Antioxidant and anti-inflammatory agents in chronic liver diseases: Molecular mechanisms and therapy

Table 1 Antioxidant and anti-inflammatory agents for the treatment of hepatocellular carcinoma

Molecules	Model	Function	Ref.
β-sitosterol	HepG2 cells; Rat HCC	Treatment of β-sitosterol niosomes displays direct cytotoxicity to HepG2 cells in vitro and anti-HCC ability in rats	[182]
Curcumin	HepG2 and SK-Hep-1 cells. A nude mouse xenograft model bearing HepG2 cells	It can inhibit cell proliferation and increase cell apoptosis and cell cycle arrest at the G0/G1 phase of cancer cells by downregulating the expression of BCLAF1 and inhibiting the activation of the PI3K/AKT/GSK-3β pathway	[183]
Empagliflozin	DENA-induced HCC in mice	It shows a synergistic effect on the control of angiogenesis, invasion, and metastasis of tumor cells in mice with DENA-induced HCC by inhibiting the expression of MAPKs and reducing liver injury enzymes	[184]
Gastrodin	Subcutaneous H22 cells-induced tumor in mice	It can specifically increase the expression of NF-κB downstream genes such as Bcl-xL, Bcl-2, and IL-2 in CD4 but not CD8 T cells	[185]
Genistein	TAA-induced HCC in rats	It displays antioxidant and anti-HCC effects by suppressing the versican/PDGF bidirectional axis and protein expression of PKC and ERK-1	[186]
Lactoferrin	DEN-induced HCC in rats	It shows a chemopreventive effect against DEN-induced HCC in rats in a dose-dependent manner by suppressing the expression and activation of AKT	[187]
Selenium	TAA-induced HCC in rats	Selenium nanoparticles improve the tumor suppressive effect of sorafenib and overcome drug resistance in rat HCC by inducing apoptosis and targeting AKT/mTOR and NF-κB signaling pathways, as well as epigenetic regulation	[188]
Silymarin	DEN/AAF/CCl4 induced HCC in rats	It suppresses cancer cell growth in rats with DEN/AAF/CCl4-induced tumors by inhibiting the expression of Ki-67 and HGF/c-Met, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways	[189]
Taraxasterol	HepG2 and Huh7H22 bearing mice	It can suppress tumor cell growth by suppressing Ki67 expression and inducing cell apoptosis via suppressing IL-6/STAT3 signaling pathway, as well as promoting T cell infiltration in tumor tissue	[190]
Telmisartan	NDEA-induced HCC in mice	It exerts an anti-HCC effect and increases tumor cell sensitivity to sorafenib treatment by suppressing phosphorylation-induced activation of TAK1 and the ERK1/2 and NF-кB signaling pathways	[191]
Delta-tocotrienol	HCC cell lines SK Hep-1 and Huh7	It promotes the anti-HCC cell activity of IFN-α by increasing ROS and increasing cell apoptosis together with an increased Bax/Bcl-xL ratio. In addition, it can activate Notch1 signaling pathway	[192]

AKT: Protein kinase B; Bax: Bcl-2-like protein 4; Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma extra-large; BCLAF1: BCL-2-associated transcription factor 1; CD4: Cluster of differentiation 4; c-Met: Tyrosine-protein kinase Met; ERK-1/2: Extracellular signal-regulated kinases 1/2; GSK-3β: Glycogen synthase kinase-3β; HCC: Hepatocellular carcinoma; HGF: Hepatocyte growth factor; IL-2: Interleukin 2; Ki-67: Marker of proliferation Ki-67; MAPK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor κB; PI3K: Phosphatidylinositol-3-kinase; PDGF: Platelet-derived growth factor; SIRT1: Sirtuin 1; SREBP-1c: Sterol regulatory element binding protein 1c; STAT3: Signal transducer and activator of transcription 3; DENA Diethylnitrosamine; TAA: Thioacetamide; ROS: Reactive oxygen species; NDEA: N-Nitrosodiethylamine; AAF: 2-acetylaminofluorene; CCl₄: Carbon tetrachloride.

Table 2 Clinical trials for evaluating the efficacy of compounds in liver disease

Treatment	Trial number	Phase	Aims or results
Curcumin	NCT02908152	2-3	To investigate the effects of curcumin supplements on metabolic factors and hepatic fibrosis in NAFLD patients with T2DM
	NCT04109742	2	To test the effect of curcumin in pediatric patients with NAFLD
Empagliflozin	NCT03867487	2	To evaluate the preliminary feasibility, initial efficacy, and safety of empagliflozin as a SGLT2 inhibitor for treating NAFLD in adolescents with obesity
	NCT04642261	4	To test the effects of empagliflozin on reducing hepatic fat content as measured by MRI-PDFF in NAFLD patients without DM
Gastrodin	NCT04035824	4	To treat hypertension together with Uncaria
Genistein	IRCT201312132480N5	3	Oral supplementation of genistein (250 mg) for 8 wk can decrease insulin resistance, oxidative stress, and inflammation and improve lipid metabolism in patients with NAFLD
Lactoferrin	NCT04335058	None	To test the effect of lactoferrin with iron versus iron alone in the treatment of anemia in CLD
Selenium	NCT00271245	None	To test the effect of selenium in patients with cirrhosis
	NCT01650181	4	To test the impacts using siliphos-selenium-methionine-alpha lipoic acid plus metformin versus metformin in patients with fatty liver and NASH
Silymarin	NCT00389376	1	An increase in silymarin is observed in NAFLD patients, compared to that in patients with HCV
	NCT00680407	2	The effect of silymarin on NASH patients remains inconclusive due to the lack of a substantial number of patients
Telmisartan	NCT02213224	4	To evaluate the therapeutic effects of telmisartan and perindopril for NAFLD patients with hypertension

T2DM: Type 2 diabetes mellitus; NAFLD: Non-alcoholic fatty liver disease; SGLT2: Sodium-glucose cotransporter-2; MRI-PDFF: Magnetic resonance imaging-derived proton density fat fraction; CLD: Chronic liver disease; NASH: Non-alcoholic steatohepatitis; HCV: Hepatitis C virus.