Therapeutic interventions of acute and chronic liver disorders: A comprehensive review

Table 1 Summarized the common pathological mechanisms of acute and chronic liver diseases

Disease	Mechanism	Model	Findings	Ref.
ALF	N-acetyl-p-APAP	Mice model	The hazardous metabolite N-acetyl-p-benzoquinone depleted GSH and caused mitochondrial oxidative stress and necrosis	[6]
	Innate immunity, apoptosis, and cytokine release	Bio-samples from roughly 2000 patients with ALF	Generated pro-inflammatory mediators and oxidative stress, vasodilatation of the peripheral microcirculatory, hypoxia, lactic acidosis, and hypotension	[8]
	MiR-122 and miR-192	APAP in mice	Increased miR-122 and miR-192 levels after acute hepatic poisoning with acetaminophen in mice before transaminases	[82]
	MiRNAs	ALF in mice	Up-regulated miR-155, miR-146a, miR-125a, miR-15b, and miR-16	[83]
			Down-regulated miR-1187
Acute liver injury	MiRNAs	Acetaminophen or carbon tetrachloride in male rats	Down-regulated miR-29c_AS, miR298, miR327, miR342, miR370, miR376c, miR494, and miR503	[66]
			Upregulated miR-153, miR-302b AS, miR-337, miR-363, miR-409-5p, and miR-542-3p
	MiR-122	I/R mouse model	Elevated miR-122 level	[67]
	MiR-192	APAP induced liver injury in mouse	Dose- and exposure-dependent elevation of miR-192 level	[79]
HBV	MiRNAs	Pooled sera obtained from HBV patients	Up-regulated miR-122 level. miR-122 could inhibit HBV replication in Huh7 and HepG2 cells	[84]
	MiR-155	Human hepatoma cells	MiR-155 enhances innate antiviral immunity by promoting JAK/STAT signaling pathway by targeting SOCS1	[86]
HCV	MiR-122	Human hepatoma Huh-7.5 cells	MiR-122 is the predominant miRNA in the liver tissue. 2’-O-methyl antisense oligonucleotide depletion of miR-122 also inhibits HCV genotype 2a replication and infectious virus production	[89]
	MiRNAs	Human hepatoma cells	MiR-24, miR-149, miR-638, and miR-1181 were identified to be involved in HCV entry, replication, and propagation	[90]
Alcoholic steatohepatitis	MiRNAs	In vitro (RAW 264.7 macrophage) and in vivo (Kupffer cells of alcohol-fed mice)	Up-regulated miR-155 expression both in vitro and in vivo	[94]
			Increased TNF alpha production in response to miR-155 induction
			Increased expression of miR-155 and miR-132 in the total liver
	MiRNAs	Bile duct ligation rat model	Down-regulated miR-150 and miR-194 expression	[98]
	MiRNAs	Human stellate cell line	Up-regulated miR-199 and miR-200 led to higher expression of fibrosis-related genes in an HSC cell line	[97]
NAFLD and alcoholic liver disease	Autophagy	In-vivo	Activation of macroautophagy and CMA eliminated damaged mitochondria, lessens oxidative stress, and promotes regeneration	[136]
Liver cancer	Autophagy	Oncogene-driven cancer models	Protein kinase C promotes autophagy and oxidative phosphorylation
			ROS generation, which through Nrf2 drives HCC through cell-autonomous and non-autonomous mechanisms
Liver cirrhosis	Hepatocyte	In-vivo	Activation of hepatic stellate cells by damaged hepatocytes	[18]
	Hepatic stellate cell	In-vivo	The activated hepatic stellate cells produce endothelin-1, TGF-β, and cytoglobin that share in the process of fibrogenesis	[24]
	Sinusoidal endothelial cells SECs	Co-culture with freshly isolated SECs	Differentiated SECs prevent HSC activation and promote reversion of activated HSCs to quiescence through VEGF-stimulated NO production	[32]
	Kupffer cells	Mouse model	Enhanced death ligand expression	[35]
			Inhibition of hepatocyte apoptosis with a caspase inhibitor prevented Kupffer cell activation
			Hepatic stellate cell activation

ALF: Acute liver failure; APAP: Aminophenol; HBV: Hepatitis B virus; HCV: Hepatitis C virus; SECs: Sinusoidal endothelial cells; VEGF: Vascular endothelial growth factor; HSCs: Hepatic stellate cells; TGF-β: Tumor growth factor-beta; CMA: Chaperone-mediated autophagy; HCC: Hepatocellular carcinoma; Nrf2: Nuclear factor erythroid 2-related factor 2; NAFLD: Non-alcoholic fatty liver; TNF: Tumor necrosis factor; GSH: Glutathione; ROS: Reactive oxygen species; miRNA: MicroRNA.

Table 2 Therapeutic interventions implicated in acute and chronic liver disorders

Therapeutic intervention	Drugs	Main findings	Ref.
Antioxidants	Silymarin	Possesses free radical scavenging activity and inhibits lipid peroxidation thus improving chronic liver diseases	[149]
	Selenium	Decrease DNA damage, hepatocyte necrosis, oxidative stress biomarkers, and liver toxicity
	Vitamin E	Reduces inflammation and protects from hepatocellular damage	[155,157,160]
	N acetylcysteine	Increasing GSH peroxidase and decreasing oxidative stress in liver fibrosis
	MitoQ	Reduces lipid peroxidation and cultured hepatic stellate cell activation	[162]
Antifibrotic agents	Pirfenidone	Pirfenidone is effective at diminishing liver fibrosis as it suppresses TGF-β1 and NF-κB and decreases inflammatory cell infiltration and excess matrix deposition	[166-168]
	Statins, and anti- NADPH oxidases	PPAR-α modulators might decrease inflammation and fibrosis in cases of primary sclerosing cholangitis
Immunosuppressants	Corticosteroids, and azathioprine	The first line of treatment for autoimmune hepatitis	[169]
Anti-HSC therapy	Imatinib and sorafenib	Respectively act as PDGF and angiogenesis inhibitors thus they modulate fibrogenesis and fibrosis in autoimmune hepatitis	[173]
	Paclitaxel, ferulic acid and methyl ferulic acid	Can inhibit hepatic stellate cell activation through TGF-β/Smad pathway modulation	[175-177]
	Curcumin	Can interrupt the PDGF-β/ERK pathway and inhibit hepatic stellate cell angiogenesis through activation of PPAR-γ. Curcumin can also activate autophagy and thus inhibit the TGF-β/Smad pathway thus reducing epithelial-mesenchymal transition	[178-180]
Gene therapy	HGF	Decreases the expression of TGF-β1, suppresses hepatocyte apoptosis, and improves fibrosis	[181]
	Matrix metalloproteinase-1	Enhances the proliferation of hepatocytes and diminishes fibrosis	[183]
	siRNA	By silencing CTGF, TGF-β, NF-κB target gene A, galectin-3, and αvβ3 integrin, siRNA effectively stops fibrogenesis by preventing HSCs activation and/or promoting their apoptosis	[184]
Cell therapy	MSCs	Inhibit hepatocyte degeneration, promote liver regeneration, and suppress fibrosis through differentiation into hepatocytes and production of various growth factors	[187]
	BMSCs	Decrease serum markers of liver injury and mRNA expression of TNF-α, IFN-γ, and FasL, and increase IL-10 mRNA expression in acute liver failure	[189]
	Matrix metalloproteinase 2, tissue inhibitor of metalloproteinase 1, and growth arrest-specific 6	Promote hepatocytes regeneration, neovascularization, and extracellular matrix remodeling all contributing to liver regeneration	[191]
Gut liver axis	Baicalin	Modulates FXR and G-protein-coupled bile acid receptor TGR5 thus modulating the levels of TNF-α, NF-kβ, and TGF-β. It also inhibits inflammation, autophagy, and necrosis of parenchymal liver cells	[195-198]
	Probiotics	Modulate gut dysbiosis and bile acid dysregulation thus aiding in the treatment of NAFLD. Probiotics also modulate inflammation and fibrosis in NASH	[199-201]
Nanoparticle drug delivery	Gold	Enhances the antifibrotic activity of silymarin through increasing the expression of protective microRNAs and suppression of inflammatory mediators in the TGF-β1/smad pathway	[204]
	Phosphatidylserine-decorated nanoparticles	Enhances curcumin efficacy in fibrosis reduction	[205]
	Liposome nanoparticles	Can be specifically delivered to integrins of activated hepatic stellate cells, in addition to facilitating gene therapy using siRNAs and mRNAs to modulate gene expression of hepatocytes	[208]
Autophagy inhibition	Becn1 knockdown	Autophagy suppression and inhibition of T lymphocyte infiltration, HSCs proliferation, as well as production of TNF-α, IFN-γ, and TGF-β1	[209]
	Carvedilol	Increased p62 protein levels and inhibited autophagic flux by increasing lysosomal pH	[210]
	Doxazosin	Inhibited HSC proliferation and migration, blocked autophagic flux and induced HSCs apoptosis	[211]
	Resolvin D1	Modulated AKT/mTOR signaling pathway resulting in the inhibition of autophagy and suppression of hepatic stellate cell activation	[212,213]

GSH: Glutathione; PPAR-α: Peroxisome proliferator-activated receptor alpha; CTGF: Connective tissue growth factor; TGR5: G-protein-coupled bile acid receptor; MitoQ: Mitoquinone; HSCs: Hepatic stellate cells; TGF-β: Tumor growth factor-beta; NF-κB: Nuclear factor-kappaB; PDGF: Platelet-derived growth factor; HGF: Hepatocyte growth factor; ERK: Extracellular signal-regulated kinase; siRNA: Small interfering RNA; mTOR: Mechanistic target of rapamycin; TNF: Tumor necrosis factor; IFN: Interferon; NAFLD: Non-alcoholic fatty liver; NASH: Non-alcoholic steatohepatitis; FXR: Farnesoid X receptor; IL: Interleukin; MSC: Mesenchymal stem cell; BMSC: Bone marrow-derived mesenchymal stromal cell.