCCl₃) and trichloromethyl (•CCl₃) oxygen free radicals associated with hepatic oxidative degeneration and cell death. Several studies indicate that the oxygen free radicals orchestrate impairment in hepatic membrane organization and antioxidant homeostasis leading to activation of aberrant signalling that favours inflammatory cascades and apoptotic cues [25], [3], [6]. Specifically, trichloromethyl radical reacts with sulfhydryl (-SH) group of thiol proteins, glutathione and glutathione-based enzymes to overrun the hepatic antioxidant system as well as glutathione metabolism [6]. These intracellular alterations in the liver predominantly provoke pathophysiology progressing to hepatic injury, non-alcoholic fatty liver disease, fibrosis, cirrhosis, hepatitis, and even hepatocellular carcinoma depending on the dose and duration [33]. For example, studies have shown that CCl₄ induces hepatotoxicity and mitochondrial damage characterized by redox imbalance, inflammation and apoptosis with consistent histological necrosis and infiltration of inflammatory cells [25], [34], [7]. In recent studies, however, the role of CCl₄-induced reactive oxygen species (ROS), pro-inflammation and altered signalling cascades in hepatic fibrosis have been confirmed [22], [24], [8]. Therefore, antioxidants such as natural polyphenols with known anti-inflammatory potentials may exert inhibitory effects against CCl₄ hepatotoxicity.

Several studies have demonstrated that natural phytoactive compounds exhibiting antioxidant potentials can combat the ROS-mediated hepatotoxicity caused by CCl₄ [33], [6]. Geraniol is a natural bioactive acyclic monoterpene with the chemical formular C₁₀H₁₈O. GRL (3, 7-dimethylocta-trans-2, 6-dien-1-ol) is an important content of palmrosa, lemon, ginger, lavender, orange essential oils, rose, and about 20 % component of GRL oil content [18]. The antioxidant and several pharmacological effects of GRL have been reported [17], [20], [8], such as the enhancement of antioxidants. GRL enhances antioxidant enzyme activities in dopaminergic neurons against ROS injury and apoptotic cell death in Parkinson’s disease [23]. GRL blocks lead-induced or 2-acetylaminofluorene-induced hepatotoxicity through attenuation of oxidative stress, inflammation and apoptosis in rats [13], [19]. The report of El Azab et al., [8] was only found on the efficacy of GRL against CCl₄-induced hepatic oxidative stress and inflammation. Till date, it is unknown whether GRL could halt CCl₄-induced oxidative stress-mediated apoptosis. Therefore, the study was conceived to explore the possible protective action of GRL against CCl₄-induced hepatic damage via oxidative stress, inflammation and apoptosis in rats.

2. Materials and methods

2.1. Chemical and reagents

CCl₄ and GRL were purchased from Aladdin (China). Commercial kits were purchased from Jiancheng Co. (Nanjing, China).

2.2. Animals

Wistar rats (weight 200–240 g, eight weeks old,) were procured from the Animal House of Faculty of Science, King Faisal University, Saudi Arabia. The study protocols were in consistent with the research ethics at the King Faisal University (Reference number: KFU-REC-2022-DEC-ETHICS399). Animal cages with wire mesh that allows for good ventilation at 25 ± 2 °C, 50–60 % relative humidity and 12 h night/12 h day were used for this study. The rats were subjected to food and water without any restriction throughout the study period. Acclimatization was conducted by allowing the rats to feed on chow and water for one week.

2.3. Experimental design

At the end of acclimatization, the rats (male) were divided randomly into 4 groups (n = 6).

2.3.1. Group 1 (Control)

Rats received olive oil (0.5 ml/kg b.w) intraperitoneally (ip) on the 1st and 4th day of each week for 4 weeks.

2.3.2. Group 2 (GRL)

Rats received only GRL (100 mg/kg/day) orally (os) for 4 weeks.

2.3.3. Group 3 (CCl₄) group

Rats was administered only CCl₄ (1 ml/kg b.w of 1:1 v/v CCl₄: olive oil, ip) on the 1st and 4th day of each week for 4 weeks.

2.3.4. Group 4 (GRL+ CCl₄)

Rats was administered CCl₄ (1 ml/kg b.w of 1:1 v/v CCl₄: olive oil, ip) on the 1st and 4th day of each week for 4 weeks + GRL (100 mg/kg/day, os) for 4 weeks.

The doses of CCl₄ and GRL were chosen according to previous studies [14], [21]. On the 29th day, rats were anesthetized, and blood samples collected into tubes for determination of liver function indices. The clotted blood was centrifuged at 2500g for 10 min at 4 °C. The serum obtained was stored at − 20 °C temperature. The rats were euthanized using 10 mg/kg xylazine and 100 mg/kg ketamine HCl for collection of liver samples for biochemical and histological analyses.

2.4. Biochemical analysis

2.4.1. Determination of hepatic markers

The serum samples were used for measuring the activities and levels of liver markers, AST, ALT, ALP, total protein (TP), albumin (ALB), and total bilirubin (TB) using standard kits and the kit instructions were followed for the assay steps.

2.4.2. Determination of oxidative stress markers

Liver sample (100 mg) was homogenized in PBS and centrifuged at 3000g for 20 min at 4 °C. The supernatant was separated into tubes. The liver activities of catalase (CAT, Cat. No. A007–1-1), superoxide dismutase (SOD, Cat. No. A001–1), and glutathione peroxidase (GPx, Cat. No. A005–1-1), as well as malondialdehyde (MDA, Cat. No. A003–1-2) level were estimated using commercial kits.

2.4.3. Determination of inflammatory markers

The liver supernatant samples were used to estimate the liver levels of pro-inflammatory TNF-α (Cat No R019) and IL-6 (Cat No R016), and anti-inflammatory IL-4 (Cat No R013) and IL-10 (Cat No R017). Rat standard ELISA kits were used and the determinations were conducted according to the manufacturer’s instructions.

2.4.4. Apoptotic caspases estimation

Hepatic caspase 9 (Cat No A069) and caspase 3 (Cat No A064) were quantitatively measured in line with the manufacturer’s directions.

2.4.5. Histopathology

Hepatic tissues were fixed with 10 % buffered formalin followed by the routine processes of blocking, paraffin and sectioning (5 µm thick) with microtome, and then mounted on glass slides. The processed sections were stained with H&E solution. Any histopathological alterations were viewed and photographed with a light microscope (Nikon 80i, Japan). The histopathological changes were scored semi-quantitatively and mean values were determined: normal histostructure (0), mild (1), moderate (2), and severe alterations consistent with congested central vein and presence of inflammatory cells and vacuolation (3) [9].

2.4.6. Statistical analysis

Data were presented as mean ± standard error of mean (SEM) obtained from the 6 rats in each group. The Graph Pad Prism statistical program (version 8; GraphPad Software Inc., San Diego, CA, USA) was used to analyse data by one-way AVONA followed by Tukey’s post-hoc test. The statistical significance was set at p < 0.05.

3. Results

3.1. Effect of GRL on liver function markers

Table 1 shows the effect of GRL on liver function markers in CCl₄-exposed rats. The CCl₄ exerted toxicity on the liver; CCl₄ significantly (p < 0.05) increased the serum activities of ALT, AST, ALP and level of TB in comparison to the control. Additionally, CCl₄ markedly reduced (p < 0.05) the levels of TP and ALB in comparison to the control. The administration of GRL prevented the toxic effect of CCl₄ demonstrated by significant reductions in serum activities of AST, ALP, ALT, and level of TB coupled with marked elevated levels of TP and ALB compared to the CCl₄ group.

Table 1.

Effect of GRL on liver function indices in CCl₄-intoxicated rats.

Group	ALT (U/L)	AST (U/L)	ALP (U/L)	TB (mg/dl)	ALB (g/dl)	TP (g/dl)
Control	35.5 ± 0.1	45.3 ± 0.2	25.9 ± 0.2	0.3 ± 0.1	4.30 ± 0.1	5.8 ± 0.11
GRL	36.2 ± 0.2	45.2 ± 0.2	28.4 ± 0.1	0.29 ± 0.1	4.30 ± 0.1	5.7 ± 0.14
CCl₄	50.3 ± 0.1*	153.3 ± 0.2*	55.0 ± 0.5*	0.66 ± 0.1*	2.11 ± 0.1*	3.1 ± 0.10*
GRL + CCl₄	40.2 ± 0.2^#	84.2 ± 0.2^#	30.1 ± 0.3^#	0.38 ± 0.1^#	3.20 ± 0.1^#	4.1 ± 0.10^#

Open in a new tab

Data are presented mean ± SEM (n = 6 rats/group). CCl₄: carbon tetrachloride; GRL: Geraniol; *P < 0.05: significant compared to the control group in the same column. ^#P < 0.05: significant compared to the CCl₄ group in the same column.

3.2. Effect of GRL on oxidative stress markers

Fig. 1 presents the effect of GRL on oxidative stress indices in CCl₄-exposed rats. The CCl₄ significantly (p < 0.05) reduced the hepatic activities of CAT, SOD and GPx, while level of MDA was increased in comparison to the control. The GRL administration in GRL + CCl₄ group significantly (p < 0.05) increased the activities of CAT, SOD and GPx, while level of MDA decreased significantly compared to the CCl₄ group.

3.3. Effect of GRL on hepatic inflammatory and anti-inflammatory markers

Fig. 2 presents the effect of GRL on hepatic anti-inflammatory and pro-inflammatory marker levels in CCl₄-injected rats. The CCl₄ exposure induced significant increases (p < 0.05) in hepatic IL-6 and TNF-α levels compared to the control; CCl₄ triggered significant decreases in the anti-inflammatory IL-4 and IL-10 levels in the current study. GRL markedly (p < 0.05) inhibited the alterations in the hepatic TNF-α, IL-6, IL-4 and IL-10 levels compared to the CCl₄ group.

3.4. Effect of GRL on hepatic apoptosis caspases

Fig. 3 presents the effect of GRL on hepatic apoptosis marker levels in CCl₄-injected rats. The CCl₄ exposure induced significant increases (p < 0.05) in the hepatic levels of caspase-3 and caspase-9 compared to the control. GRL significantly (p < 0.05) exerted reduction in the levels of caspase-3 and caspase-9 compared to the CCl₄ group.

3.5. Effect of GRL on the liver histology

Fig. 4 depicts the results of the histopathological analysis of the effect of GRL and CCl₄ on the liver of rats. The control and the GRL group liver samples revealed normal ultrastructure with evident normal hepatocyte, blood sinusoid, and central vein (a and b). In the CCl₄ group, histopathological abrasions like congested central vein and inflammatory cell infiltration; the hepatocytes appeared degenerated with vacuolated cytoplasm (c–e). However, in the GRL + CCl₄ group, we observed amelioration regarding the degeneration, congestion and infiltration of inflammatory cells (f).

4. Discussion

CCl₄ is a potential carcinogen and an established hepatotoxicant; nevertheless, it remains an industrial solvent, and humans are exposed to it at workplaces [6]. Given the critical biochemical role of the liver and its susceptibility to serious health problems worldwide, its protection from the attacks of exogenous toxicants is very important. Herein, our findings demonstrate that GRL could protect the liver from the oxidative and degenerative effects of CCl₄ via inhibition of oxidative inflammation and hepatic apoptosis.

In the current study, two times injection of CCl₄ per week for 4 consecutive weeks was used following the study of Hussein and Khan Ref. [14]. We thus found considerable liver damage revealed by significant elevations in the serum activities of liver enzymes, AST, ALT, ALP, and TB levels in comparison to the control group. Furthermore, the markers of hepatic protein synthetic capacity, ALB and TP, were markedly reduced in comparison to the control (Table 1). It therefore corroborates the earlier reports that CCl₄ is an hepatotoxicant [1], [22], [3], [8]. The liver is involved in the catabolism of drugs and xenobiotics. These enzymes, ALT and AST are preponderant in the hepatocytes and are used to monitor the effect of drugs and xenobiotics on the liver health status. The damage to the hepatocytes by the CCl₄ caused the outflow of the enzymes into the serum [11], whereas the increased activity of ALP is an indicator of hepatic-cholestatic damage [12]. Liver synthesises serum proteins to main transport and blood osmotic balance. The reduced levels of TP and ALB confirmed the reduced synthetic capacity of the liver occasioned by the CCl₄. Therefore, our results on the distortions of hepatic functional indices created by the CCl₄ injection are in agreement with the previous report [16], [6], [7]. In contrast, our concomitant administration of GRL to rats inhibited the CCl₄-induced hepatic damage in this study. We found that the activities of AST, ALT, ALP, as well as levels of TB, ALB and TP were significantly restored in the serum compared to the CCl₄-injected rats (Table 1). This demonstrates that GRL prevented the hepatic damage and also preserved the hepatic integrity such that the enzyme leakage into the blood circulation was significantly limited. Literature reveals the hepatoprotective effect of GRL in animal studies [13], [19]. Its beneficial effect has also been associated with its antioxidant properties [22], [30].

Redox homeostasis modulates the physiological production of ROS for benefits in immune responses and balance by antioxidant mechanism [2]. However, exogenous agents are known to cause impaired redox balance provoking oxidative stress-mediated damage [10]. We explored the effect of CCl₄ on the hepatic antioxidant status. CCl₄ impaired the antioxidant mechanism in the liver of rats in this study revealed by significant diminution in the hepatic activities of CAT, SOD and GPx, and the consequent elevation in MDA levels (Fig. 1). Our finding herein corroborates the literature reports that the oxidant metabolites produced upon the hepatic metabolism of CCl₄ do overwhelm hepatic antioxidant milieu [3], [32], [33], [8]. Robust body of evidence shows that covalent binding of CCl₄ metabolites, trichloromethyl free radicals, to cell proteins and antioxidant apparatus is the first step in a chain reaction that eventually leads to membrane lipid peroxidation, liver lesions and oxidative stress [29]. The cooperative effect of these conditions might contribute to the depressed SOD, CAT, and GPx activities and elevated MDA levels shown in this study [25], [7]. Evidently, the histological results showed liver lesions such as congested central vein and degenerated cells that could be linked with the oxidative milieu [29]. The antioxidant efficacy of GRL is reported in the literature [21], [23]. However, the sulfhydryl groups in glutathione, GPx and other thiol proteins can react with trichloromethyl to form an oxidative complex, and by extension, exerts deleterious effects on cellular antioxidant apparatus such as SOD and CAT, GPx, and reduced glutathione [6]. In this study, GRL exhibited antioxidant effect via improving the SOD, GPx and CAT activities against CCl₄ herein. These enzyme expressions were significantly elevated in the GRL + CCl₄ group compared to the CCl₄ group. Consequently, the level of MDA was also decimated significantly relative to the CCl₄ group. In oxidative stress-mediated diseases/disorder such as diabetes, diabetic cardiomyopathy, osteoarthritis, neuropathy and drug-induced toxicity, GRL has been underlined as a potent antioxidant agent for improvement of redox cycle balance [17], [27], [5], [8]. Mechanistically, the GRL antioxidant action has been linked to its intracellular potential to activate the redox-sensitive pathway of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) that promotes gene expression of antioxidant enzymes such as CAT, SOD and GPx among others via nuclear transcription [30]. Therefore, the GRL action in our study is in conformity with the earlier findings and could be attributed to the underlying activation/expression of antioxidant genes which were manifested via the increased activities of CAT, SOD and GPx.

Following the existing reports, CCl₄ oxidative stress causes activation of inflammatory and apoptotic cascades. CCl₄ action stimulates nuclear factor-kappa B (NF-κB), a nuclear transcriptional factor implicated in the expression of inflammatory cytokines and caspase-dependent apoptosis in liver damage [1], [26], [31], [34]. To this end, we evaluated the effect of CCl₄ on pro-inflammatory (IL-6 and TNF-α), anti-inflammatory (IL-4 and IL-10) cytokines and caspase markers of apoptosis. It was observed that the levels of TNF-α and IL-6 significantly increased, whereas IL-4 and IL-10 levels significantly reduced in CCl₄-injected rats relative to the control rats (Fig. 2). This result shows that CCl₄ provoked pro-inflammation and reduces anti-inflammation [25], [28]. NF-κB is translocated to the nucleus during cellular oxidative stress in the hepatic tissue [4], and its nuclear effect in terms of cytokine gene expression has been reported during CCl₄ hepatotoxicity [1], [25]. In addition, we found histological infiltration of inflammatory cells (Fig. 4). It is therefore conceivable, in consonance with the previous findings, that CCl₄ could induce pro-inflammation in the liver [26], [29], [31]. Moreover, the crosstalk of inflammation and apoptosis is widely reported in published papers. For example, in a model of liver mitochondrial damage orchestrated by CCl₄, the network of oxidative stress and hepatic inflammation was found to trigger apoptosis [28], [34]. Our findings herein also agree with the earlier papers in that the expression of caspase 3 and caspase-9 were significantly elevated in the liver of CCl₄-injected rats (Fig. 3). In contrast, the treatment with GRL evidently reversed the aberrant levels of the cytokines as well as the caspases. The hepatic IL-6 and TNF-α levels reduced while IL-4 and IL-10 levels increased significantly in GRL + CCl₄ group compared to the CCl₄ group in this study. We hereby confirm the anti-inflammatory effect of GRL in CCl₄-mediated inflammatory liver damage. On the other hand, the caspases were also reduced significantly as a result of the antiapoptotic effect of GRL. The anti-inflammatory and antiapoptotic effects of GRL may be associated with the mechanistic inhibitory effect of GRL on the inflammatory factors, activators and mitochondrial integrity as suggested by the literature [15], [17], [21], [30].

In conclusion, the present study has demonstrated the hepatotoxicity of CCl₄ in consistent with the literature. Importantly, the present work unravels that GRL could exert hepatoprotective effect against CCl₄‐triggered hepatic toxicity through mitigation of oxidative stress, inflammation and apoptosis. The effect could be adduced to the antioxidant, anti-inflammatory and antiapoptotic activities of GRL in this study.

CRediT authorship contribution statement

Azza Sedky: Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. Hany Elsawy: Formal analysis, Funding acquisition, Investigation, Writing – review & editing. Ademola C. Famurewa: Conceptualization, Formal analysis, Writing – original draft, Writing – review & editing. Manal A. Alfwuaires: Conceptualization, Formal analysis, Writing – review & editing. Abdulmohsen I. Algefare: Conceptualization, Formal analysis, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors acknowledge the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research at King Faisal University, Saudi Arabia for financial support under the Annual Funding track (Grant No. 5568).

Handling Editor: Prof. L.H. Lash

Contributor Information

Ademola C. Famurewa, Email: ademola.famurewa@funai.edu.ng.

Azza Sedky, Email: asadek@kfu.edu.sa.

Data availability

Data will be made available on request.

References

1.Alabbad H., Alfwuaires M., Abdel-moneim A.M., Elsawy H. Hepatoprotective mechanism of apigenin via suppression of oxidative inflammatory signaling and apoptosis against hepatotoxicity induced by CCl 4 in rats. Indian J. Anim. Res. 2023:1–6. doi: 10.18805/IJAR.BF-1609.Submitted. [DOI] [Google Scholar]
2.Albaqami J.J., Hamdi H., Narayanankutty A., Visakh N.U., Sasidharan A., Kuttithodi A.M., Famurewa A.C. Pathrose B. Chemical composition and biological activities of the leaf essential oils of Curcuma longa, Curcuma aromatica, and Curcuma angustifolia. Antibiotics. 2022;11(11):1547. doi: 10.3390/antibiotics11111547. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Almatroodi S.A., Anwar S., Almatroudi A., Khan A.A., Alrumaihi F., Alsahli M.A., Rahmani A.H. Hepatoprotective effects of garlic extract against carbon tetrachloride (CCl4)-induced liver injury via modulation of antioxidant, anti-inflammatory activities and hepatocyte architecture. Appl. Sci. (Switz. ) 2020;10(18) doi: 10.3390/APP10186200. [DOI] [Google Scholar]
4.Edeogu C.O., Kalu M.E., Famurewa A.C., Asogwa N.T., Onyeji G.N., Ikpemo K.O. Nephroprotective effect of Moringa oleifera seed oil on gentamicin-induced nephrotoxicity in rats: biochemical evaluation of antioxidant, anti-inflammatory, and antiapoptotic pathways. J. Am. Coll. Nutr. 2019:1–9. doi: 10.1080/07315724.2019.1649218. [DOI] [PubMed] [Google Scholar]
5.El-Bassossy H.M., Ghaleb H., Elberry A.A., Balamash K.S., Ghareib S.A., Azhar A., Banjar Z. Geraniol alleviates diabetic cardiac complications: Effect on cardiac ischemia and oxidative stress. Biomed. Pharmacother. = Biomed. Pharmacother. 2017;88:1025–1030. doi: 10.1016/J.BIOPHA.2017.01.131. [DOI] [PubMed] [Google Scholar]
6.El-Hadary A.E., Ramadan Hassanien M.F. Hepatoprotective effect of cold-pressed Syzygium aromaticum oil against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Pharm. Biol. 2016;54(8):1364–1372. doi: 10.3109/13880209.2015.1078381. [DOI] [PubMed] [Google Scholar]
7.El-Kashef D.H., Zaghloul R.A. Ameliorative effect of montelukast against carbon tetrachloride-induced hepatotoxicity: targeting NLRP3 inflammasome pathway. Life Sci. 2022;304(May) doi: 10.1016/j.lfs.2022.120707. [DOI] [PubMed] [Google Scholar]
8.El Azab E.F., Elguindy N.M., Yacout G.A., Elgamal D.A. Hepatoprotective impact of geraniol against CCl4-induced liver fibrosis in rats. Pak. J. Biol. Sci.: PJBS. 2020;23(12):1650–1658. doi: 10.3923/PJBS.2020.1650.1658. [DOI] [PubMed] [Google Scholar]
9.Elsawy H., Famurewa A.C., Sedky A. Resveratrol mitigates diabetic testicular dysfunction, endocrine deficits, and insulin resistance via suppression of sperm- endocrine aberrations and oxidative inflammation in rats. Andrologia. 2023:2023. [Google Scholar]
10.Famurewa A.C., Asogwa N.T., Ezea S.C. Antidiabetic drug sitagliptin blocks cyclophosphamide cerebral neurotoxicity by activating Nrf2 and suppressing redox cycle imbalance, inflammatory iNOS/NO/NF-κB response and caspase-3/Bax activation in rats. Int. Immunopharmacol. 2023;116 doi: 10.1016/j.intimp.2023.109816. [DOI] [PubMed] [Google Scholar]
11.Famurewa A.C., Ekeleme-Egedigwe C.A., David E.E., Eleazu C.O., Folawiyo A.M., Obasi N.A. Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats. Toxicol. Mech. Methods. 2020;30(2) doi: 10.1080/15376516.2019.1669243. [DOI] [PubMed] [Google Scholar]
12.Famurewa A.C., Ufebe O.G., Egedigwe C.A., Nwankwo O.E., Obaje G.S. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats. Biomed. Pharmacother. 2017;87 doi: 10.1016/j.biopha.2016.12.123. [DOI] [PubMed] [Google Scholar]
13.Hasan S.K., Sultana S. Geraniol attenuates 2-acetylaminofluorene induced oxidative stress, inflammation and apoptosis in the liver of wistar rats. Toxicol. Mech. Methods. 2015;25(7):559–573. doi: 10.3109/15376516.2015.1070225. [DOI] [PubMed] [Google Scholar]
14.Hussein M., Khan R. CCL4-Induced Hepatotoxicity: Study in Rats Intoxicated with Carbon Tetrachloride and Treated with Camel Milk and Urine. J. Chem. Stud. 2022;1(1):07–11. doi: 10.32996/jcs. [DOI] [Google Scholar]
15.Jayachandran M., Chandrasekaran B., Namasivayam N. Geraniol attenuates fibrosis and exerts anti-inflammatory effects on diet induced atherogenesis by NF-κB signaling pathway. Eur. J. Pharmacol. 2015;762:102–111. doi: 10.1016/J.EJPHAR.2015.05.039. [DOI] [PubMed] [Google Scholar]
16.Kanawati G.M., Al-Khateeb I.H., Kandil Y.I. Arctigenin attenuates CCl4-induced hepatotoxicity through suppressing matrix metalloproteinase-2 and oxidative stress. Egypt. Liver J. 2021;11(1):1–7. doi: 10.1186/S43066-020-00072-6/FIGURES/4. [DOI] [Google Scholar]
17.Lei Y., Fu P., Jun X., Cheng P. Pharmacological properties of geraniol - a review. Planta Med. 2019;85(1):48–55. doi: 10.1055/A-0750-6907. [DOI] [PubMed] [Google Scholar]
18.Leite M.C.A., De Brito Bezerra A.P., De Sousa J.P., De Oliveira Lima E. Investigating the antifungal activity and mechanism(s) of geraniol against Candida albicans strains. Med. Mycol. 2015;53(3):275–284. doi: 10.1093/mmy/myu078. [DOI] [PubMed] [Google Scholar]
19.Ozkaya A., Sahin Z., Kuzu M., Saglam Y.S., Ozkaraca M., Uckun M., Yologlu E., Comakli V., Demirdag R., Yologlu S. Role of geraniol against lead acetate-mediated hepatic damage and their interaction with liver carboxylesterase activity in rats. Arch. Physiol. Biochem. 2018;124(1):80–87. doi: 10.1080/13813455.2017.1364772. [DOI] [PubMed] [Google Scholar]
20.Pavan B., Dalpiaz A., Marani L., Beggiato S., Ferraro L., Canistro D., Paolini M., Vivarelli F., Valerii M.C., Comparone A., De Fazio L.D., Spisni E. Geraniol pharmacokinetics, bioavailability and its multiple effects on the liver antioxidant and xenobiotic-metabolizing enzymes. Front. Pharmacol. 2018;9(JAN) doi: 10.3389/fphar.2018.00018. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Prasad S.N., Muralidhara M. Protective effects of geraniol (a monoterpene) in a diabetic neuropathy rat model: attenuation of behavioral impairments and biochemical perturbations. J. Neurosci. Res. 2014;92(9):1205–1216. doi: 10.1002/jnr.23393. [DOI] [PubMed] [Google Scholar]
22.Que R., Cao M., Dai Y., Zhou Y., Chen Y., Lin L. Decursin ameliorates carbon-tetrachloride-induced liver fibrosis by facilitating ferroptosis of hepatic stellate cells. Biochem. Cell. Biol. = Biochim. Et. Biol. Cell. 2022;100(5):378–386. doi: 10.1139/BCB-2022-0027. [DOI] [PubMed] [Google Scholar]
23.Rekha K.R., Selvakumar G.P. Gene expression regulation of Bcl2, Bax and cytochrome-C by geraniol on chronic MPTP/probenecid induced C57BL/6 mice model of Parkinson’s disease. Chem. -Biol. Interact. 2014;217:57–66. doi: 10.1016/J.CBI.2014.04.010. [DOI] [PubMed] [Google Scholar]
24.Sayed E.A., Badr G., Hassan K.A.H., Waly H., Ozdemir B., Mahmoud M.H., Alamery S. Induction of liver fibrosis by CCl4 mediates pathological alterations in the spleen and lymph nodes: the potential therapeutic role of propolis. Saudi J. Biol. Sci. 2021;28(2):1272–1282. doi: 10.1016/j.sjbs.2020.11.068. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Tsai J.C., Chiu C.S., Chen Y.C., Lee M. shiou, Hao X.Y., Hsieh M.T., Kao C.P., Peng W.H. Hepatoprotective effect of Coreopsis tinctoria flowers against carbon tetrachloride-induced liver damage in mice. BMC Complement. Altern. Med. 2017;17(1):1–9. doi: 10.1186/s12906-017-1604-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Wang M., Niu J., Ou L., Deng B., Wang Y., Li S. Zerumbone protects against carbon tetrachloride (CCl4)-induced acute liver injury in mice via inhibiting oxidative stress and the inflammatory response: Involving the TLR4/NF-κB/COX-2 pathway. Molecules. 2019;24(10) doi: 10.3390/molecules24101964. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Wu Y., Wang Z., Fu X., Lin Z., Yu K. Geraniol-mediated osteoarthritis improvement by down-regulating PI3K/Akt/NF-κB and MAPK signals: In vivo and in vitro studies. Int. Immunopharmacol. 2020;86 doi: 10.1016/J.INTIMP.2020.106713. [DOI] [PubMed] [Google Scholar]
28.Yang C., Li L., Ma Z., Zhong Y., Pang W., Xiong M., Fang S., Li Y. Hepatoprotective effect of methyl ferulic acid against carbon tetrachloride-induced acute liver injury in rats. Exp. Ther. Med. 2018;15(3):2228–2238. doi: 10.3892/etm.2017.5678. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Yeh Y.H., Hsieh Y.L., Lee Y.T. Effects of yam peel extract against carbon tetrachloride-induced hepatotoxicity in rats. J. Agric. Food Chem. 2013;61(30):7387–7396. doi: 10.1021/jf401864y. [DOI] [PubMed] [Google Scholar]
30.Younis N.S., Abduldaium M.S., Mohamed M.E. Protective effect of Geraniol on oxidative, inflammatory and apoptotic alterations in isoproterenol-induced cardiotoxicity: Role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR pathways. Antioxidants. 2020;9(10):1–17. doi: 10.3390/antiox9100977. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Yue S., Xue N., Li H., Huang B., Chen Z., Wang X. Hepatoprotective effect of apigenin against liver injury via the non-canonical NF-κB pathway in vivo and in vitro. Inflammation. 2020;43(5):1634–1648. doi: 10.1007/S10753-020-01238-5. [DOI] [PubMed] [Google Scholar]
32.Zhang Y., Zhu Y., Li Y., Ji F., Ge G., Xu H. Midazolam ameliorates acute liver injury induced by carbon tetrachloride via enhancing Nrf2 signaling pathway. Front. Pharmacol. 2022;13(July):1–12. doi: 10.3389/fphar.2022.940137. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Zhao J., Zhang Z., Dai J., Wang L., Zhang C., Ye Y., Li L. Synergistic protective effect of chlorogenic acid, apigenin and caffeic acid against carbon tetrachloride-induced hepatotoxicity in male mice. RSC Adv. 2014;4(81):43057–43063. doi: 10.1039/c4ra07261h. [DOI] [Google Scholar]
34.Zhou J., Zhang Y., Li S., Zhou Q., Lu Y., Shi J., Liu J., Wu Q., Zhou S. Dendrobium nobile Lindl. alkaloids-mediated protection against CCl4-induced liver mitochondrial oxidative damage is dependent on the activation of Nrf2 signaling pathway. Biomed. Pharmacother. 2020;129(June) doi: 10.1016/j.biopha.2020.110351. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data will be made available on request.

[bib1] 1.Alabbad H., Alfwuaires M., Abdel-moneim A.M., Elsawy H. Hepatoprotective mechanism of apigenin via suppression of oxidative inflammatory signaling and apoptosis against hepatotoxicity induced by CCl 4 in rats. Indian J. Anim. Res. 2023:1–6. doi: 10.18805/IJAR.BF-1609.Submitted. [DOI] [Google Scholar]

[bib2] 2.Albaqami J.J., Hamdi H., Narayanankutty A., Visakh N.U., Sasidharan A., Kuttithodi A.M., Famurewa A.C. Pathrose B. Chemical composition and biological activities of the leaf essential oils of Curcuma longa, Curcuma aromatica, and Curcuma angustifolia. Antibiotics. 2022;11(11):1547. doi: 10.3390/antibiotics11111547. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib3] 3.Almatroodi S.A., Anwar S., Almatroudi A., Khan A.A., Alrumaihi F., Alsahli M.A., Rahmani A.H. Hepatoprotective effects of garlic extract against carbon tetrachloride (CCl4)-induced liver injury via modulation of antioxidant, anti-inflammatory activities and hepatocyte architecture. Appl. Sci. (Switz. ) 2020;10(18) doi: 10.3390/APP10186200. [DOI] [Google Scholar]

[bib4] 4.Edeogu C.O., Kalu M.E., Famurewa A.C., Asogwa N.T., Onyeji G.N., Ikpemo K.O. Nephroprotective effect of Moringa oleifera seed oil on gentamicin-induced nephrotoxicity in rats: biochemical evaluation of antioxidant, anti-inflammatory, and antiapoptotic pathways. J. Am. Coll. Nutr. 2019:1–9. doi: 10.1080/07315724.2019.1649218. [DOI] [PubMed] [Google Scholar]

[bib5] 5.El-Bassossy H.M., Ghaleb H., Elberry A.A., Balamash K.S., Ghareib S.A., Azhar A., Banjar Z. Geraniol alleviates diabetic cardiac complications: Effect on cardiac ischemia and oxidative stress. Biomed. Pharmacother. = Biomed. Pharmacother. 2017;88:1025–1030. doi: 10.1016/J.BIOPHA.2017.01.131. [DOI] [PubMed] [Google Scholar]

[bib6] 6.El-Hadary A.E., Ramadan Hassanien M.F. Hepatoprotective effect of cold-pressed Syzygium aromaticum oil against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Pharm. Biol. 2016;54(8):1364–1372. doi: 10.3109/13880209.2015.1078381. [DOI] [PubMed] [Google Scholar]

[bib7] 7.El-Kashef D.H., Zaghloul R.A. Ameliorative effect of montelukast against carbon tetrachloride-induced hepatotoxicity: targeting NLRP3 inflammasome pathway. Life Sci. 2022;304(May) doi: 10.1016/j.lfs.2022.120707. [DOI] [PubMed] [Google Scholar]

[bib8] 8.El Azab E.F., Elguindy N.M., Yacout G.A., Elgamal D.A. Hepatoprotective impact of geraniol against CCl4-induced liver fibrosis in rats. Pak. J. Biol. Sci.: PJBS. 2020;23(12):1650–1658. doi: 10.3923/PJBS.2020.1650.1658. [DOI] [PubMed] [Google Scholar]

[bib9] 9.Elsawy H., Famurewa A.C., Sedky A. Resveratrol mitigates diabetic testicular dysfunction, endocrine deficits, and insulin resistance via suppression of sperm- endocrine aberrations and oxidative inflammation in rats. Andrologia. 2023:2023. [Google Scholar]

[bib10] 10.Famurewa A.C., Asogwa N.T., Ezea S.C. Antidiabetic drug sitagliptin blocks cyclophosphamide cerebral neurotoxicity by activating Nrf2 and suppressing redox cycle imbalance, inflammatory iNOS/NO/NF-κB response and caspase-3/Bax activation in rats. Int. Immunopharmacol. 2023;116 doi: 10.1016/j.intimp.2023.109816. [DOI] [PubMed] [Google Scholar]

[bib11] 11.Famurewa A.C., Ekeleme-Egedigwe C.A., David E.E., Eleazu C.O., Folawiyo A.M., Obasi N.A. Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats. Toxicol. Mech. Methods. 2020;30(2) doi: 10.1080/15376516.2019.1669243. [DOI] [PubMed] [Google Scholar]

[bib12] 12.Famurewa A.C., Ufebe O.G., Egedigwe C.A., Nwankwo O.E., Obaje G.S. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats. Biomed. Pharmacother. 2017;87 doi: 10.1016/j.biopha.2016.12.123. [DOI] [PubMed] [Google Scholar]

[bib13] 13.Hasan S.K., Sultana S. Geraniol attenuates 2-acetylaminofluorene induced oxidative stress, inflammation and apoptosis in the liver of wistar rats. Toxicol. Mech. Methods. 2015;25(7):559–573. doi: 10.3109/15376516.2015.1070225. [DOI] [PubMed] [Google Scholar]

[bib14] 14.Hussein M., Khan R. CCL4-Induced Hepatotoxicity: Study in Rats Intoxicated with Carbon Tetrachloride and Treated with Camel Milk and Urine. J. Chem. Stud. 2022;1(1):07–11. doi: 10.32996/jcs. [DOI] [Google Scholar]

[bib15] 15.Jayachandran M., Chandrasekaran B., Namasivayam N. Geraniol attenuates fibrosis and exerts anti-inflammatory effects on diet induced atherogenesis by NF-κB signaling pathway. Eur. J. Pharmacol. 2015;762:102–111. doi: 10.1016/J.EJPHAR.2015.05.039. [DOI] [PubMed] [Google Scholar]

[bib16] 16.Kanawati G.M., Al-Khateeb I.H., Kandil Y.I. Arctigenin attenuates CCl4-induced hepatotoxicity through suppressing matrix metalloproteinase-2 and oxidative stress. Egypt. Liver J. 2021;11(1):1–7. doi: 10.1186/S43066-020-00072-6/FIGURES/4. [DOI] [Google Scholar]

[bib17] 17.Lei Y., Fu P., Jun X., Cheng P. Pharmacological properties of geraniol - a review. Planta Med. 2019;85(1):48–55. doi: 10.1055/A-0750-6907. [DOI] [PubMed] [Google Scholar]

[bib18] 18.Leite M.C.A., De Brito Bezerra A.P., De Sousa J.P., De Oliveira Lima E. Investigating the antifungal activity and mechanism(s) of geraniol against Candida albicans strains. Med. Mycol. 2015;53(3):275–284. doi: 10.1093/mmy/myu078. [DOI] [PubMed] [Google Scholar]

[bib19] 19.Ozkaya A., Sahin Z., Kuzu M., Saglam Y.S., Ozkaraca M., Uckun M., Yologlu E., Comakli V., Demirdag R., Yologlu S. Role of geraniol against lead acetate-mediated hepatic damage and their interaction with liver carboxylesterase activity in rats. Arch. Physiol. Biochem. 2018;124(1):80–87. doi: 10.1080/13813455.2017.1364772. [DOI] [PubMed] [Google Scholar]

[bib20] 20.Pavan B., Dalpiaz A., Marani L., Beggiato S., Ferraro L., Canistro D., Paolini M., Vivarelli F., Valerii M.C., Comparone A., De Fazio L.D., Spisni E. Geraniol pharmacokinetics, bioavailability and its multiple effects on the liver antioxidant and xenobiotic-metabolizing enzymes. Front. Pharmacol. 2018;9(JAN) doi: 10.3389/fphar.2018.00018. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib21] 21.Prasad S.N., Muralidhara M. Protective effects of geraniol (a monoterpene) in a diabetic neuropathy rat model: attenuation of behavioral impairments and biochemical perturbations. J. Neurosci. Res. 2014;92(9):1205–1216. doi: 10.1002/jnr.23393. [DOI] [PubMed] [Google Scholar]

[bib22] 22.Que R., Cao M., Dai Y., Zhou Y., Chen Y., Lin L. Decursin ameliorates carbon-tetrachloride-induced liver fibrosis by facilitating ferroptosis of hepatic stellate cells. Biochem. Cell. Biol. = Biochim. Et. Biol. Cell. 2022;100(5):378–386. doi: 10.1139/BCB-2022-0027. [DOI] [PubMed] [Google Scholar]

[bib23] 23.Rekha K.R., Selvakumar G.P. Gene expression regulation of Bcl2, Bax and cytochrome-C by geraniol on chronic MPTP/probenecid induced C57BL/6 mice model of Parkinson’s disease. Chem. -Biol. Interact. 2014;217:57–66. doi: 10.1016/J.CBI.2014.04.010. [DOI] [PubMed] [Google Scholar]

[bib24] 24.Sayed E.A., Badr G., Hassan K.A.H., Waly H., Ozdemir B., Mahmoud M.H., Alamery S. Induction of liver fibrosis by CCl4 mediates pathological alterations in the spleen and lymph nodes: the potential therapeutic role of propolis. Saudi J. Biol. Sci. 2021;28(2):1272–1282. doi: 10.1016/j.sjbs.2020.11.068. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib25] 25.Tsai J.C., Chiu C.S., Chen Y.C., Lee M. shiou, Hao X.Y., Hsieh M.T., Kao C.P., Peng W.H. Hepatoprotective effect of Coreopsis tinctoria flowers against carbon tetrachloride-induced liver damage in mice. BMC Complement. Altern. Med. 2017;17(1):1–9. doi: 10.1186/s12906-017-1604-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib26] 26.Wang M., Niu J., Ou L., Deng B., Wang Y., Li S. Zerumbone protects against carbon tetrachloride (CCl4)-induced acute liver injury in mice via inhibiting oxidative stress and the inflammatory response: Involving the TLR4/NF-κB/COX-2 pathway. Molecules. 2019;24(10) doi: 10.3390/molecules24101964. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib27] 27.Wu Y., Wang Z., Fu X., Lin Z., Yu K. Geraniol-mediated osteoarthritis improvement by down-regulating PI3K/Akt/NF-κB and MAPK signals: In vivo and in vitro studies. Int. Immunopharmacol. 2020;86 doi: 10.1016/J.INTIMP.2020.106713. [DOI] [PubMed] [Google Scholar]

[bib28] 28.Yang C., Li L., Ma Z., Zhong Y., Pang W., Xiong M., Fang S., Li Y. Hepatoprotective effect of methyl ferulic acid against carbon tetrachloride-induced acute liver injury in rats. Exp. Ther. Med. 2018;15(3):2228–2238. doi: 10.3892/etm.2017.5678. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib29] 29.Yeh Y.H., Hsieh Y.L., Lee Y.T. Effects of yam peel extract against carbon tetrachloride-induced hepatotoxicity in rats. J. Agric. Food Chem. 2013;61(30):7387–7396. doi: 10.1021/jf401864y. [DOI] [PubMed] [Google Scholar]

[bib30] 30.Younis N.S., Abduldaium M.S., Mohamed M.E. Protective effect of Geraniol on oxidative, inflammatory and apoptotic alterations in isoproterenol-induced cardiotoxicity: Role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR pathways. Antioxidants. 2020;9(10):1–17. doi: 10.3390/antiox9100977. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib31] 31.Yue S., Xue N., Li H., Huang B., Chen Z., Wang X. Hepatoprotective effect of apigenin against liver injury via the non-canonical NF-κB pathway in vivo and in vitro. Inflammation. 2020;43(5):1634–1648. doi: 10.1007/S10753-020-01238-5. [DOI] [PubMed] [Google Scholar]

[bib32] 32.Zhang Y., Zhu Y., Li Y., Ji F., Ge G., Xu H. Midazolam ameliorates acute liver injury induced by carbon tetrachloride via enhancing Nrf2 signaling pathway. Front. Pharmacol. 2022;13(July):1–12. doi: 10.3389/fphar.2022.940137. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib33] 33.Zhao J., Zhang Z., Dai J., Wang L., Zhang C., Ye Y., Li L. Synergistic protective effect of chlorogenic acid, apigenin and caffeic acid against carbon tetrachloride-induced hepatotoxicity in male mice. RSC Adv. 2014;4(81):43057–43063. doi: 10.1039/c4ra07261h. [DOI] [Google Scholar]

[bib34] 34.Zhou J., Zhang Y., Li S., Zhou Q., Lu Y., Shi J., Liu J., Wu Q., Zhou S. Dendrobium nobile Lindl. alkaloids-mediated protection against CCl4-induced liver mitochondrial oxidative damage is dependent on the activation of Nrf2 signaling pathway. Biomed. Pharmacother. 2020;129(June) doi: 10.1016/j.biopha.2020.110351. [DOI] [PubMed] [Google Scholar]

PERMALINK