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Table of Contents
Year : 2022  |  Volume : 12  |  Issue : 5  |  Page : 185-196

Hepato- and reno-protective effects of thymoquinone, crocin, and carvacrol: A comprehensive review

Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran

Date of Submission05-Feb-2022
Date of Decision01-Mar-2022
Date of Acceptance04-Apr-2022
Date of Web Publication29-Apr-2022

Correspondence Address:
Akbar Anaeigoudari
Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2221-1691.343386

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Medicinal plants are rich in nutrients and phytochemicals which prevent and treat a wide range of ailments. Accumulating experimental studies exhibit that some bioactive ingredients extracted from medicinal plants have suitable therapeutic effects on hepatic and renal injuries. This review focuses on the hepato- and reno-protective effects of thymoquinone, crocin, and carvacrol. The relevant literature was retrieved from PubMed, Scopus, Web of Science, and Google Scholar databases from the beginning of 2015 until the end of November 2021. According to the scientific evidence, the considered phytochemicals in this review have been applied with useful therapeutic effects on hepatic and renal damage. These therapeutic effects were mainly mediated through the amelioration of oxidative stress, suppression of inflammatory responses, and inhibition of apoptosis. Intracellular signaling pathways linked to nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase, c-jun N-terminal kinase, and extracellular signal-regulated kinase 1/2 and Toll-like receptors are the most important pathways targeted by these phytochemicals. Up-regulation of transcription factor Nrf2 and down-regulation of transforming growth factor-beta 1 by these natural compounds also contribute to the alleviation of hepatic and renal injuries.

Keywords: Carvacrol; Crocin; Thymoquinone; Hepatoprotective; Reno-protective; Inflammatory; Oxidative stress; NF-κB; Nrf2

How to cite this article:
Anaeigoudari A. Hepato- and reno-protective effects of thymoquinone, crocin, and carvacrol: A comprehensive review. Asian Pac J Trop Biomed 2022;12:185-96

How to cite this URL:
Anaeigoudari A. Hepato- and reno-protective effects of thymoquinone, crocin, and carvacrol: A comprehensive review. Asian Pac J Trop Biomed [serial online] 2022 [cited 2022 May 24];12:185-96. Available from:

  1. Introduction Top

The liver and kidney have a key role in body hemostasis[1],[2]. In normal conditions, these vital organs remove toxins and free radicals and prevent the accumulation of noxious substances threatening body organs[3]. Oxidative stress[4], inflammation[5], vascular dysfunction[6], and uncontrolled diabetes mellitus[7] have been shown to disturb liver and kidney function. Liver malfunction is recognized by increased blood levels of liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP)[8]. Kidney damage also can be characterized by a significant enhancement in serum level of creatinine and blood urea nitrogen as well as urinary excretion of proteins[9].

Medicinal plants are rich in nutrients and phytochemicals which prevent and treat a wide range of ailments[10]. Fruits and vegetables are considered the main source of phytochemicals[11]. Phytochemicals are divided into several groups according to their structure and function. These natural products include phenols, carotenoids, thiols, indoles, etc[12]. The therapeutic effects of phytochemicals have been well understood by conducting animal and clinical studies[13],[14]. Antioxidant[15], anti-inflammatory[16], antihypertensive[17], anti-obesity[18], anti-cancer[18], anti-microbial[20], cardioprotective[21], neuroprotective[22], hepatoprotective[23] and reno-protective[24] effects are attributed to phytochemicals.

Thymoquinone [Figure 1] is a slightly water-soluble phytochemical compound that is mainly extracted from Nigella sativa. This natural compound has been demonstrated to have multiple therapeutic properties including antioxidant, anti-inflammatory, anti-diabetic, anti-sepsis, anti-carcinogenic, and anti-mutagenic effects[25]. The protective effects of thymoquinone on hepatotoxicity[26], cardiotoxicity[27], and renotoxicity[28] have been well studied. The positive impacts of thymoquinone on learning and memory impairments resulting from hypothyroidism have also been documented[29].
Figure 1: Molecular structure of (A) thymoquinone, (B) crocin, and (C) carvacrol.

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Crocin [Figure 1] is a bioactive substance from Crocus sativus. In traditional medicine, it is employed for curing inflammation-related illnesses including bronchitis, diabetes, and cancer[30]. There are also ample pieces of evidence that show crocin scavenges free radicals and attenuates oxidative stress. Crocin can downregulate the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), and interleukin-1β (IL-1β)[31]. Crocin has been also found to inhibit apoptosis via down-regulation of caspases-9 and 3 activity and reduction of Bax/Bcl2 ratio[32]. In addition, the effect of crocin against angiotensin II-triggered acute hypertension in rats has been confirmed[33].

Carvacrol [Figure 1] is a phenolic ingredient found in essential oils of some plants which possesses a wide range of biological and pharmacological properties such as anti-apoptosis, anti-cancer, anti-inflammation, and anti-proliferation[34]. Carvacrol can eliminate reactive oxygen species (ROS) and increase antioxidant activities including glutathione (GSH)[35]. Based on scientific findings, carvacrol has beneficial effects on depressive-like behaviors[36], high blood pressure[37], and diabetes[38]. Considering numerous beneficial effects of these compounds, in this review, the hepato- and reno-protective effects of thymoquinone, crocin, and carvacrol are focused on and summarized.

  2. Methods Top

In the current review, findings were extracted from PubMed, Scopus, Web of Science, and Google Scholar databases from the beginning of 2015 until the end of November 2021 by searching key words incluing “hepatoprotective” or “renoprotective” and “thymoquinone”, “crocin”, and “carvacrol”. Non-English papers and letters to the editor were excluded.

  3. Hepatoprotective effects Top

3.1. Effects of thymoquinone

Hepatic damages resulting from ischemia-reperfusion (IR) are considered a basic obstacle in liver surgeries such as liver transplantation[39]. Oxidative and nitrosative stress has been considered important factors in the pathogenesis of IR-induced hepatic damages[40]. The protective effect of thymoquinone (20 mg/ kg/day) was evaluated against IR-induced hepatic injury in rats. The previous study showed that pretreatment with thymoquinone mitigated the serum level of ALT, AST, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO). In addition, overexpression of endothelial nitric oxide synthase (eNOS) and down-regulation of iNOS occurred after thymoquinone administration. The results suggested that the hepatoprotective effects of thymoquinone were probably mediated via regulating the NO signaling pathway and improving oxidative stress[41]. The liver plays a key role in lipid homeostasis. Some toxic substances such as ethanol damage the liver and consequently disturb lipid homeostasis[42]. In addition, AMP-activated protein kinase (AMPK) has a pivotal role in lipid homeostasis and its activation prevents the proliferation of hepatic stellate cells (HSC) and hepatic fibrosis[43]. Liver kinase B1 is a serine/threonine kinase linked to AMPK signaling pathway[44]. In addition, one of the basic regulators in hepatic lipid hemostasis is sirtuin 1 (SIRT1). Up-regulation of SIRT1-AMPK pathway has been shown to elevate fatty acids oxidation and suppress lipogenesis by affecting the activity of peroxisome proliferator-activated receptors (PPARs)[45]. On the other hand, it has been reported that alcohol damages the liver tissue by decreasing the activity of AMPK or SIRT1[46]. Oral administration of thymoquinone (20 and 40 mg/kg) could improve alcohol-caused liver dysfunction in mice via increased activity of liver kinase B1, AMPK, and PPARs and up-regulation of SIRT1[47].

Diabetes mellitus (DM) is a metabolic disorder associated with hyperglycemia which can be resulted from a defect in insulin secretion. The previous study demonstrated that liver injuries can be a consequence of DM. Hyperglycemia, hyperlipidemia, and inflammation resulting from DM contribute to liver damage[48]. It has been suggested that antioxidant agents can rescue liver cells from DM-triggered injuries[49]. In a study, administration of 20 mg/kg/day of thymoquinone along with beta-aminoisobutyric acid protected the hepatic tissue against streptozocin-induced diabetes. This therapeutic effect was due to antioxidant and anti-diabetic properties of thymoquinone[50].

Drug-stimulated hepatic injury has been shown to contribute to acute liver failure[51]. Acetaminophen as a fever-reducing medication causes hepatic failure when it is used at a high dose for a long time[52]. Cytochrome 2E1 (CYP2E1) converts acetaminophen into N-acetyl-p-benzoquinone imine. N-Acetyl-p-benzoquinone imine reduces GSH level and promotes oxidative stress and consequently disarranges mitochondria function[53]. Researchers reported that thymoquinone (20 mg/kg) could alleviate hepatotoxicity resulting from acetaminophen overdose in mice by regulating the activity of c-jun N-terminal kinase (JNK) and AMPK signaling pathways and reducing the cytochrome 2E1 function[54].

Lipid accumulation in liver cells alters their normal function and induces nonalcoholic fatty liver disease (NAFLD). NAFLD can lead to liver fibrosis, cirrhosis, and hepatocarcinoma[55]. In a previous study, the effects of a low dose (10 mg/kg) and a high dose (20 mg/kg) of thymoquinone were evaluated against high-fat high-cholesterol diet-caused NAFLD in rats. The results demonstrated that both doses of thymoquinone ameliorated insulin resistance and blood glucose. In addition, the serum level of total cholesterol and triglyceride (TG) was reduced and the blood concentration of high-density lipoprotein (HDL) was elevated in thymoquinone-treated rats[56].

Hepatocellular carcinoma is one of the main causes of death resulting from cancer worldwide[57]. Binding of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to its receptors, TRAILR1 and TRAILR2, can be a spark for inducing programmed cell death by activating the caspase-8[58]. Production of B cell lymphoma (Bcl) anti-apoptotic proteins such as Bcl-2 and Bcl-XL also prevents apoptosis and increases the resistance of cancer cells against chemotherapy drugs[59]. Furthermore, transforming growth factor-beta 1 (TGF-β1) can prepare a suitable environment for the proliferation of tumor cells[60]. Thymoquinone (20 mg/kg) attenuated thioacetamide-caused hepatocellular carcinoma in rats via down-regulation of Bcl-2, Bcl-XL, and TGF-β1 expression, and up-regulation of TRAIL-linked apoptosis[61]. The hepatoprotective effects of thymoquinone are illustrated in [Table 1].
Table 1: Hepatoprotective effects of thymoquinone.

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3.2. Effects of crocin

IR can disturb liver tissue function by inducing the release of ROS and inflammatory cytokines[62]. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects organs such as the liver against oxidative stress damage[63]. Furthermore, the increased level of miR-122 that is expressed in liver cells has a relationship with liver enzymes in IR-induced hepatic damages[64]. The inhibition of miR-34a can prevent the hepatic injuries induced by IR[65]. P53 as a tumor suppressor protein also targets miR-34a[66]. It has been revealed that inhibition of p53 down-regulates miR-34a and finally castrates oxidative stress and ameliorates hepatic damage[67]. It has been recognized that crocin (200 mg/kg) can rescue liver tissue from IR-induced injury in rats, which is associated with the elevation of antioxidant enzymes activity including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), reduction of liver enzymes concentration, increase of Nrf2 expression and down-regulation of miR-122, miR-34a and p53[68].

Thioacetamide is an organosulfur carcinogenic compound that is employed in some industries including leader, paper, and textile. In addition, thioacetamide has been reported to have fungicidal properties. Therefore, it has been used to prevent the decay of some fruits such as oranges. However, thioacetamide has been revealed to have detrimental effects on different body organs such as the lungs, kidney, intestine, pancreas, and liver[69]. Intraperitoneally injection of crocin (10 mg/kg) exerted protective effects against thioacetamide-induced hepatocellular carcinoma in rats via modulating the oxidative stress status. In addition, treatment with crocin increased Nrf2 and heme oxygenase-1 (HO-1) expression, suppressed the level of c-JNK, stimulated TRAIL-mediated apoptosis, up-regulated the expression of caspase-8, p53, and Bax, and reduced the expression of Bcl-2[70]. Acrylamide is a potential carcinogenic and toxic compound that is formed at high temperatures and disturbs mitochondria function[71]. A previous study showed that crocin (50 mg/kg) improved acrylamide-induced liver injury in rats. This protective effect could be attributed to the antioxidant activity of crocin[72]. Bisphenol A is also a toxic substance that is used in production of polycarbonate plastics and epoxy resins[73]. Crocin (20 mg/kg for 30 d) has been found to decrease the bisphenol A-triggered liver toxicity in rats. The ameliorative effect of crocin against liver damage was mediated by the reduction of TG and liver enzymes, inhibition of oxidative stress, decrease of miR-122 expression, and up-regulation of JNK, extracellular signal-regulated kinase 1/2 (ERK1/2), and mitogen-activated protein kinase (MAPK)[74]. Scientific evidence also demonstrated that oral administration of crocin (20 mg/kg for 8 weeks) suppressed lipogenesis and induced β-oxidation of fatty acids by activating the AMPK signaling pathway in diabetic and obese db/ db mice[75].

Toll-like receptors (TLRs) are membrane receptors that play an important role in inflammation-caused tissue damage. They can be stimulated by exogenous and endogenous ligands[76]. TLRs were also expressed in hepatic parenchymal and non-parenchymal cells and contributed to the development of inflammatory responses resulting from alcoholic and non-alcoholic liver diseases, viral hepatitis, and drugs-linked liver disorders[77]. Some chemotherapeutic agents including cisplatin have been shown to induce hepatotoxicity via stimulating the inflammatory reactions when they are used at high doses[78]. Accumulating pieces of evidence exhibit that pretreatment with crocin (200 mg/kg) afford hepatoprotective effects against cisplatin-stimulated liver injury through antagonizing the activity of TLR4/nuclear factor kappa B (NF-κB) signaling pathway, elevating the level of anti-fibrogenic agents including activin membrane-bound inhibitor and miRNA-9 and miRNA-29 and inhibiting the expression of TGF-β1[79].

Liver fibrosis is a disorder followed by over-deposition of extracellular matrix ingredients. Malfunction of biliary system and accumulation of fat in the liver has been known as one of the most important causes of hepatic fibrosis[80]. Carbon tetrachloride (CCl4) can induce hepatic fibrosis in animal studies[81]. Chhimwal et al. reported that crocin (20, 40, and 80 mg/kg) could alleviate the CCl4-triggered hepatic fibrosis in rats through the improvement of PPAR-γ expression, modulation of inflammation, and suppression of fibrogenic signaling pathways[82].

Aging is considered an important factor in body organ dysfunction such as the liver. Oxidative stress and inflammation have been illustrated to play a key role in the harmful effects of aging on tissues[83]. Long-term injection of D-galactose can induce aging in animal studies[84]. The study of Omidkhoda et al. demonstrated that D-galactose (400 mg/kg) disturbed liver function with elevated levels of ALT, AST, ALP, MDA, and iNOS and reduced activity of GSH. Crocin at 7.5, 15, and 30 mg/kg could ameliorate D-galactose-stimulated hepatotoxicity via the suppression of lipid peroxidation and iNOS expression[85]. The hepatoprotective effects of crocin are summarized in [Table 2].
Table 2: Hepatoprotective effects of crocin.

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3.3. Effect of carvacrol

Hippo-Yes-associated protein pathway (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) as one of the most vital components of tissue homeostasis has been shown to modulate endothelial cell proliferation, vascular barrier establishment, and cell migration[86]. Meanwhile, interaction of Hippo and TGF-β signaling pathways can lead to fibrotic disorders[87]. It has been also reported that YAP and TAZ excite the HSC proliferation and promote the up-regulation of connective tissue growth factor as one of the principal players in tissue fibrosis induction[88]. Scientific evidence have proved that administration of 35 and 70 mg/kg of carvacrol prevented CCl4-promoted hepatic fibrosis in rats by affecting the Hippo and TGF-β signaling pathways. Moreover, carvacrol normalized the level of liver enzymes, reduced the hepatic hydroxyproline, and down-regulated YAP/TAZ and TGF-β signaling pathways[89]. In another study, carvacrol (25 and 50 mg/kg) showed anti-fibrotic effects against thioacetamide through the mitigation of NF-κB, IL-1β, iNOS, matrix metalloproteinase-3 and 9 (MMP-3 and 9), autotaxin and TGF-β1 level in rats[90].

Lysyl oxidase, an extracellular copper-linked enzyme, catalyzes the covalent cross-linkage formation in collagen fibers and its overproduction can make a stable environment for induction of fibrotic processes[91]. It has been documented that carvacrol (70 mg/ kg) modified the oxidative stress status and decremented the level of lysyl oxidase homolog 2 and lysyl oxidase in CCl4-exposed rats and consequently ameliorated liver tissue fibrosis[92]. Additionally, carvacrol administration (25, 50, 100 mg/kg) could exert ameliorative effects against fibrotic hepatic tissues in CCl4-challenged mice through the inhibition of transient receptor potential melastatin 7, regulation of MAPK signaling pathway, and suppression of HSC proliferation[93].

Adriamycin as an antitumor antibiotic acts as a double-edged sword. It can inhibit cancer cells, but its high doses have toxic effects on organs such as the heart, liver, and kidney[94]. Oral administration of carvacrol (20 mg/kg) improved adriamycin-induced hepatic oxidative damage in rats by lowering the MDA concentration and elevating the CAT activity[95]. The anti-oxidant and anti-inflammatory effects of carvacrol against lipopolysaccharide (LPS)-induced liver injuries have been also confirmed. In an animal study, systemic injection of carvacrol (25, 50, and 100 mg/kg) reversed pernicious effects of LPS on liver function in rats by modulating liver enzymes concentration, diminishing NO, MDA, and IL-1β levels, and increasing total thiol content and SOD and CAT activities[96]. Carvacrol (20 mg/kg) also showed positive therapeutic impact on acetaminophen-prompted hepatotoxicity in rats, which was linked to its antioxidant properties[97]. The results of scientific works confirmed that the increase of cytochrome (Cyt) P450 activity by ethanol induces oxidative stress causing hepatic damage. It has been reported that carvacrol binds to the active site of Cyt P450 and suppresses its function. In animal research, carvacrol (50 mg/ kg) ameliorated alcohol-induced hepatotoxicity with the inhibition of Cyt P450 and down-regulation of NF-κB, iNOS, and eNOS levels[98]. Some toxic heavy metals such as cadmium exert toxic effects on body tissues by disturbing the oxidative stress status. Treatment of rats with 25 and 50 mg/kg of carvacrol also attenuated the detrimental effects of cadmium on liver and kidney function by lowering the concentration of ALT, ALP, AST, urea, creatinine, and MDA and elevating the activity of SOD, CAT, and GPx. In addition, carvacrol alleviated the effects of cadmium on iNOS, COX-2, NF-κB, Bcl-3, Bax, Bcl-2, MAPK-14, MPO, prostaglandin E2 (PGE2, p53, caspase-6, caspase-3, and caspase-9[99].

The positive effects of carvacrol on liver dysfunction caused by type 2 diabetes mellitus (T2DM) in mice have been also explored. The results indicated that 10 mg/kg of carvacrol for 6 weeks could improve T2DM-caused liver malfunction via the reduction of ALT, AST, TG, and low-density lipoprotein cholesterol level, enhancement of high-density lipoprotein cholesterol content, and regulation of TLR 4/NF-κB signaling pathway[100]. One of the basic intracellular signaling pathways starting the hepatic regeneration after partial hepatectomy is IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway. It has been exhibited that peripheral administration of carvacrol (73 mg/kg) could stimulate hepatocyte proliferation and hepatic regeneration 24 and 48 h after partial hepatectomy in mice by activating the IL-6/STAT3 and MAPK signaling pathways[101]. The hepatoprotective effects of carvacrol are displayed in [Table 3].
Table 3: Hepatoprotective effects of carvacrol.

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  4. Reno-protective effects Top

4.1. Effects of thymoquinone

In the kidneys, IR-induced injury contributes to pathological conditions such as acute kidney injury. IR-triggered renal injuries are due to overproduction of free radicals, pro-inflammatory and pro-fibrotic cytokines[102]. In a rat model of renal IR, oral administration of thymoquinone (10 mg/kg) ameliorated hemodynamic and tubular function indicators in the kidneys. These renoprotective effects of thymoquinone were associated with the decline of pro-inflammatory and pro-fibrotic mediators such as tumor necrosis factor (TNF)-α, TGF-1β, and plasminogen activator inhibitor-1[103]. Structural and functional abnormalities of the kidney can be a consequence of formation of fibrous tissues. Oxidative stress and inflammation are considered risk factors for renal fibrosis[104]. It has been demonstrated that thymoquinone (2, 5, and 10 mg/kg/day) protects against LPS-induced renal fibrosis through the inhibition of oxidative stress and inflammation responses. According to the results, treatment with thymoquinone decreased MDA concentration and increased total thiol content and SOD and CAT activity in kidney tissues[105]. Uncontrolled production of free radicals and inflammatory cytokines has been exhibited to have a central role in sepsis-linked renal damage[106]. It has been detected that thymoquinone (50 mg/kg) mitigated kidney injuries in septic ALB/c mice. The renal protective effects of thymoquinone were associated with the reduced expression of NF-κB, TNF-α, IL-1β, and IL-6, caspase-1, caspase-3, and caspase-8 and NOD-like receptor family pyrin domain-containing 3 (NLRP3)[107]. Ionizing radiations employed for management of some diseases damage DNA and stimulate the release of free radicals. Thymoquinone (50 mg/kg/day) as a natural antioxidant has been recognized to improve gamma-induced renal injuries in rats through the potentiation of antioxidant capacity and the inhibition of free radicals production[108].

Alteration of thyroid gland function, hyperthyroidism, and hypothyroidism, can disturb renal function[109]. It has been reported that hypothyroidism decrements the production of renin and enhances the blood level of creatinine and the permeability of glomerular capillaries[110]. It has been also found that hypothyroidism can induce renal failure by disturbing the function of intracellular antioxidant system. In a rat model of hypothyroidism induced by propylthiouracil, thymoquinone (50 mg/kg) balanced the oxidative status and up-regulated the gene expression of CAT in kidney tissues and finally improved renal functioning[111]. Kidney function can be threatened when they were exposed to heavy metals such as lead. The researchers reported that thymoquinone (5 mg/ kg/day for 5 weeks) could ameliorate lead-induced nephropathy in rats through the reinforcement of intracellular antioxidant mechanisms[112]. In addition, thymoquinone (50 mg/kg) protected rats against manganese-induced nephrotoxicity via the down-regulation of TNF-α and IL-6 and the enhancement of SOD, GSH, and IL-10[113]. In an animal model of cisplatin-induced renal toxicity, systemic infusion of thymoquinone (50 mg/kg) along with curcumin reversed the harmful effects of this anti-cancer drug on the kidney of rats via attenuating the effect of NF-κB and kidney injury molecule 1, and amplifying the activity of Nrf2/HO-1 signaling pathway[114]. The improving effect of thymoquinone (20 mg/kg) against diclofenac-induced renal injury was also documented. In the study of Hashem et al., thymoquinone improved the antioxidant defense, suppressed the activity of caspase 3, and modulated the expression of mitofusin-2 and miR-34a in renal tissue of rats[115]. The renoprotective effects of thymoquinone are presented in [Table 4].
Table 4: Renoprotective effects of thymoquinone.

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4.2. Effects of crocin

Diabetic nephropathy is recognized as an important cause of renal failure. In this disease, renal cell function was disturbed by inflammation resulting from high blood sugar concentration[116]. In a mice model of nephropathy, crocin (50 mg/kg) exerted its renal protective effects via the attenuation of oxidative damage-related NF-κB signaling pathway and intensification of Nrf2 activity[117]. Moreover, hyperglycemia-caused inflammatory responses and NLRP3 inflammasome involve in the pathogenesis of diabetic nephropathy. Up-regulation of NLRP3 results in uncontrolled release of inflammatory cytokines such as IL-1β and IL-18 and ultimately disturbs renal function[118]. Administration of 50 mg/ kg of crocin could alleviate diabetic nephropathy resulting from overexpression of TNF-α, IL-1β, and IL-18 in rats by decreasing NLRP3 inflammasome[119]. Treatment of rats with crocin (40 mg/ kg) also suppressed the production of NADPH oxidase 4, p53, and IL-18 and repaired the diabetic nephropathy-induced renal damages[120]. In addition, daily administration of crocin (50 mg/ kg) could inhibit nephropathy progression in pinealectomized diabetic rats by modulating the level of TGF-β1 and oxidative stress markers[121]. Moreover, crocin (12.5, 25, and 50 mg/kg) ameliorated the detrimental effects of methotrexate on the kidneys of rats by increasing antioxidant activity and lowering MDA levels[122].

Some anthracycline antibiotics such as doxorubicin have been reported to have side effects on the liver, kidney, neurons, and heart[123]. The toxic effect of these drugs can be a consequence of oxidative damage such as DNA and proteins. Scientific evidence illustrated that crocin (100 mg/kg/day for 3 weeks) as an antioxidant alleviated doxorubicin-caused nephrotoxicity in rats and decreased the gene expression of NF-κB, iNOS, TNF-α, and COX2[124].

Acute kidney injury is a clinical disorder without definitive treatment. One of the known causes of this disease is renal IR causing vascular endothelium dysfunction and inflammation[125]. In an experimental model of IR-excited acute kidney injury, intraperitoneal injection of crocin (100, 200, and 400 mg/kg) dose-dependently lessened leukocyte infiltration, intercellular adhesion molecule (ICAM)-1 and TNF-α in kidney tissues of rats[126]. In another research, crocin (20 mg/kg) restored the noxious effects of IR by modulating oxidative stress and TLR4-linked inflammation in rats[127]. The renoprotective effects of crocin are depicted in [Table 5].
Table 5: Renoprotective effects of crocin.

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4.3. Effects of carvacrol

Nonsteroidal anti-inflammatory drugs are used for the relief of some ailments such as headache, flu, and arthritis[128]. Diclofenac is a nonsteroidal anti-inflammatory drug that is frequently used by people to remedy pain[129]. It has been propounded that there is a link between the use of diclofenac and renal damage[130]. Researchers evaluated the effect of carvacrol (10 mg/kg) against diclofenac-caused renal injury in rats. The results indicated that the reno-protective impact of carvacrol was associated with increased level of antioxidant indicators including GPx, GSH, CAT, and SOD and decreased production of oxidant and inflammatory indices such as MDA and TNF-α[131]. Sadeghi et al. reported that carvacrol reduced cisplatin-induced kidney toxicity by the reduction of NO metabolites and MDA concentration[132].

Antineoplastic compounds such as cyclophosphamide can trigger renal dysfunction by disturbing the oxidative status. Carvacrol (10 mg/kg) ameliorated cyclophosphamide-stimulated renal malfunction in rats through the attenuation of oxidative damage to renal tissues. Based on the results of Gunes et al., the concentration of MDA was decreased and GSH, SOD, and CAT activity and total antioxidant capacity levels were increased in the carvacrol-treated group compared to the cyclophosphamide group[133]. Systemic injection of 75 mg/kg of carvacrol also enhanced the SOD, CAT, GSH activity, down-regulated the eNOS expression, and decremented the MDA and MPO concentration, eventually mitigating the IR-caused disturbances in renal function of rats[134]. Restraint stress can be associated with oxidative stress resulting in body organs damage. It has been documented that carvacrol (30 and 40 mg/kg) protected the brain, liver, and kidney of rats against chronic stress-caused oxidative damage by reducing the level of MDA and increasing the activity of SOD and CAT in rats[135]. The renoprotective effects of carvacrol are summarized in [Table 6].
Table 6: Renoprotective effects of carvacrol.

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  5. Conclusion Top

This review shows that inflammation and oxidative stress play a role key in hepatic and renal injuries. The activation of intracellular signaling pathways linked to NF-κB, MAPK, JNK, and ERK1/2 in response to inflammation stimuli can result in body organ damage. Thymoquinone, crocin, and carvacrol show hepato- and reno-protective effects through the inhibition of these signaling pathways. The transcription factor Nrf2 is also considered a very important cause in the protection of organs against oxidative stress. Thymoquinone, crocin, and carvacrol also exert their anti-oxidative effects against hepatic and renal injuries via up-regulating the Nrf2 pathway and amplifying the antioxidant defense. TGFβ1 makes a suitable environment for the growth and proliferation of cancer cells. According to the previous studies, TGF-β1 pathway is one of anti-tumor targets for thymoquinone and crocin in the protection of the liver and kidney.

Although accumulating evidence reveals that thymoquinone, crocin, and carvacrol exert protective effects against hepatic and renal damages in animal studies, the therapeutic effect of these phytochemicals in the clinical study needs to be further investigated. Therefore, preclinical studies are required to elucidate the safety and efficacy of these natural compounds.

Conflict of interest statement

The author declares that there is no conflict of interest.

  References Top

Hörber S, Lehmann R, Stefan N, Machann J, Birkenfeld AL, Wagner R, et al. Hemostatic alterations linked to body fat distribution, fatty liver, and insulin resistance. Mol Metab 2021; 53: 1-7.  Back to cited text no. 1
Burghuber CK, Kandioler D, Strobl S, Mittlböck M, Böhmig GA, Soliman T, et al. Standardized intraoperative application of an absorbable polysaccharide hemostatic powder to reduce the incidence of lymphocele after kidney transplantation—a prospective trial. Transpl In 2019; 32(1): 59-65.  Back to cited text no. 2
Mohamed HRH. Alleviation of cadmium chloride-induced acute genotoxicity, mitochondrial DNA disruption, and ROS generation by chocolate coadministration in mice liver and kidney tissues. Biol Trace Elem Res 2021. Doi: 10.1007/s12011-021-02981-y.  Back to cited text no. 3
Lamia SS, Emran T, Rikta JK, Chowdhury NI, Sarker M, Jain P, et al. Coenzyme Q10 and silymarin reduce CCl4-induced oxidative stress and liver and kidney injury in ovariectomized rats—implications for protective therapy in chronic liver and kidney diseases. Pathophysiology 2021; 28(1): 50-63.  Back to cited text no. 4
Adeleke GE, Adaramoye OA. Betulinic acid abates N-nitrosodimethylamine-induced changes in lipid metabolism, oxidative stress, and inflammation in the liver and kidney of Wistar rats. J Biochem Mol Toxicol 2021; 35(11): e22901.  Back to cited text no. 5
Cóndor JM, Rodrigues CE, de Sousa Moreira R, Canale D, Volpini RA, Shimizu MH, et al. Treatment with human Wharton’s jelly-derived mesenchymal stem cells attenuates sepsis-induced kidney injury, liver injury, and endothelial dysfunction. Stem Cells Transl Med 2016; 5(8): 1048-1057.  Back to cited text no. 6
Derouiche S, Djermoun M, Abbas K. Beneficial effect of zinc on diabetes induced kidney damage and liver stress oxidative in rats. J Adv Biol 2017; 10(1): 2050-2055.  Back to cited text no. 7
Saputri FC, Astari C, Janatry DA, Kusmana D. Hepatoprotective effect of Bellamya javanica: Aspartate transaminase, alanine aminotransferase, and alkaline phosphatase activity, and liver histopathology in mice induced with carbon tetrachloride. Int J App Pharm 2018; 10(1): 203-207.  Back to cited text no. 8
Hosseini M, Beheshti F, Anaeigoudari A. Improving effect of aminoguanidine on lipopolysaccharide-caused kidney dysfunction in rats. Saudi J Kidney Dis Transpl 2020; 31(5): 1025-1033.  Back to cited text no. 9
Ma G, Chai X, Hou G, Zhao F, Meng Q. Phytochemistry, bioactivities and future prospects of mulberry leaves: A review. Food Chem 2021; 372: 1-18.  Back to cited text no. 10
Probst YC, Guan VX, Kent K. Dietary phytochemical intake from foods and health outcomes: A systematic review protocol and preliminary scoping. BMJ Open 2017; 7(2): e013337.  Back to cited text no. 11
Pham DC, Shibu M, Mahalakshmi B, Velmurugan BK. Effects of phytochemicals on cellular signaling: Reviewing their recent usage approaches. Crit Rev Food Sci Nutr 2020; 60(20): 3522-3546.  Back to cited text no. 12
Bo XM, Yu RB, Du SJ, Zhang RL, He L. Ferulic acid alleviates lipopolysaccharide-induced depression-like behavior by inhibiting inflammation and apoptosis. Asian Pac J Trop Biomed 2020; 10(12): 523-531.  Back to cited text no. 13
Cao H, Ou J, Chen L, Zhang Y, Szkudelski T, Delmas D, et al. Dietary polyphenols and type 2 diabetes: Human study and clinical trial. Crit Rev Food Sci Nutr 2019; 59(20): 3371-3379.  Back to cited text no. 14
Ayuda-Durán B, González-Manzano S, González-Paramás AM, Santos-Buelga C. Caenorhabditis elegans as a model organism to evaluate the antioxidant effects of phytochemicals. Molecules 2020; 25(14): 2-23.  Back to cited text no. 15
Zhu F, Du B, Xu B. Anti-inflammatory effects of phytochemicals from fruits, vegetables, and food legumes: A review. Crit Rev Food Sci Nut 2018; 58(8): 1260-1270.  Back to cited text no. 16
Kamyab R, Namdar H, Torbati M, Ghojazadeh M, Araj-Khodaei M, Fazljou SMB. Medicinal plants in the treatment of hypertension: A review. Adv Pharm Bull 2021; 11(4): 601-617.  Back to cited text no. 17
Abdul Rahman H, Saari N, Abas F, Ismail A, Mumtaz MW, Abdul Hamid A. Anti-obesity and antioxidant activities of selected medicinal plants and phytochemical profiling of bioactive compounds. Int J Food Prop 2017; 20(11): 2616-2629.  Back to cited text no. 18
Batool R, Aziz E, Iqbal J, Salahuddin H, Tan BKH, Tabassum S, et al. In vitro antioxidant and anti-cancer activities and phytochemical analysis of Commelina benghalensis L. root extracts. Asian Pac J Trop Biomed 2020; 10(9): 417-425.  Back to cited text no. 19
Khazdair MR, Anaeigoudari A, Agbor GA. Anti-viral and anti-inflammatory effects of kaempferol and quercetin and COVID-2019: A scoping review. Asian Pac J Trop Biomed 2021; 11(8): 327-334.  Back to cited text no. 20
Ahmadi L, El-Kubbe A, Roney SK. Potential cardio-protective effects of green grape juice: A review. Curr Nutr Food Sci 2019; 15(3): 202-207.  Back to cited text no. 21
Velmurugan BK, Rathinasamy B, Lohanathan BP, Thiyagarajan V, Weng CF. Neuroprotective role of phytochemicals. Molecules 2018; 23(10): 2-15.  Back to cited text no. 22
Sajid M, Khan MR, Shah NA, Shah SA, Ismail H, Younis T, et al. Phytochemical, antioxidant and hepatoprotective effects of Alnus nitida bark in carbon tetrachloride challenged Sprague Dawley rats. BMC Complement Altern Med 2016; 16(1): 1-17.  Back to cited text no. 23
Borgohain R, Pathak P, Mohan R. Anti-diabetic and reno-protective effect of the ethanolic extract of Solanum indicum in alloxan-induced diabetic rats. J Evol Med Dent Sci 2016; 5(99): 7294-7298.  Back to cited text no. 24
Kalam MA, Raish M, Ahmed A, Alkharfy KM, Mohsin K, Alshamsan A, et al. Oral bioavailability enhancement and hepatoprotective effects of thymoquinone by self-nanoemulsifying drug delivery system. Mater Sci Eng C Mater Biol Appl 2017; 76: 319-329.  Back to cited text no. 25
Al Aboud D, Baty RS, Alsharif KF, Hassan KE, Zhery AS, Habotta OA, et al. Protective efficacy of thymoquinone or ebselen separately against arsenic-induced hepatotoxicity in rat. Environ Sci Pollut Res Int 2021; 28(50): 6195-6206.  Back to cited text no. 26
Akgül B, Aycan İØ, Hidişoğlu E, Afşar E, Yıldınm S, Tannöver G, et al. Alleviation of prilocaine-induced epileptiform activity and cardiotoxicity by thymoquinone. Daru 2021; 29(1): 85-99.  Back to cited text no. 27
Erdemli ME, Yigitcan B, Erdemli Z, Gul M, Bag HG, Gul S. Thymoquinone protection against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induced nephrotoxicity in rats. Biotech Histochem 2020; 95(8): 567-574.  Back to cited text no. 28
Baghcheghi Y, Hosseini M, Beheshti F, Salmani H, Anaeigoudari A. Thymoquinone reverses learning and memory impairments and brain tissue oxidative damage in hypothyroid juvenile rats. Arq Neuropsiquiatr 2018; 76(1): 32-40.  Back to cited text no. 29
Korani S, Korani M, Sathyapalan T, Sahebkar A. Therapeutic effects of crocin in autoimmune diseases: A review. BioFactors 2019; 45(60): 835-843.  Back to cited text no. 30
Lv B, Huo F, Zhu Z, Xu Z, Dang X, Chen T, et al. Crocin upregulates CX3CR1 expression by suppressing NF-κB/YY1 signaling and inhibiting lipopolysaccharide-induced microglial activation. Neurochem Res 2016; 41(8): 1949-1957.  Back to cited text no. 31
Bi X, Jiang Z, Luan Z, Qiu D. Crocin exerts anti-proliferative and apoptotic effects on cutaneous squamous cell carcinoma via miR-320a/ ATG2B. Bioengineered 2021; 12(1): 4569-4580.  Back to cited text no. 32
Shafei MN, Faramarzi A, Rad AK, Anaeigoudari A. Crocin prevents acute angiotensin II -induced hypertension in anesthetized rats. Avicenna J Phytomed 2017; 7(4): 345.  Back to cited text no. 33
Sharifi-Rad M, Varoni EM, Iriti M, Martorell M, Setzer WN, del Mar Contreras M, et al. Carvacrol and human health: A comprehensive review. Phytother Res 2018; 32(9): 1675-1687.  Back to cited text no. 34
Amin F, Memarzia A, Kazemi Rad H, Shakeri F, Boskabady MH. Systemic inflammation and oxidative stress induced by inhaled paraquat in rat improved by carvacrol, possible role of PPARγ receptors.  Back to cited text no. 35
BioFactors 2021; 47(5): 778-787.  Back to cited text no. 36
Naeem K, Al Kury LT, Nasar F, Alattar A, Alshaman R, Shah FA, et al. Natural dietary supplement, carvacrol, alleviates LPS-induced oxidative stress, neurodegeneration, and depressive-like behaviors via the Nrf2/ HO-1 pathway. J Inflamm Res 2021; 14: 1313-1329.  Back to cited text no. 37
Barreto da Silva L, Camargo SB, Moraes RdA, Medeiros CF, Jesus AdM, Evangelista A, et al. Antihypertensive effect of carvacrol is improved after incorporation in β-cyclodextrin as a drug delivery system. Clin Exp Pharmacol Physiol 2020; 47(11): 1798-1807.  Back to cited text no. 38
Cicalau GIP, Babes PA, Calniceanu H, Popa A, Ciavoi G, Iova GM, et al. Anti-inflammatory and antioxidant properties of carvacrol and magnolol, in periodontal disease and diabetes mellitus. Molecules 2021; 26(22): 1-29.  Back to cited text no. 39
Tang Y, Wang T, Ju W, Li F, Zhang Q, Chen Z, et al. Ischemic-free liver transplantation reduces the recurrence of hepatocellular carcinoma after liver transplantation. Front Oncol 2021; 11: 1-10.  Back to cited text no. 40
Gdara NB, Belgacem A, Khemiri I, Mannai S, Bitri L. Protective effects of phycocyanin on ischemia/reperfusion liver injuries. Biomed Pharmacother 2018; 102: 196-202.  Back to cited text no. 41
Abd-Elbaset M, Arafa E-SA, El Sherbiny GA, Abdel-Bakky MS, Elgendy ANA. Thymoquinone mitigate ischemia-reperfusion-induced liver injury in rats: A pivotal role of nitric oxide signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 2017; 390(1): 69-76.  Back to cited text no. 42
Rasineni K, Kubik JL, Casey CA, Kharbanda KK. Inhibition of ghrelin activity by receptor antagonist [d-Lys-3] GHRP-6 attenuates alcohol-induced hepatic steatosis by regulating hepatic lipid metabolism. Biomolecules 2019; 9(10): 2-16.  Back to cited text no. 43
Liu J, Zhang T, Zhu J, Ruan S, Li R, Guo B, et al. Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy. Chin Med 2021; 16(1): 1-13.  Back to cited text no. 44
Al-Damry NT, Attia HA, Al-Rasheed NM, Al-Rasheed NM, Mohamad RA, Al-Amin MA, et al. Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy. Biomed Pharmacother 2018; 107: 347-358.  Back to cited text no. 45
Deleye Y, Cotte AK, Hannou SA, Hennuyer N, Bernard L, Derudas B, et al. CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKa2-SIRT1-PPARa signaling pathway. J Biol Chem 2020; 295(50): 17310-17322.  Back to cited text no. 46
Lee SE, Koh H, Joo DJ, Nedumaran B, Jeon HJ, Park CS, et al. Induction of SIRT1 by melatonin improves alcohol-mediated oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway. J Pineal Res 2020; 68(30): e12638.  Back to cited text no. 47
Yang Y, Bai T, Yao YL, Zhang DQ, Wu YL, Lian LH, et al. Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury. Toxicol Lett 2016; 262: 80-91.  Back to cited text no. 48
Han LP, Li CJ, Sun B, Xie Y, Guan Y, Ma ZJ, et al. Protective effects of celastrol on diabetic liver injury via TLR4/MyD88/NF-κB signaling pathway in type 2 diabetic rats. J Diabetes Res 2016; 2016: 2641248.  Back to cited text no. 49
Beheshti F, Hosseini M, Arab Z, Asghari A, Anaeigoudari A. Ameliorative role of metformin on lipopolysaccharide-mediated liver malfunction through suppression of inflammation and oxidative stress in rats. Toxin Rev 2020; 41(1): 55-63.  Back to cited text no. 50
Aktaş İ, Mehmet Gür F. Hepato-protective effects of thymoquinone and beta-aminoisobutyric acid in streptozocin induced diabetic rats. Biotech Histochem 2021; 97(1): 67-76.  Back to cited text no. 51
Hamilton LA, Collins-Yoder A, Collins RE. Drug-induced liver injury. AACN Adv Crit Care 2016; 27(40): 430-440.  Back to cited text no. 52
BinMowyna MN, AlFaris NA. Kaempferol suppresses acetaminophen-induced liver damage by upregulation/activation of SIRT1. Pharm Biol 2021; 59(1): 146-156.  Back to cited text no. 53
Du K, Ramachandran A, Jaeschke H. Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential. Redox Biol 2016; 10: 148-156.  Back to cited text no. 54
Cui BW, Bai T, Yang Y, Zhang Y, Jiang M, Yang HX, et al. Thymoquinone attenuates acetaminophen overdose-induced acute liver injury and inflammation via regulation of JNK and AMPK signaling pathway. Am J Chin Med 2019; 47(3): 577-594.  Back to cited text no. 55
Anaeigoudari A, Safari H, Khazdair MR. Effects of Nigella sativa, Camellia sinensis, and Allium sativum as food additive on metabolic disorders, a literature review. Front Pharmacol 2021; 12: 1-15.  Back to cited text no. 56
Awad AS, Abd Al Haleem EN, El-Bakly WM, Sherief MA. Thymoquinone alleviates nonalcoholic fatty liver disease in rats via suppression of oxidative stress, inflammation, apoptosis. Naunyn Schmiedebergs Arch Pharmacol 2016; 389(4): 381-391.  Back to cited text no. 57
Tian H, Zhao S, Nice EC, Huang C, He W, Zou B, et al. A cascaded copper-based nanocatalyst by modulating glutathione and cyclooxygenase-2 for hepatocellular carcinoma therapy. J Colloid Interface Sci 2022; 607(2): 1516-1526.  Back to cited text no. 58
Huang CC, Cheng YC, Lin YC, Chou CH, Ho CT, Wang HK, et al. CSC-3436 sensitizes triple negative breast cancer cells to TRAIL-induced apoptosis through ROS-mediated p38/CHOP/death receptor 5 signaling pathways. Environ Toxicol 2021; 36(12): 2578-2588.  Back to cited text no. 59
Verma S, Singh A, Kumari A, Tyagi C, Goyal S, Jamal S, et al. Natural polyphenolic inhibitors against the antiapoptotic BCL-2. J Recept Signal Transduct Res 2017; 37(4): 391-400.  Back to cited text no. 60
Wang J, Xu Z, Wang Z, Du G, Lun L. TGF-beta signaling in cancer radiotherapy. Cytokine 2021; 148: 1-13.  Back to cited text no. 61
Helmy SA, El-Mesery M, El-Karef A, Eissa LA, El Gayar AM. Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model. Life Sci 2019; 233: 1-12.  Back to cited text no. 62
Zhou Y, Tan Z, Huang H, Zeng Y, Chen S, Wei J, et al. Baicalein pretreatment alleviates hepatic ischemia/reperfusion injury in mice by regulating the Nrf2/ARE pathway. Exp Ther Med 2021; 22(60): 1-9.  Back to cited text no. 63
Soliman MM, Aldhahrani A, Elshazly SA, Shukry M, Abouzed TK. Borate ameliorates sodium nitrite-induced oxidative stress through regulation of oxidant/antioxidant status: Involvement of the Nrf2/HO-1 and NF-κB pathways. Biol Trace Elem Res 2022; 200(1): 197-205.  Back to cited text no. 64
Bakshi S, Kaur M, Saini N, Mir A, Duseja A, Sinha S, et al. Altered expressions of circulating microRNAs 122 and 192 during antitubercular drug induced liver injury indicating their role as potential biomarkers. Hum Exp Toxicol 2021; 40(9): 1474-1484.  Back to cited text no. 65
Akbari G, Savari F, Mard SA, Rezaie A, Moradi M. Gallic acid protects the liver in rats against injuries induced by transient ischemia-reperfusion through regulating microRNAs expressions. Iran J Basic Med Sci 2019; 22(4): 439-444.  Back to cited text no. 66
Li W, Jin S, Hao J, Shi Y, Li W, Jiang L. Metformin attenuates ischemia/ reperfusion-induced apoptosis of cardiac cells by downregulation of p53/ microRNA-34a via activation SIRT1. Can J Physiol Pharmacol 2021; 99(9): 875-884.  Back to cited text no. 67
Kim HJ, Joe Y, Yu JK, Chen Y, Jeong SO, Mani N, et al. Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway. Biochim Biophys Acta 2015; 1852(7): 1550-1559.  Back to cited text no. 68
Akbari G, Mard SA, Dianat M, Mansouri E. The hepatoprotective and microRNAs downregulatory effects of crocin following hepatic ischemia-reperfusion injury in rats. Oxid Med Cell Longev 2017; 2017: 1702967.  Back to cited text no. 69
Akhtar T, Sheikh N. An overview of thioacetamide-induced hepatotoxicity. Toxin Rev 2013; 32(3): 43-46.  Back to cited text no. 70
Elsherbiny NM, Eisa NH, El-Sherbiny M, Said E. Chemo-preventive effect of crocin against experimentally-induced hepatocarcinogenesis via regulation of apoptotic and Nrf2 signaling pathways. Environ Toxicol Pharmacol 2020; 80: 103494.  Back to cited text no. 71
Wei Q, Zhang P, Liu T, Pu H, Sun DW. A fluorescence biosensor based on single-stranded DNA and carbon quantum dots for acrylamide detection. Food Chem 2021; 356: 1-9.  Back to cited text no. 72
Gedik S, Erdemli ME, Gul M, Yigitcan B, Bag HG, Aksungur Z, et al. Hepatoprotective effects of crocin on biochemical and histopathological alterations following acrylamide-induced liver injury in Wistar rats. Biomed Pharmacother 2017; 95: 764-770.  Back to cited text no. 73
Uçkun M. Assessing the toxic effects of bisphenol A in consumed crayfish Astacus leptodactylus using multi biochemical markers. Environ Sci Pollut Res Int 2021. Doi: 10.1007/s11356-021-17701-1.  Back to cited text no. 74
Hassani FV, Mehri S, Abnous K, Birner-Gruenberger R, Hosseinzadeh H. Protective effect of crocin on BPA-induced liver toxicity in rats through inhibition of oxidative stress and downregulation of MAPK and MAPKAP signaling pathway and miRNA-122 expression. Food Chem Toxicol 2017; 107: 395-405.  Back to cited text no. 75
Luo L, Fang K, Dan X, Gu M. Crocin ameliorates hepatic steatosis through activation of AMPK signaling in db/db mice. Lipids Health Dis 2019; 18(1): 1-9.  Back to cited text no. 76
Peek V, Neumann E, Inoue T, Koenig S, Pflieger FJ, Gerstberger R, et al. Age-dependent changes of adipokine and cytokine secretion from rat adipose tissue by endogenous and exogenous toll-like receptor agonists. Front Immunol 2020; 11: 1-17.  Back to cited text no. 77
Pan MX, Zheng CY, Deng YJ, Tang KR, Nie H, Xie JQ, et al. Hepatic protective effects of Shenling Baizhu powder, a herbal compound, against inflammatory damage via TLR4/NLRP3 signalling pathway in rats with nonalcoholic fatty liver disease. J Integr Med 2021; 19(5): 428-438.  Back to cited text no. 78
Habib SA, Suddek GM, Rahim MA, Abdelrahman RS. The protective effect of protocatechuic acid on hepatotoxicity induced by cisplatin in mice. Life Sci 2021; 277: 1-11.  Back to cited text no. 79
Khedr L, Rahmo RM, Farag DB, Schaalan MF, Hekmat M. Crocin attenuates cisplatin-induced hepatotoxicity via TLR4/NF-κBp50 signaling and BAMBI modulation of TGF-β activity: Involvement of miRNA-9 and miRNA-29. Food Chem Toxicol 2020; 140: 111307.  Back to cited text no. 80
Brusilovskaya K, Königshofer P, Lampach D, Szodl A, Supper P, Bauer D, et al. Soluble guanylyl cyclase stimulation and phosphodiesterase-5 inhibition improve portal hypertension and reduce liver fibrosis in bile duct-ligated rats. United European Gastroenterol J 2020; 8(10): 1174-1185.  Back to cited text no. 81
Lee JH, Lee S, Park HJ, Kim YA, Lee SK. Human liver stem cell transplantation alleviates liver fibrosis in a rat model of CCl4-induced liver fibrosis. Int J Stem Cells 2021; 14(4): 475-484.  Back to cited text no. 82
Chhimwal J, Sharma S, Kulurkar P, Patial V. Crocin attenuates CCl4-induced liver fibrosis via PPAR-γ mediated modulation of inflammation and fibrogenesis in rats. Hum Exp Toxicol 2020; 39(12): 1639-1649.  Back to cited text no. 83
Li Y, Zhang D, Li L, Han Y, Dong X, Yang L, et al. Ginsenoside Rg1 ameliorates aging-induced liver fibrosis by inhibiting the NOX4/NLRP3 inflammasome in SAMP8 mice. Mol Med Rep 2021; 24(50): 1-14.  Back to cited text no. 84
Liu X, Zhao Y, Zhu H, Wu M, Zheng Y, Yang M, et al. Taxifolin retards D-galactose-induced aging process through inhibiting Nrf2-mediated oxidative stress and regulating gut microbiota in mice. Food Funct 2021; 12(23): 12142-12158.  Back to cited text no. 85
Omidkhoda SF, Mehri S, Heidari S, Hosseinzadeh H. Protective effects of crocin against hepatic damages in D-galactose aging model in rats. Iran J Pharm Res 2020; 19(3): 440-450.  Back to cited text no. 86
Boopathy GT, Hong W. Role of hippo pathway-YAP/TAZ signaling in angiogenesis. Front Cell Dev Biol 2019; 7(49): 1-12.  Back to cited text no. 87
Piersma B, Bank RA, Boersema M. Signaling in fibrosis: TGF-β, WNT, and YAP/TAZ converge. Front Med 2015; 2: 1-14.  Back to cited text no. 88
Jin H, Lian N, Zhang F, Bian M, Chen X, Zhang C, et al. Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine. Eur J Pharm Sci 2017; 96: 323-333.  Back to cited text no. 89
Mohseni R, Karimi J, Tavilani H, Khodadadi I, Hashemnia M. Carvacrol ameliorates the progression of liver fibrosis through targeting of Hippo and TGF-β signaling pathways in carbon tetrachloride [CCl4]-induced liver fibrosis in rats. Immunopharmacol Immunotoxicol 2019; 41(1): 163-171.  Back to cited text no. 90
El-Gendy Z, Ramadan A, El-Batran S, Ahmed R, El-Marasy S, Abd El-Rahman S, et al. Carvacrol hinders the progression of hepatic fibrosis via targeting autotaxin and thioredoxin in thioacetamide-induced liver fibrosis in rat. Hum Exp Toxicol 2021; 40(12): 2188-2201.  Back to cited text no. 91
Pehrsson M, Mortensen JH, Manon-Jensen T, Bay-Jensen AC, Karsdal MA, Davies MJ. Enzymatic cross-linking of collagens in organ fibrosis-Resolution and assessment. Expert Rev Mol Diagn 2021; 21(100): 1049-1064.  Back to cited text no. 92
Mohseni R, Karimi J, Tavilani H, Khodadadi I, Hashemnia M. Carvacrol downregulates lysyl oxidase expression and ameliorates oxidative stress in the liver of rats with carbon tetrachloride-induced liver fibrosis. Indian J Clin Biochem 2020; 35(4): 458-464.  Back to cited text no. 93
Cai S, Wu L, Yuan S, Liu G, Wang Y, Fang L, et al. Carvacrol alleviates liver fibrosis by inhibiting TRPM7 and modulating the MAPK signaling pathway. Eur J Pharmacol 2021; 898: 1-10.  Back to cited text no. 94
Asaad GF, Hassan A, Mostafa RE. Anti-oxidant impact of Lisinopril and Enalapril against acute kidney injury induced by doxorubicin in male Wistar rats: Involvement of kidney injury molecule-1. Heliyon 2021; 7(1): e05985.  Back to cited text no. 95
Mohebbati R, Paseban M, Soukhtanloo M, Jalili-Nik M, Shafei MN, Yazdi AJ, et al. Effects of standardized Zataria multiflora extract and its major ingredient, Carvacrol, on Adriamycin-induced hepatotoxicity in rat. Biomed J 2018; 41(60): 340-347.  Back to cited text no. 96
Mortazavi A, Kargar HMP, Beheshti F, Anaeigoudari A, Vaezi G, Hosseini M. The effects of carvacrol on oxidative stress, inflammation, and liver function indicators in a systemic inflammation model induced by lipopolysaccharide in rats. Int J Vitam Nutr Res 2021. Doi: 10.1024/0300-9831/a000711.  Back to cited text no. 97
Mohebbati R, Paseban M, Beheshti F, Soukhtanloo M, Shafei MN, Rakhshandeh H, et al. The preventive effects of standardized extract of Zataria multiflora and carvacrol on acetaminophen-induced hepatotoxicity in rat:-Zataria multiflora and carvacrol and hepatotoxicity. J Pharmacopuncture 2018; 21(4): 249-257.  Back to cited text no. 98
Khan I, Bhardwaj M, Shukla S, Min SH, Choi DK, Bajpai VK, et al. Carvacrol inhibits cytochrome P450 and protects against binge alcohol-induced liver toxicity. Food Chem Toxicol 2019; 131: 110582.  Back to cited text no. 99
Kandemir FM, Caglayan C, Darendelioğlu E, Küçükler S, İzol E, Kandemir Ö. Modulatory effects of carvacrol against cadmium-induced hepatotoxicity and nephrotoxicity by molecular targeting regulation. Life Sci 2021; 277: 1-10.  Back to cited text no. 100
Zhao W, Chen L, Zhou H, Deng C, Han Q, Chen Y, et al. Protective effect of carvacrol on liver injury in type 2 diabetic db/db mice. Mol Med Rep 2021; 24(5): 1-11.  Back to cited text no. 101
Ozen BD, Uyanoglu M. Effect of carvacrol on IL-6/STAT3 pathway after partial hepatectomy in rat liver. Bratisl Lek Listy 2018; 119(9): 593-601.  Back to cited text no. 102
Wu R, Li J, Tu G, Su Y, Zhang X, Luo Z, et al. Comprehensive molecular and cellular characterization of acute kidney injury progression to renal fibrosis. Front Immunol 2021; 12: 1-8.  Back to cited text no. 103
Hammad FT, Lubbad L. The effect of thymoquinone on the renal functions following ischemia-reperfusion injury in the rat. Int J Physiol Pathophysiol Pharmacol 2016; 8(4): 152.  Back to cited text no. 104
Lawson J, Elliott J, Wheeler-Jones C, Syme H, Jepson R. Renal fibrosis in feline chronic kidney disease: Known mediators and mechanisms of injury. Vet J 2015; 203(1): 18-26.  Back to cited text no. 105
Bargi R, Asgharzadeh F, Beheshti F, Hosseini M, Farzadnia M, Khazaei M. Thymoquinone protects the rat kidneys against renal fibrosis. Res Pharm Sci 2017; 12(6): 479-487.  Back to cited text no. 106
Liu JX, Yang C, Liu ZJ, Su HY, Zhang WH, Pan Q, et al. Protection of procyanidin B2 on mitochondrial dynamics in sepsis associated acute kidney injury via promoting Nrf2 nuclear translocation. Aging 2020; 12(15): 15638-15655.  Back to cited text no. 107
Guo LP, Liu SX, Yang Q, Liu HY, Xu LL, Hao YH, et al. Effect of thymoquinone on acute kidney injury induced by sepsis in BALB/c mice. Biomed Res Int 2020; 2020: 1594726.  Back to cited text no. 108
Alkis H, Demir E, Taysi MR, Sagir S, Taysi S. Effects of Nigella sativa oil and thymoquinone on radiation-induced oxidative stress in kidney tissue of rats. Biomed Pharmacother 2021; 139: 1-5.  Back to cited text no. 109
Joo EY, Kim YJ, Go Y, Song JG. Relationship between perioperative thyroid function and acute kidney injury after thyroidectomy. Sci Rep 2018; 8(1): 1-7.  Back to cited text no. 110
Iglesias P, Bajo MA, Selgas R, Díez JJ. Thyroid dysfunction and kidney disease: An update. Rev Endocr Metab Disord 2017; 18(1): 131-144.  Back to cited text no. 111
Ayuob N, Balgoon MJ, El-Mansy AA, Mubarak WA, Firgany AEL. Thymoquinone upregulates catalase gene expression andpreserves the structure of the renal cortex of propylthiouracil-induced hypothyroid rats. Oxid Med Cell Longev 2020; 2020: 3295831.  Back to cited text no. 112
Mabrouk A. Thymoquinone attenuates lead-induced nephropathy in rats. J Biochem Mol Toxicol 2019; 33(1): e22238.  Back to cited text no. 113
Mostafa HES, El-Din EAA, El-Shafei DA, Abouhashem NS, Abouhashem AA. Protective roles of thymoquinone and vildagliptin in manganese-induced nephrotoxicity in adult albino rats. Environ Sci Pollut Res Int 2021; 28(24): 31174-31184.  Back to cited text no. 114
Al Fayi M, Otifi H, Alshyarba M, Dera AA, Rajagopalan P. Thymoquinone and curcumin combination protects cisplatin-induced kidney injury, nephrotoxicity by attenuating NFκB, KIM-1 and ameliorating Nrf2/HO-1 signalling. J Drug Target 2020; 28(9): 913-922.  Back to cited text no. 115
Hashem KS, Abdelazem AZ, Mohammed MA, Nagi AM, Aboulhoda BE, Mohammed ET, et al. Thymoquinone alleviates mitochondrial viability and apoptosis in diclofenac-induced acute kidney injury [AKI] via regulating Mfn2 and miR-34a mRNA expressions. Environ Sci Pollut Res Int 2021; 28(8): 10100-10113.  Back to cited text no. 116
Syed AA, Reza MI, Garg R, Goand UK, Gayen JR. Cissus quadrangularis extract attenuates diabetic nephropathy by altering SIRT1/DNMT1 axis. J Pharm Pharmacol 2021; 73(11): 1442-1450.  Back to cited text no. 117
Qiu Y, Jiang X, Liu D, Deng Z, Hu W, Li Z, et al. The hypoglycemic and renal protection properties of crocin via oxidative stress-regulated NF-κB signaling in db/db Mice. Front Pharmacol 2020; 11: 1-11.  Back to cited text no. 118
Hou Y, Lin S, Qiu J, Sun W, Dong M, Xiang Y, et al. NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy. Biochem Biophys Res Commun 2020; 521(3): 791-798.  Back to cited text no. 119
Zhang L, Jing M, Liu Q. Crocin alleviates the inflammation and oxidative stress responses associated with diabetic nephropathy in rats via NLRP3 inflammasomes. Life Sci 2021; 278: 1-9.  Back to cited text no. 120
Yaribeygi H, Mohammadi MT, Rezaee R, Sahebkar A. Crocin improves renal function by declining Nox-4, IL-18, and p53 expression levels in an experimental model of diabetic nephropathy. J Cell Biochem 2018; 119(7): 6080-6093.  Back to cited text no. 121
Keelo RMAH, Elbe H, Bicer Y, Yigitturk G, Koca O, Karayakali M, et al. Treatment with crocin suppresses diabetic nephropathy progression via modulating TGF-β1 and oxidative stress in an experimental model of pinealectomized diabetic rats. Chem Biol Interact 2022; 351: 109733.  Back to cited text no. 122
Jalili C, Ghanbari A, Roshankhah S, Salahshoor MR. Toxic effects of methotrexate on rat kidney recovered by crocin as a consequence of antioxidant activity and lipid peroxidation prevention. Iran Biomed J  Back to cited text no. 123
2020; 24(1): 39-46.  Back to cited text no. 124
Kumral A, Giriş M, Soluk-Tekkeşin M, Olgac V, Doğru-Abbasoğlu S, Türkoğlu Ü, et al. Beneficial effects of carnosine and carnosine plus vitamin E treatments on doxorubicin-induced oxidative stress and cardiac, hepatic, and renal toxicity in rats. Hum Exp Toxicol 2016; 35(6): 635-643.  Back to cited text no. 125
Hussain MA, Abogresha NM, AbdelKader G, Hassan R, Abdelaziz EZ, Greish SM. Antioxidant and anti-inflammatory effects of crocin ameliorate doxorubicin-induced nephrotoxicity in rats. Oxid Med Cell Longev 2021; 2021: 8841726.  Back to cited text no. 126
Bruzzese L, Lumet G, Vairo D, Guiol C, Guieu R, Faure A. Hypoxic preconditioning in renal ischaemia-reperfusion injury: A review in pre-clinical models. Clin Sci 2021; 135(23): 2607-2618.  Back to cited text no. 127
Yarijani ZM, Pourmotabbed A, Pourmotabbed T, Najafi H. Crocin has anti-inflammatory and protective effects in ischemia-reperfusion induced renal injuries. Iran J Basic Med Sci 2017; 20(7): 753-759.  Back to cited text no. 128
Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin reverses unilateral renal ischemia reperfusion injury-induced augmentation of oxidative stress and toll like receptor-4 activity. Environ Toxicol Pharmacol 2018; 59: 182-189.  Back to cited text no. 129
Rastogi A, Tiwari MK, Ghangrekar MM. A review on environmental occurrence, toxicity and microbial degradation of Non-Steroidal Anti-Inflammatory Drugs [NSAIDs]. J Environ Manage 2021; 300: 1-20.  Back to cited text no. 130
Irizarry E, Restivo A, Salama M, Davitt M, Feliciano C, Cortijo-Brown A, et al. A randomized controlled trial of ibuprofen versus ketorolac versus diclofenac for acute, non-radicular low back pain. Acad Emerg Med 2021; 28(11): 1228-1235.  Back to cited text no. 131
Jeon N, Park H, Segal R, Brumback B, Winterstein AG. Non-steroidal anti-inflammatory drug-associated acute kidney injury: Does short-term NSAID use pose a risk in hospitalized patients? Eur J Clin Pharmacol 2021; 77(9): 1409-1417.  Back to cited text no. 132
Nouri A, Izak-Shirian F, Fanaei V, Dastan M, Abolfathi M, Moradi A, et al. Carvacrol exerts nephroprotective effect in rat model of diclofenac-induced renal injury through regulation of oxidative stress and suppression of inflammatory response. Heliyon 2021; 7(11): e08358.  Back to cited text no. 133
Sadeghi H, Kazemi S, Doustimotlagh AH. Nephroprotective effects of Zataria multiflora Boiss. hydroalcoholic extract, carvacrol, and thymol on kidney toxicity induced by cisplatin in rats. Evid  Back to cited text no. 134
Based Complement Alternat Med 2021; 2021: 8847212.  Back to cited text no. 135
Gunes S, Ayhanci A, Sahinturk V, Altay DU, Uyar R. Carvacrol attenuates cyclophosphamide-induced oxidative stress in rat kidney. Can J Physiol Pharmacol 2017; 95(7): 844-849.  Back to cited text no. 136
Ozturk H, Cetinkaya A, Duzcu SE, Tekce BK, Ozturk H. Carvacrol attenuates histopathogic and functional impairments induced by bilateral renal ischemia/reperfusion in rats. Biomed Pharmacother 2018; 98: 656-661.  Back to cited text no. 137
Samarghandian S, Farkhondeh T, Samini F, Borji A. Protective effects of carvacrol against oxidative stress induced by chronic stress in rat’s brain, liver, and kidney. Biochem Res Int 2016; 2016: 2645237.  Back to cited text no. 138


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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