Abstract

Silymarin, from the fruit of Silybum marianum, is known for its hepatoprotective action. The aim of this study was to review the mechanisms of action of the silymarin phytocomplex to expand the possibilities for its application in human health. The search for published articles was carried out on the CAPES Journals Portal platform, which covers worldwide scientific databases. Publications from 2010 to 2022 were included. Of the 311 articles retrieved, 21 were included. The articles discuss the diversity of silymarin’s applications and the possibility of optimizing its bioavailability using drug delivery systems. Silymarin shows promise in numerous diseases, such as liver, kidney, cardiovascular, respiratory and others. Its antiviral action has been demonstrated in studies and silymarin has the potential to be used as a complementary therapy in the treatment of many diseases, with the expectation that, in the future, it will be used in therapeutic protocols for exclusive use.

Keywords

Silymarin, Flavonoids, Phytotherapeutic Drugs

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1. Introduction

The phytocomplex extracted from the fruit of Silybum marianum is known as silymarin, which is composed of flavonoids and their isomers, including silybin, silydianin and silicristin, and is recognized for its hepatoprotective action. Records of its medicinal use date back to the 4^th century BC, initially related to the administration of extracts from parts of the plant and giving rise to its common name: thistle milk [1] [2] .

Parts of the plant can be used to treat diseases related to the digestive system and liver and biliary disorders [3] . The hepatoprotection attributed to silymarin is due to the antioxidant action of silybin, which helps prevent damage to liver cells by toxins, alcohol and harmful substances [3] ; nephroprotective action by reducing insulin resistance and maintaining the glomerular filtration rate [4] ; anti-aging and anti-inflammatory effect on the skin [5] ; silymarin reduces serum cholesterol levels [6] ; it can also reduce the inflammatory process in the airways and contribute to asthma control [4] .

Silymarin has been shown to provide protection against hepatic necrosis caused by carbon tetrachloride, as well as against toxic liver damage caused by poisonous mushroom toxins [4] . However, its curative effect is generally weaker than its preventive effect. Furthermore, silymarin stimulates the functions of hepatocytes, including cell proliferation, protein synthesis, oxygen assimilation, energy formation, and repair of damaged cell membranes. This gives liver tissue greater resilience against degenerative and toxic actions [4] [6] [7] and has effect on cirrhosis and hepatocellular carcinoma [8] .

Silymarin has been found to have neuroprotective effects through modulation of several antioxidant mechanisms and kinases in cell signaling pathways [9] . It also inhibits the inflammatory response generated during neurodegeneration, has neurotropic effects, regulates neurotransmitters, and inhibits apoptosis. These properties, along with the compound’s low cost, availability, and safety profile, provide additional advantages for using silymarin as a potential drug with important clinical benefits. However, the challenge of low bioavailability must be addressed, and robust clinical trials are needed to validate the neuroprotective efficacy of this natural compound. Some authors [10] evaluated the co-administration of silymarin on the changes induced by aspartame in the behaviour and brain of mice, demonstrating a significant attenuation of the effects on the central nervous system. Other effects are protection against cardiotoxicity induced by creatine phosphate and oxidative stress in rats [11] ; antitumor and chemo preventive actions [2] .

In general, the dry extract is used orally in tablets and capsules, but the bioavailability could be improved with drug delivery systems [12] , especially considering its potential to combat other diseases. Thus, it is important to review the molecular mechanisms of silymarin action and interaction with the different types of receptors and cell signals.

The aim of this study was to review the mechanisms of action of the silymarin phytocomplex to expand the possibilities of application in human health.

2. Method

The guiding question for the systematic review was: Can the use of silymarin as an active ingredient, considering its mechanisms of action and the innovative technologies used for its delivery, be proposed as a potential method for mitigating or controlling systemic autoimmune responses or generalized inflammatory processes?

The search for relevant articles was conducted on the CAPES Periodicals Portal search engine, to cover the main health databases such as PubMed, LILACS, and Scielo. Some articles cited in those initially selected were later included to enrich the discussion. The search was carried out using the descriptors indexed in DeCS/MeSH: silymarin; silibum marianum; hepatoprotective; lipoperoxidation; nanotechnology; transdermal absorption; anti-aging effects; antioxidant; pharmaceutical technology.

To select relevant articles, we used the following inclusion criteria: publications from 2010 to 2022, written in any language, and related to the research topic. The extraction, selection, and analysis of the articles were conducted by a main researcher (ABCE), with support from two additional researchers (GMSG and PPB) who also contributed to the discussion.

3. Results

The search retrieved 311 articles and 21 were included for our review (Figure 1). The results were summarized in two tables: pharmacological aspects of silymarin (Table 1) and nanotechnology, chemical studies, and clinical studies (Table 2).

4. Discussion

The beneficial properties of silymarin can be attributed to its unique combination of components, which includes a flavonoid called taxifolin and seven

flavolignans: silycristin A, silycristin B, silidianin, silybin B, silybin A, isosilybin A, and isosilybin B. Among these, silybin [also known as silybinin] is the most prevalent flavolignan, constituting around 50-70% of the total extracted [3] [15] .

Studies conducted in vitro and in vivo have highlighted comprehensive analysis of the metabolism of silymarin and its flavonolignans. These studies have shown that phase II reactions play a much more dominant role in the metabolism of flavonolignans than phase I reactions, which only have a marginal effect. Phase II metabolism begins in intestinal cells and continues in the liver, with conjugated silymarin metabolites being excreted directly from the intestinal cells into the bile. These conjugates can be cleaved by bacteria in the intestine and reabsorbed, as evidenced by secondary peaks or plateaus observed in some in vivo studies [14] .

Although there is evidence of metabolic efflux of silymarin in the gut, the extent of conjugation in the gut and the mechanism of efflux of flavonolignans from silymarin are still not fully understood. However, it has been observed that the concentration of silymarin components in the Vein-Portal System is relatively high, and the concentration of total silybin in bile is greater than in the systemic circulation [13] [14] [15] [16] [17] .

With regard to pharmacokinetic properties, data compilation and improvement strategies for these properties are presented by Di Costanzo and Angelico [18] , that discuss the encapsulation of silymarin, highlighting: 1) nanocrystals, nanosuspensions and solid dispersions: colloidal dispersions of submicron particles of pure drugs, which are stabilized by surfactants or steric polymeric stabilizers [19] , to improve bioavailability if administered orally and its dissolution rates, in addition to prolonging the half-life of moderately soluble drugs, such as silymarin; 2) complexes with cyclodextrins and phospholipids: the inclusion complex prepared by the co-precipitation method led to the best results in terms of sustained drug release performance. Kellici et al. [20] , investigated a lyophilized silymarin-2hydroxypropyl-β-cyclodextrin complex, performing detailed physicochemical analyses on silymarin-cyclodextrin interactions at the molecular level, and verifying the respective bioavailability in MCF-7 cancer cells. Gharbia et al. [21] studied the inclusion complexes of silymarin with hydropropylchlorixidine and methyl-b-cyclodextrin, developed in order to improve the antifibrotic activity of silymarin at low therapeutic doses, increasing its solubilization potential and to prevent its metabolic degradation within the gastrointestinal tract after administration oral; 3) lipid-based formulations: designed to effectively encapsulate the silymarin complex in biocompatible and biodegradable polymeric nano systems, such as polymeric micelles, compounds and solid nano dispersions, thus promoting the polymeric erosion of this protection, releasing the phytopharmaceutical in the form of very fine particles to Rapid dissolution and improve oral bioavailability [18] [22] ; 4) inorganic nanomaterial compounds: very efficient vectors due to their versatile nanostructure, functional properties and controlled drug release behaviors, which may show excellent biocompatibility, biodegradation, in vivo stability, low cytotoxicity and non-immunogenic profiles [23] [24] .

Silymarin is consecrated as an herbal medicine for the treatment of liver diseases. Its protective actions are attributed to the antioxidant properties, Gillessen and Schmidt [25] consolidate and reinforce all the principles widely presented many years ago, compiling clinical studies.

Surai [7] propose some antioxidant mechanisms for silymarin: a] direct elimination of free radicals and chelators; b] prevent the formation of free radicals by inhibiting enzymes that produce molecules with free reactive oxygen and molecules with reactive nitrogen, or improve the integrity of mitochondria under stress conditions; c] maintain an ideal redox balance in the cell, activating enzymatic and non-enzymatic antioxidants, mainly through the activation of erythroid factor 2 Nrf2 [nuclear factor-erythroid related factor 2] also proposed by [12] ; d] decrease in the inflammatory response by inhibiting nuclear factor kappa B [NF-κB] pathways; e] activation of vitagenes [group of redox-sensitive genes that are involved in sensing stress and preserving cellular adaptive homeostasis] responsible for the synthesis of protective molecules, including the heat shock proteins, thioredoxin and sirtuins, and providing additional protection under conditions of stress that deserve further attention; and f] affect the gut microenvironment, including interactions between silymarin and bacteria, a factor not yet deeply investigated.

The interruption of the inflammatory cascade may be related to the activation of the erythroid factor 2 Nrf2 related to the erythroid nuclear factor [NFE2], known as a master regulator of the cytoprotective response. Nrf-2 is a redox-sensitive nuclear transcription factor capable of inducing associated genes downstream in this cascade. Some silymarin components have been shown to participate in the Nrf-2 signaling pathway as activators that interrupt interactions in the Keap1-Nrf-2 system [an important adaptive mechanism of the antioxidant response to several pathological conditions, such as diabetes] and as antioxidants or with additional related actions regulation of Nrf-2. In the last decade, several efforts have been directed towards the definition, observation and verification of the mechanisms and principles of pharmacotherapeutic action of silymarin [3] .

Anand et al. [26] performed a comparative study of herbal complexes for antiviral activity. Since silymarin was widely disseminated in eastern culture as a medicine for the treatment of liver diseases, the extrapolation and verification of results in the treatments of hepatitis, including hepatitis C, led to its in-depth investigation. Bioavailability needs to be guaranteed and, in this sense, technological advances have significantly corroborated [27] .

Other authors [27] [28] [29] [30] evidence the activity of silymarin against several viruses, including flaviviruses [hepatitis C virus and dengue virus], togaviruses [Chikungunya virus and Mayaro virus], influenza virus, human immunodeficiency virus and hepatitis B virus. Idebroy [31] evaluated therapy with Legalon® SIL, intended for the treatment of hepatitis C, verifying the decrease in the anti-inflammatory and anti-proliferative gene, associated with a decrease in tumor necrosis factor α [TNF-α] and NF-κB, related to viral transcription mechanisms. Clinical studies presented and compiled by Palit et al. [32] , also demonstrated the antiviral properties of silymarin and silybinin.

In the context of the Sars-cov-2 pandemic, it has become essential to understand the structure of the virus and its viral capsule, as well as the primary mechanisms of action on the host.

The similarity of the structure and pathology of Sars-cov-2 in relation to other known viruses allows the comparison of the genetic material due to its spherical structure, glycoprotein peaks, hemagglutinin, lipid bilayer, nucleocapsid, and site of infection with Sars-cov-2. This allows the identification of potential active principles for use in combat and in complementary therapies to the therapeutic protocol for Sars-cov-2: Zika virus is a positive-sense single-stranded RNA virus with a nucleocapsid, the open reading frames encode a single protein that is processed into the capsid, membrane protein, and envelope structural proteins [33] ; Rabies virus belongs to the RNA viruses and although it is a negative RNA virus, it has a lipid bilayer membrane covered by transmembrane glycoprotein spikes and a nucleocapsid that covers its genetic material [34] ; Dengue virus has a positive sense RNA [35] ; H1NI [swine flu virus] also affects the respiratory tract with a minimum incubation period of 5 to 7 days and is an enveloped virus with spikes of glycoprotein in the lipid bilayer membrane and also hemagglutinin in the envelope [36] ; Chikungunya virus is also a spherical virus with an envelope consisting of glycoprotein spikes and a positive-sense single-stranded RNA [37] ; Ebola virus, although a tube-shaped virus with negative-stranded RNA, has a lipid bilayer membrane and glycoprotein spikes [38] .

The Sars-cov2 Mpro and HCV NS3/4A proteases show similarity in the three-dimensional structure and in the arrangement of the active site residues. Furthermore, eight HCV protease inhibitors are also able to bind to the Mpro active site suggesting that HCV protease inhibitors can effectively inhibit Sars-cov-2 protease and Sars-cov-2 replication [39] . The HE spike protein found in Sars-cov-2 and the influenza virus hemagglutinin has a similar function [40] .

From the understanding of these principles, Anand et al. [26] carried out a review of numerous medicinal plants intended to combat and improve the immune response against viruses with agents similar in structure to Sars-cov-2. Sikander et al. [41] describe that the Sars-cov-2 virus uses protein cleavage enzymes to cleave the viral S protein and further facilitate virus-host cell fusion [42] [43] . As shown by Wrapp et al [44] in the structure model analysis, Sars-cov-2 binds to Angiotensin I 2 Converting Enzyme [ACE2], a host receptor, with an affinity of more than 10 times higher compared to Sars-cov-2. Hypertensive patients pre-treated with an angiotensin-1 receptor blocker showed relative protection against aggravation of the infection and reduced mortality and recovery time [45] , assuming that it acts in the containment of the post-infectious cytokine storm and organ damage [as an anti-inflammatory and anti-fibrotic agent].

Some authors [46] [47] discussed the use of various drugs in China, aimed at virus infection or immunomodulation during the pandemic.

Due to the complexity of the disease and factors such as the initial lack of drugs, protocols and vaccines, the scenario of the Sars-cov-2 pandemic has been extremely serious, triggered by an unpredictable pathophysiological response, such as hyperinflammatory disorders, blood clots, pulmonary embolism, thrombosis and organ damage caused by cytokine storm [48] [49] [50] . The immunopathological response of Sars-cov-2 is unprecedented and discordant about host defense with clinical manifestation based on symptoms and immunogenomic variation [51] [52] .

Clinical management of patients was often based on trial-and-error with re-proposed antiviral drugs such as ritonavir lopinavir [protease inhibitors], remdesivir [adenosine analogue], antiprotozoals such as hydroxychloroquine [endosomal inhibitor], among others [50] . In acute cases, patients sometimes failed to recover due to nonspecific drug binding or adverse drug reaction and comorbid conditions including organ malfunction [53] [54] [55] . This led to the death of these patients [54] [56] . Patients with pre-existing blood coagulopathy may have stroke due to an underlying mechanism that could likely mimic sepsis-like syndrome and disseminated intravascular coagulation [57] [58] [59] .

Silymarin may contribute to patient well-being due to effects against various pathophysiological disorders [41] , such as in hepatic and neurological tissues [60] .

Palit et al [32] analyzed the commercially available silymarin and the ingredients recommended by the Food and Drug Administration [FDA], silybin and silybinin, with fundamental contributions to the understanding of the complex pathophysiology involved in the worsening of Sars-cov-2 and clinical trials Recent studies suggest that elevated transaminases, elevated bilirubin, prolonged prothrombin period, hypoproteinemia and other abnormalities in blood tests may predict a greater possibility of worsening of the clinical status of these patients [61] . According to Sikander et al. [41] the factors involved in the hepatic aggression associated with Sars-cov-2 are toxicity and injury, promoting cytokine storm, direct viral replication, toxicity induced by antipyretics, hypoxia, induced toxicity by antivirals and pre-existing liver disease.

More than a third of patients with COVID-19 have some abnormalities in liver function tests [62] and the proportion of patients admitted to intensive care units [ICU] with liver injury (61.5%) was greater than patients not admitted to the ICU (25.0%) [63] .

Several studies have shown that plant-derived secondary metabolites have a blocking action on the inflammatory cascade of the lower airways, which can be beneficial in reducing the damage caused by viral infections from the Coronaviridae family, including Sars-cov-2. Phytochemicals with various molecular targets and signaling mechanisms have been found to reduce the production of pro-inflammatory and oxidative mediators such as TNF-α, IL-1, IL-6, IL-8, IL-1β, NF-κB, MMPs, iNOS, MAPK, COX-2, and ROS, thus minimizing lung damage. These protective effects, along with antiviral effects, have drawn attention to the potential use of phytochemicals as strategies to develop new anti-CoV agents for controlling related complications [26] [64] - [71] .

5. Conclusion

Silymarin shows promise in hepatoprotection, nephroprotection, anti-aging of the skin, cardiovascular protection, protection against respiratory diseases, prevention and treatment of various types of cancer, anti-diabetes, anti-tuberculosis, neuroprotection, Parkinson’s and Alzheimer’s, prevention of hemolysis and immunomodulation with blocking of adhesion and adsorption of TCD4+ cells, as well as direct action on the nuclear membrane, hindering the introduction of viral RNA and preventing its replication.

Acknowledgements

We thank Dr. Pedro Paulo Barros for his collaboration.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

References