Role of Natural Phenolics in Hepatoprotection: A Mechanistic Review and Analysis of Regulatory Network of Associated Genes

Abstract

The liver is not only involved in metabolism and detoxification, but also participate in innate immune function and thus exposed to frequent target Thus, they are the frequent target of physical injury. Interestingly, liver has the unique ability to regenerate and completely recoup from most acute, non-iterative situation. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease, long term alcohol abuse and chronic use of medications can cause persistent injury in which regenerative capacity eventually becomes dysfunctional resulting in hepatic scaring and cirrhosis. Despite the recent therapeutic advances and significant development of modern medicine, hepatic diseases remain a health problem worldwide. Thus, the search for the new therapeutic agents to treat liver disease is still in demand. Many synthetic drugs have been demonstrated to be strong radical scavengers, but they are also carcinogenic and cause liver damage. Present day various hepatic problems are encountered with number of synthetic and plant based drugs. Nexavar (sorafenib) is a chemotherapeutic medication used to treat advanced renal cell carcinoma associated with several side effects. There are a few effective varieties of herbal preparation like Liv-52, silymarin and Stronger neomin phages (SNMC) against hepatic complications. Plants are the huge repository of bioactive secondary metabolites viz; phenol, flavonoid, alkaloid etc. In this review we will try to present exclusive study on phenolics with its mode of action mitigating liver associated complications. And also its future prospects as new drug lead.

Keywords: gene network; hepatoprotection; in silico analysis; liver disease; mechanism; natural product; phenolics.

Figure 1

Statistical representation of mortality (in percentage) from various diseases in human (Finkelstein et al., 2012).

Figure 2

Occurrence and prevalence of various liver diseases worldwide.

Figure 3

Structures of various groups of phenolic compounds (Hussain, ; Mandal et al., ; Xi et al., 2018).

Figure 4

Flowchart showing various descendants of the phenolic groups.

Figure 5

Structures of some bioactive phenolics acting as hepatoprotective compounds.

Figure 6

Structures of some bioactive phenolics acting as hepatoprotective compounds.

Figure 7

Metabolism of phenols in the living system. The metabolism of the dietary components rich in phenols is easily absorbed by various part of the animal body where the small intestine process and deviates the potent part to hepatic cells and remains are hydrolysed in colon and excreted via feces. Simultaneously, a part of it is methylated in kidney through liver and the last remains are excreted through urination. The red arrows mark is used to show the various route of metabolism of phenols.

Figure 8

Detailed Mechanism of generation of hepatotoxicity. When the elicitors like alcohol, CCl₄, enter the cell membrane they instigate various metabolic reactions activating the CYP systems viz; activating the endogenous glutathione enzyme, hydrogen peroxide. Formation of the reactive oxygen species are responsible for the lipid peroxidation reaction. A conjugation reaction takes place alongside this resulting in the deterioration in the ATP levels and elevation in the caspases levels. This clinical manifestation leads to the building up of hepatotoxicity and induces apoptosis. The nucleus also takes part in such build up by upregulating various transcription factors associated with inflammation. The adhesion molecules present in the cell membrane further create a hepatic fibrotic response by coupling with various reactive oxygen species. The activated Kupffer cells, on the other hand, further activate the prostaglandin by COX-2 and thus increases the cytokines level in the blood. These reactions are catalyzed by arachidonic acid. Such atrocities give rise to associated diseases with inflammation and further fibrogenesis. Hepatic necrosis is another condition imparted by the activated neutrophil which, though inactive during a normal state, increase in number when the cytokine level increases in the blood. The fatal condition, hepatic cirrhosis, is also encountered from hepatotoxicity, which is the additive effect of the prolonged inflammation and interaction with the ROS generation.

Figure 9

Alcohol mediated Hepatotoxicity. Hepatotoxicity caused by increased production of ROS; due to alcohol damages antioxidant defenses and mitochondrial function as well as structure. It leads to liver inflammation, fibrosis and steatosis. Cellular responses, which are sturdily involved in Kupffer cell may also activated due to action of ROS which contribute to an increase of inflammatory responses, resulting liver injury. Furthermore, activated Kupffer cells release ROS and cytokines that are crucial for HSC activation and inducing the pro-fibrogenic pathway.

Figure 10

Protective effect of phenols in various metabolic pathways in liver diseases. The upward arrow indicating upregulation and down arrow indicating downregulation of the enzymes.

Figure 11

Gene networking showing hepatotoxicity mediated gene expression and subsequent mode of action of various natural products. This network was generated by a software Cytoscape version 3.6.1.

Figure 12

Gene-modeling showing various hepatic diseases and associated genes with it. A tool named Circus on shiny Circos server generated this image. The blue band is showing various genes responsible for pathophysiological conditions, the green showing various hepatic complications and the red band shows the bioactive natural compounds possessive hepatoprotective activity. Various shades indicating the degree of relatedness between the various bands.