Table 2.
Molecular mechanisms of the pharmacological activity of ferulic acid.
| Author/year | Animals or cells | Models | Dose/concentration of FA/MFA/SF | Course of treatment | Molecular mechanism | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Protective effect on drug-induced liver injury | |||||||||||
| Yuan et al. (2016) | 6-8 week old BALB/c mice weighting 18- 22 g | acetaminophen-induced | 10, 30, or 100 mg/kg | every 8 h one time for three times within 24 h prior to APAP exposure | inhibited the expression of cytochrome P450 2E1 (CYP2E1), enhanced the activities of superoxide dismutase (SOD) and catalase (CAT) as well as the contents of glutathione (GSH);suppressed Toll-like receptor (TLR) 4 expression and dampened p38 mitogen-activated (MAPK) and nuclear factor kappa (NF-κB) activation | ||||||
| hepatotoxicity | |||||||||||
| Wu et al. (2022) | C57BL/6J mice (22-24 g, male and female) | acetaminophen-induced acute liver injury | 25, 50, 100 mg/kg | once per 12 hr for three times | associated with anti-oxidant and anti-apoptosis, regulate AMPK signal pathway and autophagy | ||||||
| Roghani et al. (2020) | Male Swiss albino mice (22–25 g) | Methotrexate-Induced Hepatotoxicity | 50, 100 mg/kg | once every day for one week | reduce the levels of nitric oxide (NO), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α increased (TNF-α) and increase glutathione (GSH), catalase (CAT), total antioxidant capacity (TAC), superoxide dismutase (SOD), and glutathione peroxidase (GPx) content | ||||||
| Mahmoud et al. (2020) | Twenty-four male Wistar rats (150–160 g) aged 7-8 weeks | a single dose of MTX at day 16 | 25 and 50 mg/kg | 15 days | activating Nrf2/HO-1 signaling and PPARγ, and attenuating oxidative stress, inflammation, and cell death | ||||||
| Yi, 2015 (in Chinese) | Male SD rats weighed 180∼220g | Liver injury model induced by antituberculous drugs in rats | 30, 60, 120g/kg | 8 weeks | inhibit NF-κB | ||||||
| Niu et al. (2016) | Specific pathogen free male ICR mice (18-22 g body weight) | Diosbulbin B (DB) induced acute liver injury | 20, 40, 80 mg/kg | once daily for 6 consecutive days | inhibiting intrahepatic inflammation and liver apoptosis | ||||||
| Liu Wei, 2006 (in Chinese) | male Kunming mice, weight 18-22 g | Liver injury model of mice induced by tripterygium wilfordii glycosides | 150 mg/kg | 9 days | decrease ALT and AST activity | ||||||
| Protective effect on experimental liver injury | |||||||||||
| Cheng et al. (2018) | Sprague Dawley (SD) rats (8-10 weeks) weighing 250-300 g | Carbon tetrachloride-induced acute liver injury | 25, 50 or 100 mg/kg body weight | a week | modulate the NOX4/p22phox/ROS-JNK/p38 MAPK signaling pathway | ||||||
| Kim et al. (2011) | Male ICR mice weighing 25-30g | CCl4-induced liver injury | 20, 40, and 80 mg/kg | 1 h before and 2h after CCl4 injection | down-regulated the expressions of COX-2, TNF-α, TLR4, TLR2 and TLR9, and inhibited JNK, ERK and P38 signaling pathways | ||||||
| Zhou Qin, 2020 (in Chinese) | Male Balb/C mice weighing 18-22g | Concanavalin A-induced immune liver injury model in mice | 10, 30, 100 mg/kg | once per 8 hr for three times | inhibit the activation of CD4+T lymphocytes and the release of cytokines, reduce inflammation and apoptosis of liver tissue | ||||||
| Zhong and Zhengling, 2018 (in Chinese) | BALB/C mice, male, (20 ± 2) g | D-galactosamine/lipopolysaccharide induced acute liver injury in mice | 30、15、7.5 mg/kg | 21 days | antioxidation | ||||||
| Li Chen (2017) | adult male C57BL/6 mice, weighing 20±2 g | alcohol-induced liver oxidative injury | 5, 10, 20 mg/kg | 4 weeks | inhibited the expression of inflammatory factors tumour necrosis factor (TNF)- α, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1β and IL-6; attenuated both mRNA and protein expression of NOX4, p22phox, CYP2E1, Bax/Bcl-2; inhibited the activation of caspase 3 and 9 and downregulated the levels of p-JNK, p-p38 MAPK and p-ERK in liver. | ||||||
| Cao et al. (2021a) | C57BL/6 mice (18–22 g); | cecal ligation and perforation (CLP)-induced murine ALI and lipopolysaccharide (LPS)-induced cellular ALI models | 6 or 12 mg/kg; | 5 days; | through the GSK-3β/NF-κB/CREB pathway | ||||||
| RAW264.7 cells | 25, 50, 100 μM | 24 h | |||||||||
| Xie et al., 2004 (in Chinese) | Male ICR mice, 16-18g | Inflammatory liver injury induced by lipopolysaccharide (LPS) combined with Bacillus Calmette-Guerin (BCG) | 100 mg/kgw | 10 days | inhibit the expression of adhesion molecules (ICAM-1 and e-selectin) in inflammatory tissues | ||||||
| Protective effect on liver injury induced by physical and chemical factors | |||||||||||
| Srinivasan et al. (2006) | primary culture of isolated rat hepatocytes | γ-irradiated and FA pretreated hepatocytes | 1,5,10 ug/ml | 30 min | decrease the levels of TBARS and DNA damage; increased antioxidant enzymes, GSH, Vitamins A, E and C, uric acid and ceruloplasmin levels | ||||||
| Panneerselvam et al. (2013) | Male Wistar rats (130-140 g) | Fluoride-Induced Oxidative | 20 mg/kg | 12 weeks | reduced the degree of histological abberations and rescued lipid peroxidation | ||||||
| Hepatotoxicity | |||||||||||
| Sanjeev et al. (2019) | male Wistar rats, weighing approximately180–190 g | cadmium-induced liver and renal oxidative damage | 50 mg/kg body weight | 15 and 30 days | decrease liver oxidative stress markers (MDA, LOOH, NO, TOS, PCC, OSI); inhibit inflammatory cells infiltration;reduce inflammation markers (TNF-α, COX-2, HSP-70);regulate antioxidant defense System (TTH, TSH, GSH, SOD, CAT, GPx) | ||||||
| Wang Z et al. (2021) | Six-week-old male Wistar rats | aflatoxin B1-induced liver injury | 120 mg/kg | 30 days | Inhibiting cytochrome P450 enzyme, activating Nrf2/GST pathway and regulating mitochondrial pathway | ||||||
| Inhibition of liver fibrosis | |||||||||||
| Xu et al. (2015) | HSC-T6 cells | Hepatic stellate cells (HSCs) | 3–30 uM | 0-72h | Blocking transforming growth factor-b by a neutralizing antibody caused a marked reduction in both ERK1/2 and Smad signaling | ||||||
| Wang Z et al., 2021 (in Chinese) | Male SD rats (6 weeks, 180-220 g) | Carbon tetrachloride (CCl4) -induced liver fibrosis model | 15, 30mg/kg | 6 weeks | inhibited mitogen-activated protein kinase (MAPK) signaling pathway and NF-κB/IκBα pathway | ||||||
| Wu et al. (2021) | C57BL/6J mice (22–24 g, male and female, SPF grade); RAW 264.7 cells and LX-2 cells, Mouse primary hepatocytes (MPHs) | carbon tetrachloride (CCl4)-induced chronic inflammation and liver fibrosis | FA (25, 50 and 100 mg/kg); FA or MF (both 50, 100, and 200 μM), FA or MF (both 12.5, 25 and 50 μM) | 4 weeks; | through PTP1B-AMPK signaling pathways | ||||||
| 24 h | |||||||||||
| Li Chen, 2017 (in Chinese) | Male SD rats, body weight 180-220 g | Carbon tetrachloride (CCl4) -induced liver fibrosis rat model | 20、10、5 mg/kg | 2 w | improve the oxidative stress injury of liver and reduce the accumulation of extracellular matrix | ||||||
| Guo Ling, 2019 (in Chinese) | Rat hepatocytes BRL | Transforming growth factor-β (TGF-β) -induced hepatocyte injury | 100, 200, 400 μmol | 12 h | inhibit the expression of Smad3 induced by TGF-β1, promote the expression of MMP-2 and MMP-9, and reduce the apoptosis of hepatocytes | ||||||
| Mu et al. (2018) | Human hepatic stellate cell line (HSC) LX-2;Male Wistar rats (180±20g) | CCl4-induced rat liver fibrosis | 30 µM | 8 weeks | inhibit the TGF-β1/Smad pathway in vitro and in vivo | ||||||
| 10 mg/kg | |||||||||||
| Cheng et al. (2019b) | Male Sprague-Dawley (SD) rats (180 ± 20 g); Human hepatic stellate cells (LX-2) | CCl4 induced liver fibrosis | MFA (20 and 5 mg/kg); 5, 10, 20 μM | 5 weeks; | inhibiting the TGF-β1/Smad and NOX4/ROS signalling pathways | ||||||
| 48 h | |||||||||||
| Xiong Meili, 2016 (in Chinese) | Human hepatic stellate cell line HSC-LX-2 | Transforming growth factor (TGF) -β1 stimulates human hepatic stellate cell (HSCS) -LX-2 | 1.25、2.5、5 mg/L | 72h | decreased the expression of α -SMA and PC I, and inhibited the synthesis of HSC-LX-2 extracellular matrix and phenotype transformation of HSC-LX-2 | ||||||
| Zhao H et al. (2020) | Male Wistar rats (200-230 g) | Bile Duct-Ligated Cirrhotic Rats | FA (4.8, 10.8 mg/kg) | 28 days | inhibition of the TGF-β pathway and activation of the Nrf2 pathway | ||||||
| Juan Yang, 2014 (in Chinese) | Wistar rats, 180-200 g | Experimental hepatic fibrosis model induced by bile duct ligation in rats | 50 mg/kg | 1 week | decrease the expression of α-SMA in liver | ||||||
| Liu et al. (2015) | Male Wistar rats with approximate body weight of 180–200 g | Bile duct ligation method was used to induce cirrhosis | 50 mg/kg/day | 1 week | inhibits hepatic RhoA/Rho-kinase signaling and activates the NO/PKG pathway | ||||||
| Wei et al. (2014) | Male Wistar rats (180–200 g; n=73) | bile duct ligation (BDL) model of portal hypertension | 50 mg/kg/day | 1 week | inhibits the activation of the RhoA/Rho-kinase signaling pathway | ||||||
| Hussein et al. (2020) | male albino Wistar rats weighing from 180 to 220 g | thioacetamide-induced fibrosis | 20 mg/kg | 6 weeks | inhibit TGF-β1/Smad3 signaling and differentially regulate the hepatic expression level of miR-21, miR-30 and miR-200 | ||||||
| Inhibiting liver steatosis and reducing lipid toxicity | |||||||||||
| Xu et al. (2021) | AML-12, a nontransformed mouse hepatocyte cell line | AML-12 mouse hepatocytes were exposed to palmitate to mimic lipotoxicity | 25, 50, and 100 μM | 2h | regulate the SIRT1/autophagy pathway | ||||||
| Cheng et al. (2018) | Human hepatocyte L-02 cells (human normal liver cells; no | ethanol-induced hepatic steatosis | 12.5, 25, 50, 100, 200, 400 μM | 24 h | activate AMPK-ACC/MAPK-FoxO1 pathway and up-regulating the expression levels of SIRT1, PPAR-α, and CPT-1α | ||||||
| GDC079); Sprague-Dawley (SD) rats weighing 180–220 g | 5, 10, 20mg/(kg day) | 16 weeks | |||||||||
| Wang X et al. (2021) | C57BL/6 mice (male, 4-week-old); HepG2 cells | oleic acid (OA)-treated HepG2 cells and C57BL/6 mice fed a high fat diet (HFD) | FA (20 mg/kg bw⋅day); FA (25 and 50 μg/mL) | 17 weeks; 24 h | suppress of ERK1/2, JNK1/2/3, and HGMB1 expression | ||||||
| Improving insulin resistance in the liver and anti-liver cancer | |||||||||||
| Cheng et al. (2019b) | Male Sprague-Dawley (SD) rats (180–220 g); Human hepatocyte L-02 cells | Ethanol-Induced Hepatic Insulin | MFA (5, 10, 20 mg/kg/day); MFA (20 mg/kg/day) | 4 weeks; | activated the hepatic phosphatidylinositol 3-kinase (PI3K)/AKT pathway | ||||||
| Resistance | 24h | ||||||||||
| Zhang et al. (2022) | Four-week-old male C57BL/6J mice | alcohol-induced hepatic insulin resistance | 5, 10, 20 mg/kg | 2 weeks | attenuate the inhibition of miR-378b on IR/p110α and activate the insulin signaling | ||||||
| Ezhuthupurakkal et al. (2018) | Huh-7 and HepG2 cells; | hepatocellular cancer | 0.05, 0.1, 1, 5, 10 and 20 μg/ml; | 24 h | promote intracellular ROS generation, induce DNA damage, promote cell apoptosis | ||||||
| Wistar rats of 4-5 weeks old and weighing 80-120 g | 5mg/kg/b.wt | 4 weeks | |||||||||
| Das et al. (2019) | The HepG2, A549, CT26 and WI-38 cells | lung (A549) and liver (HepG2) carcinoma cells by treatment with ferulic acid (FA) prior to irradiation | 10-400 mM | 6 h, 72 h | collapse redox homeostasis and regulate Akt/p38 MAPK signaling pathway | ||||||
| Other mechanisms | |||||||||||
| Kim and Lee (2012) | Male ICR mice (24–26 g) | ischemia/reperfusion-induced hepatocyte apoptosis | 50, 100, 200mg/kg | 30 min | inhibit JNK activation and apoptosis | ||||||
| RUKKUMANI et al. (2012) | Male Wistar albino rats strain of body weight ranging 140-160g | alcohol and PUFA induced toxicity | 20 mg/kg body weight | 45 days | decreased the levels of collagen, tissue inhibitors of metalloproteinases (TIMPs) and promote the expression of matrix metalloproteinases (MMPs). | ||||||
| WANG et al. (2014) | ICR male mice (18–22 g) | diosbulbin B-induced | 8 mg/kg | 12 d | increase the enzymatic activities of CuZn-SOD and CAT | ||||||