CN108348566A - For treating liver and maintaining composition, method and the pharmaceutical composition of liver health - Google Patents

Abstract

Compositions and methods for treating the liver and maintaining liver health comprising a mixture of plant extracts comprising at least one Artemisia extract, at least one Aloe vera gel powder and at least one Schisandra extract. Compositions and methods for treating the liver and maintaining liver health comprising a mixture of plant extracts comprising at least one Artemisia extract enriched in at least one polymer or biopolymer are disclosed , at least one Aloe vera gel powder enriched in at least one chromone, and at least one Schisandra extract enriched in at least one lignan and organic acid.

Description

Compositions, methods and pharmaceutical compositions for treating the liver and maintaining liver health

This application claims U.S. Provisional Patent Application Serial No.: 62192711, filed July 15, 2015, entitled "Compositions and Methods for Liver Health" and filed July 12, 2016 Priority of U.S. Utility Application Serial No.: 15208075 entitled "Compositions, Methods, and Medical Compositions for Treatment of and Maintaining the Health of the Liver" rights, which are jointly owned, and are hereby incorporated by reference in their entirety.

subject area

The subject area is compounds and compositions for liver health management, including stereoisomers, pharmaceutically or healthcare acceptable salts, tautomers, glycosides and prodrugs of the disclosed compounds, improving and maintaining liver health Healthy compositions and related methods.

background

The liver is an important organ that plays a key role in the metabolism and detoxification of various endogenous and exogenous harmful substances. It is believed that over 500 chemical reactions take place in the liver. Various xenobiotics or foreign chemicals are known to cause liver toxicity, among which acetaminophen (n-acetyl-para-aminophenol or APAP) and carbon tetrachloride (CCl ₄ ) are commonly used to develop analogs with similar Animal model of human hepatotoxicity type of mechanism of action. A range of biomarkers from serum or liver homogenates have been used to examine and/or analyze the health of the liver, where deviations from normal ranges are considered indicative of damage to the organ. Among these biomarkers, the most commonly used are: ALT (alanine aminotransferase), AST (aspartate aminotransferase), MDA (malondialdehyde), GSH (glutathione), SOD (superoxide dismutation enzyme), c-Jun N-terminal kinase (JNK), GSH-Px (glutathione peroxidase), CAT (catalase) and TNF-α (tumor necrosis factor-α). Liver panels such as AST, ALT, total bilirubin, conjugated and unconjugated bilirubin, bile acids, total protein, albumin, globulin, and alkaline phosphatase have been used as standard screens for liver health check method. While it is recognized that ALT and AST are non-specific for liver injury, ALT has been shown to be relatively specific for the liver. For example, AST has a starting ratio of liver (9000:1) to muscle (5200:1); in contrast, ALT has a starting ratio of liver (7600:1) to muscle (750:1). The half-lives of total AST and ALT were 17±5 hours and 47±10 hours, respectively. ALT is stable for 3 days at room temperature, 3 weeks in the refrigerator, and 24 hours in whole blood; however, ALT deteriorates rapidly with repeated freeze-thaw cycles. In our study, serum ALT was used for efficacy screening of plant extracts.

APAP is a very safe and effective pain reliever and antipyretic at therapeutic doses. It is the most common cause of acute liver failure in the United States. APAP-induced hepatotoxicity is clinically relevant, well-studied, can be rapidly induced in vivo with a single dose, and has become a routine model for evaluating the potential hepatoprotective effects of phytotherapy.

APAP-induced cell death is not caused by a single unfortunate event that shuts down a vital function of the cell, rather, it induces a cascade of events beginning with the formation of reactive metabolites and triggering mitochondrial dysfunction, which is amplified by the JNK pathway , eventually leading to non-functional mitochondria and massive DNA degradation, leading to cell necrosis.

APAP toxicity occurs through a very complex mechanistic pathway of action. As previously determined, the intracellular signaling mechanism of APAP-induced cell death is the metabolism of a fraction of the administered dose by P450 enzymes, mainly Cyp 2e1 and 1a2 (Zaher et al., 1998) to n-acetyl Initiated by p-benzoquinone imine (NAPQI). Under normal conditions, this highly active metabolite will be detoxified by GSH, leading to widespread hepatic GSH depletion (Mitchell et al., 197), which becomes critical in the event of overdose. Simultaneously, more and more NAPQI reacts with protein sulfhydryl groups, leading to covalent addition of cellular proteins (Jollow et al., 1973). Interestingly, studies have shown that total protein association in cells is less important than adducts in mitochondria (Tirmenstein and Nelson, 1989; Qiu et al., 2001). Mitochondrial protein binding triggers mitochondrial oxidative stress (Jaeschke, 1990), which leads to activation of apoptosis signal-regulated kinase 1 (Nakagawa et al., 2008) and c-Jun N-terminal kinase (JNK) (Hanawa et al., 2008), and amplification of peroxynitrite formation by mitochondrial oxidative stress and mitochondrial JNK translocation (Saito et al., 2010a). Extensive oxidative stress eventually triggers the opening of membrane permeability transition (MPT) pores in mitochondria, with a concomitant collapse of membrane potential (Kon et al., 2004; Masubuchi et al., 2005; Ramachandran et al., 2011a; Loguidice and Boelsterli, 2011) , followed by the release of intermembrane proteins such as endonuclease G and apoptosis-inducing factor (AIF) from mitochondria (Kon et al., 2004; Bajt et al., 2008). Both endonuclease G and AIF translocate to the nucleus and cause DNA fragmentation (Cover et al., 2005; Bajt et al., 2006, 2011) and eventually cell death. Collapse of mitochondrial membrane potential accompanied by ATP depletion and nuclear degradation is a key event leading to cell necrosis. Thus, when designing therapeutic interventions for liver protection, there are multiple points of interference at which these mechanisms can be intercepted.

Understanding the chronological events of a model pathological process provides guidance for therapeutic intervention. Although oxidative stress and sterile inflammation play important roles in APAP toxicity, the pathophysiology of the model is characterized by a sequence of events including metabolic activation between 0 and 2 hours, GSH depletion within the first 30 minutes, 2 Intracellular mechanisms of cell death between and 12 hours, inflammatory responses in the 6-24 hour timeframe, and regeneration in the 24-72 hour timeframe after APAP toxicity (Jaeschke et al., 2012a).

As noted above, APAP overdose can lead to nuclear DNA fragmentation characterized by protein adduct formation (Davern et al., 2006; James et al., 2009), mitochondrial damage, and cell death (McGill et al., 2012a) severe hepatotoxicity in humans. Therefore, when testing plant extracts for liver protection, it is necessary to utilize animal models that may share similar pathophysiological features. Therefore, for in vivo experiments, the mouse is the preferred model because the injury closely resembles human pathophysiology in terms of mechanism and dose dependence. Indeed, some argue that the main significant difference in APAP hepatotoxicity between mice and humans is the more delayed toxicity in humans, which exhibits an ALT peak at 24-48 hours post-exposure, compared to the mouse ALT peak at 6 -12 hours (Larson, 2007). This difference can partly be explained by differences in uptake between the two species. In contrast, rats, although commonly used for natural product testing, are poor models since most rat strains are largely insensitive to APAP toxicity (Mitchell et al., 1973; McGill et al., 2012b). Even at high doses ≥1 g/kg, APAP causes little associated liver damage (Jaeschke et al., 2013). Although GSH depletion and protein adducts can be measured, lower amounts of adducts appear to be insufficient in rat liver mitochondria compared with mice to trigger sufficient mitochondrial dysfunction and subsequent amplification events to result in necrotic cells death (McGill et al., 2012b). These fundamental differences between the two species have been reflected in the evaluation process of phytotherapy. For example, in a rat study, an APAP dose of 3 g/kg resulted in an approximately 3-fold increase in plasma ALT levels compared to baseline, and phytotherapy attenuated this moderate liver injury by 33% (Ajith et al., 2007) . Any histological changes in this rat model are small and difficult to detect. On the other hand, in a mouse study, ALT increased >60-fold from baseline following a 300mg/kg APAP dose and was reduced by 75% by phytotherapy (Wan et al., 2012). Histological changes caused by APAP toxicity and the protective effect of the drug were readily observed.

CCl ₄ , a haloalkane industrial chemical of limited use, is a well-known hepatotoxin widely used to induce acute toxic liver injury in a large number of laboratory animals. Humans have been exposed to _CCl4 in occupational settings and from environmental pollution such as contaminated drinking water. Nevertheless, the chemical still provides important use today as a model compound to elucidate the mechanism of action for hepatotoxic effects such as steatosis, fibrosis, hepatocyte death, and carcinogenicity (Slater 1981; Renner H. 1985; Reynolds 1963) . It is considered to be one of the classic animal models of chemically induced hepatotoxicity, which is mainly related to the formation of free radicals and lipid peroxidation.

Like APAP, CCl ₄ toxicity is initiated by cytochrome P450s primarily (CYP) 2E1, CYP2B1, or CYP2B2 (Nelson andHarrison, 1987), producing a reactive metabolite, trichloromethyl radical (CCl ₃ -), which can trigger Lipid peroxidation ultimately leads to overproduction of reactive oxygen species (ROS) and liver cell damage (Poyer et al., 1980; Albano et al., 1982). In the process, these free radicals can bind to cellular molecules (nucleic acids, proteins, and lipids), impairing key cellular processes, such as lipid metabolism, with possible consequences of steatosis (fatty degeneration) and damage to these macromolecules Direct injury (Weddle et al., 1976). These radicals can also react with oxygen to form the trichloromethylperoxy radical _CCl3OO- , a highly reactive species. Once produced, it starts a chain reaction of lipid peroxidation that attacks and destroys polyunsaturated fatty acids, especially those associated with phospholipids. This affects the permeability of mitochondria, endoplasmic reticulum and plasma membrane, leading to loss of cellular calcium sequestration and homeostasis, which may contribute significantly to subsequent cellular damage. In this regard, antioxidants and free radical scavengers have been used to study the mechanisms of _CCl4 toxicity and the protection of hepatocytes from _CCl4 -induced damage by disrupting the cascade of lipid peroxidation (Cheeseman et al., 1987). At the molecular level, _CCl4 activates TNF-α (Czaja et al., 1995), nitric oxide (NO) (Chamulitrat et al., 1994, 1995) and transforming growth factor (TGF) (Luckey et al., 2001) in cells ), a process shown to direct cells primarily to destruction or fibrosis. These plant extracts showing anti-inflammatory activity may have potential hepatoprotective applications. Although acute administration of high doses of _CCl4 resulted in severe necrosis, chronic administration of lower doses was often used to induce liver fibrosis.

Oxidative stress is an imbalance between the production of free radicals and the body's innate ability to counteract or neutralize their deleterious effects by interacting with various reducing and chelating endogenous antioxidant defense networks. When the body's antioxidant defense system lacks proper regulation, the accumulation of reactive oxygen species will lead to the activation of stress-sensitive intracellular signaling pathways, thereby promoting cellular damage leading to necrosis. While damage from oxidative stress affects the entire body as a system, the effects become even more detrimental when it involves vital organs such as the liver (where major detoxification occurs to remove and metabolize harmful toxins such as alcohol) . Thus, the liver is vulnerable to alcohol-induced damage because alcohol and its main metabolite acetaldehyde generate reactive oxygen species (ROS) and hydroxyl radicals (OH), thereby altering the liver's antioxidant defense system. The most common pathological conditions observed in alcohol-related liver diseases due to repeated exposure to alcohol, such as fatty liver, hepatitis, fibrosis and cirrhosis. These results related to the oxidation of cellular lipids, proteins and DNA have been confirmed in various experimental animals (Wu and Cederbaum, 2003). Here, we used the most commonly used animal models with real clinical significance, such as APAP, and confirmed the findings of the classical _CCl4- induced hepatotoxicity model. Regardless of the chemical agent used to induce hepatotoxicity, the APAP and _CCl4 models share the key steps of oxidative stress induced by reactive oxygen species generated from excess intermediate metabolites, leading to protein oxidation, lipid peroxidation, and DNA damage.

To this end, it would be desirable to develop, produce and utilize compositions, pharmaceutical compositions and related methods aimed at treating the liver and maintaining liver health. Desirably compounds, pharmaceutical compositions and compositions would be sufficient to achieve therapy, including any one or more of the following: (1) treating or preventing damage to mammalian liver cells; (2) promoting liver health; (3) protecting mammalian (4) increase liver detoxification ability in mammals; (5) treat or prevent liver diseases in mammals; (6) reduce liver inflammation in mammals; and (7) improve liver renewal function. Desirable compounds and compositions may be derived from or comprise at least one plant extract, which may or may not be enriched in the plant extract. As part of this development, it would be ideal to test prospective compounds and compositions using commonly used and accepted models. It would also be desirable to reliably design therapeutic interventions for liver health by intercepting points in the liver's degradation mechanisms and studying those consequences.

overview of topics

Compositions and methods for treating the liver and maintaining liver health comprising a mixture of plant extracts comprising at least one Artemisia extract, at least one Aloe Gel powder and at least one Schizandra extract.

Compositions and methods for treating the liver and maintaining liver health comprising a mixture of plant extracts comprising at least one Artemisia extract enriched in at least one polymer or biopolymer are disclosed , at least one Aloe vera gel powder enriched in at least one chromone, and at least one Schisandra extract enriched in at least one lignan and organic acid.

Also disclosed are uses in mammals to maintain liver function, minimize liver cell damage, promote healthy liver, protect liver antioxidant integrity, neutralize toxins, reduce free radical effects affecting liver health, scavenge reactive oxygen species, reduce oxidation Stress, prevents formation of toxic metabolism, improves liver detoxification capacity and/or function, cleanses liver, restores liver structure, protects liver cells from toxins, aids liver blood flow and circulation, supports liver function, strengthens and soothes liver, calms and nourishes Liver, relieves liver pain, removes harmful chemicals and organisms, supports metabolic processes in the liver, relieves liver discomfort, relieves fatty liver, improves liver detoxification, reduces liver enzymes, provides natural oxidants, increases SOD, increases GSH, reduces liver Pharmaceutical compositions and methods for cellular peroxidation, reduction of fatty acid accumulation, maintenance of healthy anti-inflammatory processes, improvement of liver immune function, promotion of liver cell regeneration, improvement of liver renewal function, stimulation of bile release, promotion of healthy bile flow, liver restoration, etc., wherein The pharmaceutical composition contains the desired composition as an active ingredient.

Brief description of the drawings

Figure 1 shows the HPLC chromatogram of the 70% ethanol extract of Artemisia capillaris .

Detailed Description

Briefly, the present disclosure relates to compounds and compositions useful for the management of liver health, including stereoisomers, pharmaceutically or nutraceutical acceptable salts, tautomers, glycosides and prodrugs of the disclosed compounds, And related ways to improve liver health.

Contemplated compounds and compositions are derived from or comprise at least one plant extract, which plant extract may or may not be enriched. As part of this development, commonly used and accepted models are used to test prospective compounds and compositions. Additionally, therapeutic interventions for liver health can be designed by intercepting points in the liver's degradation mechanisms and studying those outcomes. The expected compound, pharmaceutical composition and composition are sufficient to achieve treatment, including any one or more of the following: (1) treating or preventing damage to mammalian liver cells; (2) promoting liver health; (3) protecting mammalian liver cells Detoxifying and antioxidative liver enzymes; (4) increasing liver detoxification capacity in mammals; (5) treating or preventing liver disease in mammals; (6) reducing inflammation in mammalian liver; and (7) improving liver renewal function.

In particular, compositions, compounds and methods for treating the liver and maintaining liver health are disclosed comprising a mixture of plant extracts, wherein the plant extract comprises at least one Artemisia extract, at least one Aloe Gel powder and at least one Schisandra extract.

In addition, compositions, compounds and methods for treating the liver and maintaining liver health are disclosed, comprising mixtures of plant extracts, wherein the plant extracts comprise at least one Artemisia extract, at least one Aloe vera gel powder enriched in at least one chromone and at least one Schisandra extract enriched in at least one lignan and organic acid.

Also disclosed are uses in mammals to maintain liver function, minimize liver cell damage, promote healthy liver, protect liver antioxidant integrity, neutralize toxins, reduce free radical effects affecting liver health, scavenge reactive oxygen species, reduce oxidation Stress, prevents formation of toxic metabolism, improves liver detoxification capacity and/or function, cleanses liver, restores liver structure, protects liver cells from toxins, aids liver blood flow and circulation, supports liver function, strengthens and soothes liver, calms and nourishes Liver, relieves liver pain, removes harmful chemicals and organisms, supports metabolic processes in the liver, relieves liver discomfort, relieves fatty liver, improves liver detoxification, reduces liver enzymes, provides natural oxidants, increases SOD, increases GSH, reduces liver Pharmaceutical compositions and methods for cellular peroxidation, reduction of fatty acid accumulation, maintenance of healthy anti-inflammatory processes, improvement of liver immune function, promotion of liver cell regeneration, improvement of liver renewal function, stimulation of bile release, promotion of healthy bile flow, liver restoration, etc., wherein The pharmaceutical composition contains the desired composition as an active ingredient.

Concerned about alcohol-induced liver damage, general fatigue and exhaustion, a unique blend of compounds and extracts found to have enhanced efficacy was developed with the concept of protecting the liver against repeated exposure to oxidative stress. Historically, some plants rich in phenolic compounds have been reported to be associated with antioxidant effects in biological systems, acting as scavengers of singlet oxygen and free radicals, making them useful in herbal medicine. Combining such plant materials with comprehensible efficacy and safety data is expected to be beneficial to overall liver health. Therefore, the APAP and _CCl4 models were used to screen various plant extracts. As a result, some plant extracts showed a reduction in serum ALT in only one model, but the criterion for a lead to be considered was to show efficacy in both models.

Among a total of 38 plant materials tested, Schisandra, Artemisia, and N931 were the only materials that showed their efficacy in both models. N931 is a composition containing a unique combination of 1-4% aloesin and 96-99% 200:1 Aloe vera inner leaf fell powder polysaccharide. As disclosed herein, contemplated compositions generally comprise Artemisia extracts enriched in one or more biopolymers, aloe vera gel powders enriched in one or more chromones, and aloe gel powders enriched in one or more Mixture of plant extracts of various lignans and organic acids of Schisandra genus extract.

The degree of inhibition observed for these materials was not the same between the models. For example, although extracts of Schisandra genus appeared to show a high protective effect against APAP-induced liver injury (up to 48.9% at a dose of 500 mg/kg), at the same dose, the extracts were only effective in a _CCl4- induced hepatotoxicity model Shows 22.8% inhibition. On the other hand, in a _CCl4 -induced hepatotoxicity model, Artemisia extracts such as Artemisia captivaris showed a 48.0% reduction in serum ALT levels at a dose of 400 mg/kg; At this dose level, only 24.0% inhibition was observed in the APAP-induced liver injury model. Given these strongly unique representations of each plant observed in the individual models, the idea of combining these plant extracts for better results in both models was strengthened. N931 showed modest hepatoprotective activity in both models. As mentioned above, quite a few studies have confirmed the antioxidant activity of Schisandra, Artemisia, and N931 with varying degrees of hepatoprotective abilities. However, they have never been combined together in specific ratios before to produce the intended and disclosed compositions, including SAL, which is generally understood to be a unique combination of Schisandra, Artemisia, and N931.

An interesting finding was that only 2 :1 (Schisandra is twice as large as Artemisia capillary) and 1:2 in the CCL ₄ model (Artemisia capillary is twice as large as Schisandra) showed 48.0% and 40.6% higher serum ALT levels, respectively, compared to the injured vehicle control decrease. They did not show the expected efficacy in both models at a single ratio, indicating that a third component was required to complete the composition. N931 was considered this component as it showed moderate inhibition in both models. The addition of N931 to the two lead blends showed a similar degree of hepatoprotective activity in both models: namely, 52.5% and 46.3% in the two models, which is believed to be due to the composition or compound The added benefit of three components. When testing the advantages of formulating these three plant materials, an unexpected synergistic effect was observed from the combination of these three plant materials beyond the predicted results based on the ratio of each of its components at a given ratio and Simple additive of the effects observed at the 400 mg/kg dose.

In fact, none of the components showed the same degree of hepatoprotective activity as that shown by the expected compounds or compositions comprising Schisandra, Artemisia and N931. In addition, data from a liver function panel including AST, ALT, bile acids, total protein, total bilirubin, conjugated bilirubin, albumin, and total protein showed that all Contemplated compositions comprise hepatoprotective activity. As reflected by the data from liver homogenates, the expected composition including SAL also replenished depleted hepatic glutathione associated with increased hepatic superoxide dismutase activity. The expected and unique ratio of 4S:8A:3L demonstrated hepatoprotective activity in multiple animal models associated with modulation of several oxidative stress-specific biomarkers.

As disclosed herein, Artemisia extract and Schisandra extract may be blended in a weight ratio of 4:1 to 1:4. In some contemplated embodiments, the Aloe vera gel powder may further be blended with a mixture of Artemisia and Schisandra extracts at a weight percentage of about 5% to about 50%. In other contemplated embodiments, a mixture of Artemisia, Schisandra, and Aloe leaf gel powders may be provided in a ratio of 8:4:3, respectively.

Schisandra extracts are contemplated components or ingredients that may be used as part of a compound or composition of interest. Schisandra extracts may be obtained from any suitable source, including Schisandra chinensis, Schisandra elongate, Schisandra glabra, Schisandra glaucescens, Schisandra henryi, Schisandra incarnate, Schisandra lancifolia, Schisandra neglecta, Schisandra nigra, Schisandra propinqua, Schisandra pubescens, Schisandra repanda, Schisandra rubriflora, Schisandra rubrifolia, Schisandra sinensis, ball stamens Schisandra sphaerandra, Schisandra sphenanthera, Schisandra tomentella, Schisandra tuberculata, Schisandra vestita, Schisandra viridis, Schisandra wilsoniana ) or a combination thereof.

As contemplated herein, Schisandra extracts may be enriched in one or more lignans and organic acids. The lignans expected to be isolated from extracts of the genus Schizandrin are Schizandrin, DeoxySchisandrin, γ-Schisandrin, Pseudo-γ-Schisandrin, Schisandrin B, Schizandrin C, Isschizandrin, Pregomisin, eoschizandrin, Schisandrin alcohol, schisandrin A, schisandrin B, schisandrin esters A, B, C, D, E, safflower schisandrin, schisandrol acetate (Schisanhenol acetate), schisandrol B, schisandrin, gomisin A, B , C, D, E, F, G, H, J,N, O, R, S, T, U, epigomisin O, angeloylgomisin H, O, Q, T, igloylgomisin H, P , Angeloyl-isogomisin O, Benzoyl-isogomisin H, O, P, Q, Benzoyl-isogomisin or combinations thereof. Organic acids contemplated for isolation from Schisandra extracts include malic acid, citric acid, shikimic acid, or combinations thereof.

Artemisia extracts are contemplated components or ingredients useful as part of a compound or composition of interest. Artemisia extracts may be obtained from any suitable source, including Artemisia absinthium, Artemisia abrotanum L., Artemisia afra, Artemisia annua L., Artemisia abrotanum ( Artemisia arborescens), Artemisia asiatica, Artemisia campestris, Artemisia deserti, Artemisia iwayomogi, Artemisialudoviciana, Artemisia vulgaris, Artemisia oelandica, Artemisiaprinceps Pamp, Artemisia white lotus (Artemisiaprinceps Pamp) sacrorum), Artemisia scoparia, Artemisia stelleriana, Artemisia frigida Willd, Artemisia anethoides Mattf., Artemisia anethifolia Weber., Artemisia faurierNakai, Origanum vulgare), Siphenostegia chinensis or any combination thereof.

As contemplated herein, Artemisia extracts can be enriched in one or more biopolymers. The desired polymers and biopolymers isolated from the Artemisia extract are extracted with any suitable solvent, including water, methanol, ethanol, alcohol, water-mixed solvents, or combinations thereof. In contemplated embodiments, the Artemisia extract comprises from about 0.01% to about 99.9% biopolymers having an individual or median molecular weight above about 500 g/mol. In some contemplated embodiments, the Artemisia extract comprises from about 0.01% to about 99.9% biopolymers having an individual or median molecular weight above about 750 g/mol. In other contemplated embodiments, the Artemisia extract comprises from about 0.01% to about 99.9% biopolymers having an individual or median molecular weight above about 1000 g/mol.

Aloe gel powder is another contemplated component or ingredient, which may be provided by any suitable source, including Aloe arborescens, Aloe barbadensis, Aloe cremnophila, Aloe ferox, Aloe saponaria, Aloe vera, Aloe vera var. chinensis or combinations thereof.

As contemplated herein, the aloe gel powder can be enriched with one or more chromones. Contemplated chromones comprise or are selected from aloesin, aloesinol, aloeresin A, aloe resin B, aloe resin C, aloe resin D, aloe resin E, or any combination thereof. In contemplated embodiments, the at least one chromone composition may comprise from about 0.01% to about 100% of one or more chromones. In some contemplated embodiments, the chromone composition comprises from about 1% to about 4% aloesin, wherein the composition is substantially free of anthraquinones and wherein the aloe gel is selected from Aloe vera or Aloe vera and wherein the at least one chromone is isolated from Aloe vera or Aloe vera or any combination thereof.

The contemplated compounds, pharmaceutical compositions and compositions may comprise or additionally comprise or consist of at least one hepatoprotective agent. In some embodiments, the at least one hepatoprotective agent may comprise or consist of milk thistle, turmeric, Bupleurum, licorice, sage, mulberry, aurantium aurantium, agrimony, acanthus, lyceum, citrus , plum, yellow plum, Korea gim, dandelion, grape, grape seed, rubus, camellia, green tea, krill oil, yeast, soybean plant powder or plant extract; isolated and enriched silymarin, flavonoids, phospholipids, thios , Pycnogenol, Gelatin, Soy Lecithin, Pancreatin; Natural or Synthetic N-acetylcysteine, Taurine, Riboflavin, Niacin, Pyridoxine, Folic Acid, Carotene, Vitamin A, Vitamin A B2, B6, B16, vitamin C, vitamin E, glutathione, branched-chain amino acids, selenium, copper, zinc, manganese, coenzyme Q10, L-arginine, L-glutamine, phosphatidylcholine, etc. and / or a combination thereof.

Also contemplated herein are in vivo metabolites of the disclosed compounds. These products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes. Accordingly, contemplated compounds are those produced by methods comprising administering the contemplated compound or composition to a mammal for a time sufficient to produce its metabolites. Typically by administering a radiolabeled compound of the present disclosure to an animal (e.g., a rat, mouse, guinea pig, dog, cat, pig, sheep, horse, monkey, or human) in a detectable dose, allowing sufficient time for metabolism to occur, Such products can then be identified by isolating their conversion products from urine, blood or other biological samples.

As used herein, the phrases "stable compound" and "stable structure" are used interchangeably and are used to refer to a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

As used herein, the term "mammal" includes humans and domestic and non-domestic animals, such as laboratory animals or household pets, such as rats, mice, guinea pigs, cats, dogs, pigs, cows, sheep, goats, horses , rabbits, primates, non-domestic animals such as wild animals, etc.

As used herein, the terms "optional" or "optionally" are used interchangeably and mean that an element, component, event or circumstance described subsequently may or may not occur, and includes the occurrence of said element, component , events or circumstances and their absence. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted - in other words, the description includes substituted aryl groups as well as unsubstituted aryl groups.

The contemplated compounds, pharmaceutical compositions and compositions may comprise or additionally comprise or consist of at least one pharmaceutically or healthcare acceptable carrier, diluent or excipient. As used herein, the phrase "pharmaceutically or hygienically acceptable carrier, diluent or excipient" includes any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/ Coloring agents, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizing agents, isotonic agents, solvents or emulsifying agents, which have been approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

The contemplated compounds, pharmaceutical compositions and compositions may comprise or additionally comprise or consist of at least one pharmaceutically or hygienically acceptable salt. As used herein, the phrase "pharmaceutically or hygienically acceptable salt" includes acid addition salts and base addition salts.

As used herein, the phrase "pharmaceutically or hygienically acceptable acid addition salt" refers to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are Formed with inorganic acids and organic acids, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid Acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamate, dodecane Hydroxyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucose Aldehydic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, propanediol acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2sulfonic acid, 1-hydroxy-2-naphthoic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid Acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid , trifluoroacetic acid, undecylenic acid, etc.

As used herein, the phrase "pharmaceutically or hygienically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salt is an ammonium, sodium, potassium, calcium, or magnesium salt. Salts derived from organic bases include those of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, Amine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histamine Acid, procaine, halamine, choline, betaine, phenethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine , piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. Particularly useful organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline or caffeine.

Often crystallization results in a solvate of or includes the desired compound. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the desired compound, pharmaceutical composition or composition and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, a contemplated compound, pharmaceutical composition or composition may exist as a hydrate, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc. and the corresponding solvated form. The contemplated compound, pharmaceutical composition or composition may be a true solvate, while in other cases the contemplated compound, pharmaceutical composition or composition may retain only extrinsic water or be a mixture of water and some extrinsic solvent.

"Pharmaceutical composition" or "healthcare composition" refers to the contemplated compound, pharmaceutical composition or composition and formulation of vehicles generally accepted in the art for the delivery of biologically active compounds to mammals, eg, humans. For example, a contemplated pharmaceutical compound, pharmaceutical composition or composition may be formulated or used as a standalone composition, or as a prescription, over-the-counter (OTC), herbal, herbal, homeopathic or otherwise reviewed and approved by a government agency ingredients in any other form of health care product. Exemplary and contemplated health care compositions can be formulated or used as stand-alone compositions, or as foods, novel foods, functional foods, beverages, bars, food flavors, food additives, medicinal foods, dietary supplements, or herbal remedies Nutraceutical or biologically active ingredients in products. A medium generally accepted in the art includes all pharmaceutically or healthcare acceptable carriers, diluents or excipients used in the art.

As used herein, the phrase "enriched" means that a plant extract or other preparation has one or more active compounds in an amount or activity equal to that found in said weight of plant material or other source or other preparation prior to extraction. The amount or activity of the one or more active compounds is increased by at least about 2-fold up to at most about 1000-fold. In certain embodiments, the weight of the plant material or other source or other preparation prior to extraction may be dry weight, wet weight, or a combination thereof.

As used herein, "main active ingredient" or "major active ingredient" refers to one or more active desired compounds found or enriched in a plant extract or other preparation , which is capable of producing at least one biological activity. In certain embodiments, the major active ingredient of an enriched extract will be the one or more active compounds enriched in the extract. Typically, one or more major active components will confer, directly or indirectly, a majority (ie, greater than 50%) of one or more measurable biological activities or effects compared to other extract components. In certain embodiments, the major active ingredient by weight percent of the extract may be a minor component (e.g., less than about 50%, 25%, 20%, 15%, 10%, 5% contained in the extract % or 1% of the component), but still provide most of the desired biological activity. Any contemplated composition comprising a primary active ingredient may also contain secondary active ingredients which may or may not contribute to enrich the pharmaceutical or health care activity of the composition, but not to the level of the primary active ingredient, and only secondary active Ingredients may not be effective without the main active ingredient.

As used herein, the phrase "effective amount" or "therapeutically effective amount" refers to an amount of a contemplated compound, pharmaceutical composition or composition sufficient to effect treatment when administered to a mammal, such as a human, including any of One or more: (1) treating or preventing liver cell damage in mammals; (2) promoting liver health; (3) protecting detoxification and antioxidative liver enzymes in mammals; (4) increasing liver detoxification ability in mammals; (5) treating or preventing liver disease in a mammal; (6) reducing inflammation in the liver of a mammal; and (7) improving liver renewal function. The amount of a contemplated compound, pharmaceutical composition or composition that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition being treated and its severity, the mode of administration, the duration of the treatment or the weight and age of the subject being treated, but can be determined by this Those of ordinary skill in the art determine based on their own knowledge and this disclosure.

As used herein, "supplement" means a product that improves, promotes, supports, increases, regulates, regulates, controls, maintains, optimizes, modifies, reduces, inhibits, or prevents a particular condition, structure, or function associated with a natural state or biological process , compound and/or composition (ie not for diagnosis, treatment, mitigation, cure or prevention of disease). In certain embodiments, the supplement is a dietary supplement. For example, for diseases related to liver health, dietary supplements can be used in mammals to maintain liver function, minimize hepatocellular damage, promote a healthy liver, protect the antioxidant integrity of the liver, neutralize toxins, and reduce effects on the liver Healthy free radical action, scavenging reactive oxygen species, reducing oxidative stress, preventing formation of toxic metabolism, improving liver detoxification ability and/or function, clearing liver, restoring liver structure, protecting liver cells from toxins, helping liver blood circulation and circulation, supports liver function, strengthens and soothes the liver, calms and nourishes the liver, relieves liver pain, removes harmful chemicals and organisms, supports metabolic processes in the liver, relieves liver discomfort, relieves fatty liver, improves liver detoxification, reduces Liver enzymes, provide natural oxidants, increase SOD, increase GSH, reduce liver cell peroxidation, reduce fatty acid accumulation, maintain healthy anti-inflammatory process, improve liver immune function, promote liver cell regeneration, improve liver renewal function, stimulate bile release, promote Healthy bile flow, liver recovery and more. In certain embodiments, a dietary supplement is a special class of meal, food, or both, and is not a drug.

The terms "treating" or "treating" or "improving" are used interchangeably and refer to therapeutic treatment of a disease or condition of interest in a mammal (e.g., a human) suffering from or suspected of having the disease or condition of interest. Therapeutic or prophylactic/prophylactic treatment, and includes: (i) preventing the occurrence of a disease or condition in a mammal, especially when such mammal is susceptible to the condition but has not been diagnosed with the condition; (ii) inhibiting the disease or condition, i.e. arresting its development; (iii) relieving the disease or condition, i.e. causing the disease or condition to regress; or (iv) relieving the symptoms caused by the disease or condition without addressing the underlying disease or condition (e.g. relieving pain, reduce inflammation and reduce loss of detoxification capacity).

As used herein, the terms "disease" and "disorder" may be used interchangeably, or may be distinct, except that a particular condition or disorder may not have a known etiological factor (and thus an etiology has not been determined), thus Not yet considered a disease, but only an undesirable condition or syndrome in which a clinician has identified a more or less specific set of symptoms. In certain embodiments, the contemplated compounds, pharmaceutical compositions, compositions and methods are used in the treatment of, for example, hepatitis, alcoholic liver disease, cirrhosis, or both.

As used herein, "statistical significance" refers to a p-value of 0.050 or less calculated using the Students' t-test, and indicates that it is unlikely that a particular event or measurement occurred by chance.

The chemical naming protocol and any structural drawings used herein are a modified form of the I.U.P.A.C. naming system using the ACD/Name Version 9.07 software program or the ChemDraw Ultra Version 11.0 software naming program (CambridgeSoft), where compounds of the present disclosure are named centrally herein Core structures such as derivatives of imidazopyridine structures. For complex chemical names used herein, a substituent is named before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituents.

In certain embodiments, contemplated compounds and compositions (e.g., pharmaceutical, nutraceutical) may be administered in an amount sufficient to promote liver health; improve liver health; maintain liver health; treat or manage liver health; support liver Healthy; supports normal and comfortable range of liver detoxification function; improves free radical scavenging capacity of the liver; reduces damage from harmful free radicals derived from chemicals, drugs, metabolites and biotoxins; protects enzymes affecting liver Hepatitis/HCV infection, alcohol consumption, metabolic disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, hepatic encephalopathy, hepatic fibroproliferative disease (hepatic fibrosis ), hepatocellular injury during hypoxia/reoxygenation, or any combination thereof; or any other relevant indication described herein, and generally has acceptable toxicity to the patient.

In certain other embodiments, the contemplated compounds and compositions (e.g., pharmaceutical, therapeutic) can be administered in sufficient amounts to treat liver disorders or diseases, including viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic hepatitis, Liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease, drug-induced liver disease, cirrhosis, fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary Primary biliary cirrhosis, capillary cholangiocarcinoma, Gilbert's syndrome, jaundice, or any other hepatotoxicity-related indication or combination thereof, and generally has acceptable toxicity to the patient.

The administration of the intended compound, pharmaceutical composition or composition, or a pharmaceutically or hygienically acceptable salt thereof, in pure form or in a suitable pharmaceutical or hygienic composition may be by any of the accepted administrations of medicaments for similar purposes. mode to proceed. The desired pharmaceutical or healthcare composition can be prepared by combining the desired compound with a suitable pharmaceutically or healthcare acceptable carrier, diluent or excipient, and can be formulated in solid, semi-solid, liquid or gaseous form formulations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical routes of administration of such pharmaceutical or healthcare compositions include oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal or intranasal.

As used herein, the term "parenteral" includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Contemplated pharmaceutical or healthcare compositions are formulated such that the active ingredients contained therein are bioavailable at or shortly after administration of the composition to a patient. In some embodiments, contemplated compositions and compounds can be designed or formulated such that they are timed to be released after administration.

In certain embodiments, a contemplated composition is administered to a subject or patient in one or more dosage units, where, for example, a tablet may be a single dosage unit, and a container of the contemplated compound in aerosol form may contain multiple dosage units. Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art; see, eg, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). Contemplated compositions to be administered in accordance with the teachings of the present disclosure will in any case contain a therapeutically effective amount of the contemplated compound, or a pharmaceutically or hygienically acceptable salt thereof, for the treatment of the disease or condition of interest.

The contemplated pharmaceutical or healthcare compositions may be in solid or liquid form. In one aspect, the carrier is particulate, such that the composition is, for example, in tablet or powder form. The carrier can be a liquid, in which the composition is, for example, an oral syrup, an injectable liquid or an aerosol, which can be used for administration, for example by inhalation.

When intended for oral administration, the pharmaceutical or nutraceutical composition is in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included within forms considered herein as solid or liquid.

As a solid composition for oral administration, the pharmaceutical or healthcare composition can be formulated into powder, granule, compressed tablet, pill, capsule, chewing gum, wafer, stick or the like. Such solid compositions will generally contain one or more inert diluents or edible carriers. Additionally, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, cyclodextrins, microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch, Lactose or dextrin; disintegrants such as alginic acid, sodium alginate, Primojel®, corn starch, etc.; lubricants such as magnesium stearate or Sterotex®; glidants such as colloidal silicon dioxide; sweeteners, Such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate, or orange flavoring; and coloring agents.

When the pharmaceutical or healthcare composition is in the form of a capsule, such as a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

The contemplated pharmaceutical or healthcare composition may be in liquid form such as elixirs, syrups, gels, solutions, emulsions or suspensions. Liquids can be used for oral administration or delivered by injection, as two examples. When intended for oral administration, useful compositions contain, in addition to a compound of the present invention, one or more of a sweetening agent, a preservative, a dye/colorant and a flavor enhancer. In compositions intended to be administered by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents may be included.

Contemplated liquid pharmaceutical or healthcare compositions, whether they are solutions, suspensions or other similar forms, may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solutions, such as physiological saline, forest Grignard solution, isotonic sodium chloride, fixed oils that can be used as a solvent or suspending medium, such as synthetic mono- or diglycerides, polyethylene glycol, glycerol, propylene glycol, or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; Such as sodium chloride or glucose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a commonly useful adjuvant. Injectable pharmaceutical or healthcare compositions are sterile.

Contemplated liquid pharmaceutical or nutraceutical compositions intended for parenteral or oral administration should contain the desired compound, pharmaceutical composition or composition in an amount such that a suitable dosage will be obtained.

The intended pharmaceutical or nutraceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, cream, lotion, ointment or gel base. For example, the base may contain one or more of petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in pharmaceutical or healthcare compositions for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoretic device.

The contemplated pharmaceutical or healthcare composition may be intended for rectal administration, for example in the form of a suppository, which will melt in the rectum and release the drug. Compositions for rectal administration may contain an oily base as a suitable non-irritating excipient. Such bases include lanolin, cocoa butter and polyethylene glycols.

Contemplated pharmaceutical or nutraceutical compositions may include various materials which modify the physical form of solid or liquid dosage units. For example, the composition may include a material that forms a coating shell around the active ingredient. The material forming the coating shell is generally inert and may be selected from, for example, sugars, shellac and other enteric coating agents. Alternatively, the active ingredient may be enclosed in gelatin capsules.

A contemplated pharmaceutical or healthcare composition in solid or liquid form may include agents that bind to the desired compound to facilitate delivery of the compound. Suitable agents that act in this capacity include monoclonal or polyclonal antibodies, proteins or liposomes.

Contemplated pharmaceutical or healthcare compositions in solid or liquid form may include reduced particle size, for example to improve bioavailability. The powders, granules, microparticles, microspheres, etc. in the composition can be, with or without excipients, macroscopic (e.g., visible to the eye or at least 100 μm in size), micron (e.g., can be ranging from about 100 μm to about 100 nm in size), nanoscale (eg, may be no larger than 100 nm in size), and any size in between or any combination thereof to improve size and packing density.

The contemplated pharmaceutical or healthcare composition may comprise or consist of dosage units which may be administered as an aerosol. The term aerosol is used to denote systems ranging from those of a colloidal nature to those consisting of pressurized packs. Delivery can be by liquefied or compressed gas or by a suitable pump system which dispenses the active ingredient. Aerosols of the disclosed compounds may be delivered as monophasic, biphasic or triphasic systems to deliver the active ingredient. Aerosol delivery includes the necessary containers, activators, valves, sub-containers, etc., which together may form a kit. Those skilled in the art can determine the most suitable aerosol formulation without undue experimentation.

The desired pharmaceutical or healthcare composition can be prepared by methods well known in the field of pharmacy or healthcare. For example, a pharmaceutical or healthcare composition intended to be administered by injection can be prepared by combining the desired compound with sterile distilled water to form a solution. Surfactants can be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with a desired compound to facilitate dissolution or uniform suspension of the compound in an aqueous delivery system.

The contemplated compounds, compositions and pharmaceutical compositions, or pharmaceutically or nutraceutical acceptable salts thereof, are administered in a therapeutically effective amount which will vary depending on a number of factors, including the activity of the particular compound employed; metabolic stability and duration of action; patient age, weight, general health, sex, and diet; mode and timing of administration; excretion rate; drug combination; severity of specific disease or condition; treat.

The contemplated compounds, compositions and pharmaceutical compositions, or pharmaceutically or hygienically acceptable derivatives thereof, may also be administered concurrently with, or after the administration of, one or more other therapeutic agents. Give before or after. Such combination therapies include the administration of a single pharmaceutical or therapeutic dosage formulation containing the desired compound and one or more additional active agents, as well as the administration of the desired compound and each active agent in its own separate pharmaceutical or therapeutic dosage formulations. For example, the contemplated compound and another active agent may be administered to a patient together in a single oral dosage composition such as a tablet or capsule, or each drug may be administered in separate oral dosage formulations. When separate dosage formulations are used, the contemplated compound and the one or more additional active agents can be administered at substantially the same time, i.e. simultaneously, or at separate staggered times, i.e. sequentially; combination therapy is It is understood to include all such schemes.

It should be understood that in this specification, combinations of substituents or variables of the described formulas are permissible only if such contributions result in stable compounds.

Those skilled in the art will also understand that in the methods described herein, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy groups include trialkylsilyl or diarylalkylsilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl ), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include C(O)R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters. Protecting groups can be added or removed according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in "Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley", the entire contents of which are incorporated herein by reference. As will be understood by those skilled in the art, the protecting group may also be a polymeric resin such as Wang resin, Rink resin or 2-chlorotrityl chloride resin.

It will also be appreciated by those skilled in the art that although such protected derivatives of the contemplated compounds may not themselves be pharmacologically active, they can be administered to a mammal and then metabolized in vivo to form pharmacologically active compounds. These derivatives can therefore be described as "prodrugs". All prodrugs of the contemplated compounds are included within the scope of this disclosure.

Furthermore, the desired compound in free base or acid form can be converted into its pharmaceutically or hygienically acceptable salt by treatment with a suitable inorganic or organic base or acid by methods known to those skilled in the art. Salts of desired compounds can be converted to their free base or acid forms by standard techniques.

In some embodiments, contemplated compounds, compositions and/or pharmaceutical compositions can be isolated from plant sources, such as those included in the Examples and elsewhere throughout this application. Suitable plant parts for isolating the desired extracts and compounds include leaves, bark, trunk, trunk bark, stem, stem bark, branch, tuber, root, root bark, bark surface (e.g., peribark or peribark) , may include cork, cork cambium, cork inner layer or any combination thereof), shoots, rhizomes, seeds, fruits, stamen clusters, pistils, calyxes, stamens, petals, sepals, carpels (gynoecium), flowers or any combination thereof. Contemplated plant extracts are derived from at least one plant part selected from the group consisting of stems, stem barks, trunks, trunk barks, shoots, tubers, roots, root barks, shoots, seeds, rhizomes, flowers and other reproductive organs, Leaves, other aerial parts, or combinations thereof. In some related embodiments, the desired compound is isolated from a plant source and synthetically modified to contain any of the described substituents. In this regard, synthetic modification of desired compounds isolated from plants can be accomplished using any number of techniques known in the art and well within the knowledge of one of ordinary skill in the art.

Example

Example 1: Animals

Breed mice weighing 25-30 g at 7-8 weeks of age were purchased from Charles River Laboratories (Wilmington, MA). Animals acclimatized for one week upon arrival before being weighed and randomly assigned to their respective groups. ICR mice (5/cage) were housed in polypropylene cages and identified individually by numbers on their tails. Each cage was covered with a wire bar lid and filtered top (Allentown, NJ). Each individual cage is identified with a cage card indicating item number, test article, dose level, group and animal number. Harlan T7087 soft cob bedding was used and changed at least twice a week. Animals were provided ad libitum with fresh water and rodent chow #T2018 (Harlan Teklad, 370W, Kent, WA) and housed in a temperature-controlled chamber (22.2°C) with a 12-hour light-dark cycle. All animal experiments were performed according to established guidelines and in accordance with the Guide for the Care and Use of Laboratory Animals.

Example 2: Animal model of liver injury induced by acetaminophen (APAP) or carbon tetrachloride (CCL4)

A balanced treatment regimen was generated and optimized to address prevention and intervention as follows: For the APAP-induced hepatotoxicity model, a 400 mg/kg dose was dissolved in warm saline (Lot# 132908 from G-Biosciences, Lot# 720729 from Quality Biological) ( APAP (Lot# MKBQ8028V from Sigma) heated to 60 ^◦ C and cooled to ambient temperature) was orally administered to overnight fasted ICR/CD-1 mice to induce toxicity. For the _CCl4- induced liver toxicity model, a dose of 25 μl/kg of _CCl4 in corn oil (Lot#SHBD5351V from Sigma) was administered intraperitoneally to overnight fasted ICR/CD-1 mice to induce toxicity. For both models, material was administered at -48hr, -24hr, -2hr prior to APAP or _CCl4 administration and +6hr after induction. Overall, mice received 3 doses before chemical induction and 1 dose after chemical induction. 10% Tween-20 (Lot# 0134C141 from Amresco), 1% CMC (Lot# NH0454 from Spectra) or 1% MC (Lot#SLBK4357V) were used as carrier vehicles for all materials. Control mice without APAP or _CCl4 received vehicle vehicle only. Serum ALT was measured at T24 (Phoenix Laboratories, Everett, WA).

Embodiment 3: the preparation of plant extract

Plants were collected and prepared with different solvents based on their active compound properties and screened in our mouse animal model of hepatotoxicity. The following 19 plants in Table 1, including different parts from 16 genera, showed different levels of serum ALT suppression in either the mouse acetaminophen-induced model or the _CCl4- induced model. Only plants with efficacy in both models will be selected for further study.

The milk thistle extract was prepared as 80% ethanol/20% water extract of milk thistle (Silybum marianum) seeds with an extraction ratio of 40-50:1. The ground seeds were extracted with 80% ethanol/20% water, and the filter cake was separated from the supernatant by filtration. The solvent was removed in vacuo to obtain a soft extract which was mixed with maltodextrin and further dried with a spray drier. The milk thistle extract is standardized to meet the specification of not less than 50% total silymarin and not less than 30% silybin. Silymarin consists of a mixture of the flavonoid lignans silybin, silybinin and silymarin. Silybin is the main active ingredient of silymarin. Standardized extracts of milk thistle seeds are commercially available.

As previously disclosed, N931 is a composition containing a unique combination of 1-4% aloesin and 96-99% 200:1 true aloe vera inner leaf gel powder polysaccharide blended by conventional methods. Aloe Vera Inner Leaf Gel Powder Polysaccharide is supplied by Aloecorp in the form of lyophilized powder. The outer bark was manually removed from freshly cleaned leaves of Aloe vera plants, then the aloe juice was collected and treated with cellulase to inactivate the enzyme. Activated charcoal is used to remove color during enzyme inactivation. The decolorized filtrate was further transferred to a freeze-drying trap to obtain true aloe vera inner leaf gel powder, which was blended with 1-4% aloesin to prepare N931.

Table 1: Summary of Plant Extracts Used for In Vivo Hepatoprotective Evaluation

Example 4: Hepatoprotective Activity of Plant Extracts on APAP and CCL4-Induced Hepatotoxicity Models

Plant material from legacy mining collected based on its historical use for liver protection and regeneration was extracted using 70% ethanol and screened for its efficacy in APAP and CCl ₄ -induced liver toxicity. Materials were orally administered to animals at the doses specified in Tables 2-3. Although most plant extracts showed inhibition of serum ALT in one model, a few plants showed efficacy in both models. Among them, Schisandra, Artemisia capillary, Milk Thistle and Loesyn were selected for further study.

Table 2: Percent Inhibition of Serum ALT by Plant Extracts in a _CCl4- Induced Hepatotoxicity Model

Table 3: Percent Inhibition of Serum ALT by Plant Extracts in APAP-Induced Hepatotoxicity Model

Example 5: Dose-response effects of selected plant extracts in the APAP model

Mulberry leaves (E1375), mulberry fruits (E1374), mulberry stems (E1377), Artemisia capillary (R0594) and Schisandra (2 %) (L0498). 10% Tween 20 was used as the carrier vehicle for all materials. Control mice without APAP received vehicle only (10% Tween 20). Serum ALT was measured at T24. As shown in Table 4 below, at a dose of 300 mg/kg, two plant materials Schisandra (2%) (L0498) and Artemisia captiva (R0594) showed 36.8% and 32.2% inhibition of serum ALT levels, respectively. These reductions were statistically significant. L0498 showed a 100% survival rate at a dose of 300 mg/kg, while R0594 had a 90% survival rate. At the lowest dose (100 mg/kg), L0498 showed only a 30% survival rate. At this dose, R0594 had a 70% survival rate. All mulberry extracts had survival rates as low as 40 regardless of dosage. These high mortality rates resulted in unclear percent reductions in serum ALT levels. Therefore, in this model, Schisandra (2%) (L0498) and Artemisia annua (R0594) can be considered as true candidates with optimal efficacy at about 300 mg/kg.

Table 4: Summary of dose-response studies using the APAP-induced hepatotoxicity model

Example 6: Dose-response effects of selected plant extracts in the _CCl4 model

Agrimony (E1399) and Loesyn (QMA2) at doses of 400 mg/kg, 300 mg/kg and 200 mg/kg and Artemisia capillary (R0594) and Schisandra (2%) (L0498) at doses of 400 mg/kg and 300 mg/kg were prepared as described above Tested in the CCl ₄ -induced hepatotoxicity model. 10% Tween-20 was used as vehicle for all materials. Control mice without _CCl4 received vehicle only (10% Tween-20). Serum ALT was measured at T24.

As shown in Table 5 below, a dose-related decrease in serum ALT levels was observed for almost all extracts. The greatest reduction in serum ALT levels was observed in mice treated with 400 mg/kg Artemisia capillary (R0594) (48.0%) followed by 300 mg/kg of the same plant material (29.9%). These reductions were statistically significant. At 400mg/kg, Agrimony and Loesyn showed a very similar level of reduction in ALT levels (ie 28%) with P values of 0.07 and 0.04, respectively. All groups had 100% survival, including the vehicle-treated CCl4 control. At least in this batch, Artemisia annua (R0594) was shown to be superior to any other tested hit in inhibiting serum ALT levels.

Table 5: Summary of dose studies using the _CCl4- induced hepatotoxicity model

Example 7: Preparation of the organic extract of Artemisia captivarii

The dry ground aerial part of Artemisia caprifolia (2.5 kg) was cut, pulverized, and then extracted with about 15 volumes (37.5 L) of 70% ethanol/water (v/v). Extraction was performed at 85°C for 3 hours. After filtration, the ethanol solution was concentrated by rotary evaporator under vacuum at 40 °C. This extraction and concentration procedure was repeated twice for 2 hours with 10 volumes (25 L) of 70% ethanol/water (v/v). The concentrated extract solution was evaporated to dryness by a vacuum drying oven to obtain 480 g of Artemisia capillary 70% ethanol extract powder (lot#RN367-3-60M), with an extraction yield of 19.2%.

Dried ground Artemisia caprifolia herb (180.4) g was extracted three times with 70% ethanol/water at reflux for 1 hour each time. The organic solutions were combined and evaporated in vacuo to provide 37.7 g of the 70% ethanol extract (R594-70EE), a yield of 20.9%. Similar results were obtained using the same procedure, but replacing the organic solvent with methanol or ethanol to provide methanol extract (ME) or ethanol extract (EE), ethanol: _H2O (7:3) extract, ethanol:H ₂ O (1:1) extract, ethanol:H ₂ O (3:7) extract and water extract. The solvent extraction procedure is summarized in Table 6.

Table 6: Summary of Solvent Extraction of the Dry-Milled Aerial Fraction of Artemisia caprifolia sample code extraction solvent Extraction yield (%) R684-100EE 100% EtOH 11.7 R684-70EE 70% EtOH 19.2 R684-50EE 50% EtOH 22.5 R684-30EE 30% EtOH 22.9 R684-W water 25.7 R594-70EE 70% EtOH 20.9 RN425-6-70EE 70% EtOH 17.9 RN425-7-70EE 70% EtOH 18 RN425-8-70EE 70% EtOH 17.4 RN425-11-70EE 70% EtOH 19.2 RN425-12-70EE 70% EtOH 19.2 RN425-13-70EE 70% EtOH 19.2 RN425-14-70EE 70% EtOH 19.1

Example 8: Bioassay-Guided Fractionation of Artemisia annua Extracts

A 70% ethanol extract of Artemisia caprifolia (RN425-7-70EE, 20 g) was partitioned three times between hexane (200 mL) and water (250 mL). The combined hexane solutions were freed of solvent by vacuum to give the hexane extract (HE) 1.43 g. The aqueous layer was extracted three times with ethyl acetate (200 mL). The combined ethyl acetate layers were dried in vacuo to obtain 2.29 g of ethyl acetate extract (EA). The aqueous layer was further extracted three times with butanol (200 mL) to obtain 3.70 g of butanol extract (BU). The remaining water layer was freeze-dried to obtain 15.3 g of a water extract (WA). 70% EE and HE, EA, BU and WA were tested in a _CCl4 -induced mouse liver toxicity model. HE, EA, BU were inactive, while 70% EE showed 25.27% ALT inhibition at 400mg/kg, and 37.49% inhibition at 300mg/kg level in WA fraction, P≤0.05.

The active fraction WA was further isolated by HP20SS chromatography. WA (4.4 g) was dissolved in 20% EtOH/water and loaded onto a column of HP20SS (Diaion, Mitsubishi Chemical Corporation, Japan, 160 g) preconditioned with 20% EtOH/water. The column was eluted with 800mL 20%EtOH/water, 600mL 40%EtOH/water, 400mL 60%EtOH, 200mL 80%EtOH, and finally washed with 200mL EtOH and 200mL acetone. Two major fractions, HP-01 (3.67 g, 83.4%) and HP-02 (305.7 mg, 6.95%) were collected and tested in a mouse model of CCl4-induced hepatotoxicity. The main components of HP-01 are oligosaccharides and polysaccharides. HP-02 mainly contains polyphenols. HP-01 showed similar ALT inhibition compared to WA with 32.86% inhibition at 300 mg/kg. HP-02 was inactive in the same model, indicating that polyphenols did not contribute to the plant's activity.

Active fraction HP-01 was further separated by LH-20 open column. HP-01 (1.06 g) was dissolved in water and loaded onto a LH-20 column preconditioned in water, eluted with a MeOH/HO gradient to obtain 4 fractions, LH-01 (43.4 mg, 4.26%), LH-02 (799.6 mg, 78.5%), chlorogenic acid (LH-03, 45.4 mg, 4.5%) and LH-04 (23.1 mg, 2.27%). Due to sample limitations, only the main fraction LH-02 was tested in the in vivo study. LH-02, 78.5% HP-01 did not show any efficacy in _CCl4- induced animal model at 300mg/kg level. Chlorogenic acid (C3878, Sigma-Aldrich, USA), a constituent of HP-01 at a rate of about 4.5%, did not show any inhibition when tested at a level of 200 mg/kg. The in vivo data of this study clearly show that water-soluble components other than chlorogenic acid and polyphenols are responsible for the hepatoprotective activity of Artemisia extracts. The active polysaccharide content is less than 10% of the WA fraction. Table 7 summarizes this information.

Table 7: Hepatoprotective Efficacy of R684-70EE Fractions and Compounds sample code Dose (mg/kg) CCl4 dose % change in ALT p-value R684-70EE 400 25 25.27 0.040 R684-HE 300 25 -2.26 0.864 R684-EA 300 25 13.78 0.359 R684-BU 300 25 14.96 0.219 R684-WA 300 25 37.49 0.003 HP-01 300 25 32.86 0.054 HP-02 300 25 -10.03 0.537 LH-02 300 25 -0.73 0.961 Chlorogenic acid 200 25 -24.14 0.192

Example 9: Separation of Active HP-1 Samples by Membrane Dialysis Fraction

The hepatoprotective fraction-HP-01 shown in Example 8 and Table 7 from Artemisia annua was dissolved in an appropriate volume of distilled water, and was dialyzed against distilled water (cut-off molecular weight 2000) in a dialysis membrane tube, every 3 hour, 3 times. The retained and pooled dialysis solutions were lyophilized to yield two samples DA-1 (MW>2000, 13.79%) and DA-2 (MW<2000, 84.54%). DA-2 was further dialyzed to a molecular weight cutoff of 500 following the same procedure as the previous dialysis. DA-3 (500<MW<2000, 16.7%) and DA-4 (MW<500, 79.7%) were collected. DA-1, DA-3 and DA-4 were tested in a CCl4-induced mouse model. DA-1 with a molecular weight greater than 2000 had the strongest inhibitory effect on serum ALT levels, which was statistically significant compared with DA-3 and DA-4. Molecular weights below 500 did not show any efficacy in this in vivo model. Table 8 summarizes this information.

Table 8: Hepatoprotective Efficacy of Dialyzed Samples of HP-01 sample code molecular weight content% Dose (mg/kg) CCl4 dose % of ALT lowered p-value DA-1 MW>2000 13.79% 300 25 47.47 0.04 DA-3 500<MW<2000 16.7% 300 25 39.19 0.09 DA-4 MW<500 79.7% 300 25 -14.14 0.441

Example 10: HPLC Analysis and Quantification of Artemisia captiva Extract

Based on LCMS analysis and literature reports, the marker compounds chlorogenic acid (1, C3878, Sigma-Aldrich, USA) and dicaffeoyl acid (2-3) in the extract of Artemisia caprifolia were identified, and the C18 reversed-phase column (Phenomenex , Luna C18, 10 µm, 250 mm x 4.6 mm) were quantified at a UV wavelength of 320 nm on a Hitachi HPLC system. The column was eluted with a binary gradient of 0.1% trifluoroacetic acid (TFA)/water and acetonitrile at a flow rate of 1 mL/min. Compounds 1-3 were quantified based on the reference compound chlorogenic acid. Based on the calculation of peak areas, the content of chlorogenic acid in 70% EE of Artemisia caprinari collected from different sources varied in the range of 1.5–4.8% (w/w). This information is summarized in Tables 9-10.

Table 9: HPLC Gradient Table for Artemisia Analysis time (min) 0.1% TFA/H ₂ O (%) ACN (%) 0 90 10 5 90 10 15 80 20 30 60 40 31 0 100 34 0 100 34.1 90 10 40 90 10

Table 10: Chlorogenic acid* content in 70% ethanol extract of Artemisia capillary Sample ID 1 (%) 2 (%) 3 (%) Total 1-3 (%) R684-70EE 4.72% 3.57% 2.35% 10.63% R594-70EE 1.56% 1.51% 0.72% 3.80% L0523 3.12% 1.48% 1.73% 6.33% Honsea 2.31% 2.60% 3.32% 8.23% E1466 4.55% 3.02% 2.18% 9.76% E1453 1.83% 1.17% 1.13% 4.13% RN425-6-70EE 4.17% 2.33% 2.07% 8.56% RN425-7-70EE 3.97% 2.60% 2.34% 8.91% RN425-8-70EE 3.90% 2.57% 2.26% 8.73% RN425-11-70EE 3.14% 3.30% 2.10% 8.54% RN425-12-70EE 5.05% 3.56% 2.52% 11.12% RN425-13-70EE 3.60% 3.49% 2.02% 9.11% RN425-14-70EE 4.79% 4.12% 2.08% 11.00%

*Chlorogenic acid was used as a standard compound for the quantification of all three peaks (1-3)

Example 11: Quantification of catechins in Artemisia capillaris extract

The catechins in the water fraction (WA) of the Artemisia caprifolia extract were quantified by the HPLC method. Catechins were detected and quantified using a Hitachi HPLC/PDA system with a C18 reversed-phase column (Phenomenex, USA, Luna 5 um, 250 mm x 4.6 mm), with a flow rate of 1.0 mL/min, column temperature of 35 °C, and UV wavelength 275nm. No epicatechin (E1753, Sigma-Aldrich, USA) was detected in all Artemisia samples, and only low levels of catechin were detected and quantified based on a catechin standard (C1251, Sigma-Aldrich, USA). Based on the results of our in vivo study, the catechin content in the range of 0.02-0.32% in the WA fraction of the Artemisia caprifolia extract was not related to the hepatoprotective properties of the Artemisia capillaris extract. This information is summarized in Tables 11-12.

Table 11: Gradient Table for HPLC Analytical Method time (min) 0.1% H ₃ PO ₄ /H ₂ O (%) ACN (%) 0.0 85.0 15.0 7.0 85.0 15.0 12.0 10.0 90.0 16.5 10.0 90.0 16.6 85.0 15.0 24.0 85.0 15.0

Table 12: Quantification of catechins in Artemisia annua extracts

Example 12: Separation of polysaccharides by membrane dialysis

The crude polysaccharide of HP-01 from Artemisia capriculum was dissolved in an appropriate volume of distilled water, and dialyzed against distilled water (cut-off molecular weight 2000) in a dialysis membrane tube for 3 hours each time, three times. The retained and pooled dialysis solutions were lyophilized to yield two samples, DA-1 (MW>2000, 13.79%) and DA-2 (MW<2000, 84.54%). Both samples were tested in the _CCl4 -induced mouse model.

Example 13: Analysis and quantification of polysaccharides by gel permeation chromatography

The active fraction WA of the Artemisia annua extract was also analyzed by gel permeation chromatography, a well-established method for evaluating the molecular weight distribution of polysaccharides. PolySep-SEC-P5000 column (Phenomenex, OOH-3145KO column, 300 mm x 7.8 mm) was used to analyze Artemisia caprubilis polysaccharides by Hitachi HPLC system equipped with a refractive index detector. The mobile phase was 0.1M NaCl at a flow rate of 0.7 mL/min for 25 minutes. For each sample, 20 μL was injected at a concentration of 10 mg/mL. Based on six dextran molecular weight standards (American Polymer Standards), divided into > 2000, 2000-1000, 100-500, 500-200, 200-50, 50-10, < 10 KDa Polysaccharides were quantified within seven ranges. The molecular weight distributions of the water fraction samples of different extracts were different. Hepatoprotective activity is associated with higher molecular distribution. Although the total polysaccharide content was similar, the weight distribution of the samples of Artemisia caprifolia samples was very different. The higher the content of the larger polysaccharides, the better the efficacy observed for Artemisia annua. The molecular weight distribution is shown in Table 13.

Table 13: Molecular weight distribution of biopolymers in Artemisia extracts MW distribution (kDa) >2000 2000-1000 1000-500 500-200 200-50 50-10 < 10 PSD (%) E1453-WA 1.2 6.6 11.7 16.9 38.2 25.3 0 0.36 L523-WA 0 0 0 13 82.7 4.3 0 0.33 E1466-WA 60.9 14.2 14.6 10.2 0.1 0 0 0.30 R594-WA 0 0 0 0 0 0 0 0.31

Example 14: Hepatoprotective Activity of Artemisia captiva Fraction on CCl ₄ Model

The hepatoprotective activity of Artemisia capcari fractions in hexane (HE), ethyl acetate (EA), butanol (BU) and water was evaluated using a _CCl4- induced hepatotoxicity model. Control mice received only 10% Tween-20. Serum ALT was measured at T24. While the Artemisia fraction was dosed at 300 mg/kg, the starting material was dosed at 400 mg/kg.

As shown in Table 14, the highest inhibition of serum ALT was observed in mice treated with the aqueous fraction of Artemisia at a dose of 300 mg/kg, suggesting the possibility of active markers being present in this fraction. However, this does not exclude the presence of other markers of activity in other fractions. The original material (R684) maintained its efficacy at a dose of 400mg/kg. All groups in this model had 100% survival.

Table 14: Activities of Artemisia capillary fractions Group N Material ID Dose (mg/kg) CCl ₄ (µl/kg) % ALT change P -value G-1 5 Control (-) - 0 0 - - G-2 10 _CCl4 - 0 25 - - G-3 10 R684-HE RN425-7-HE 300 25 -2.3 0.864 G-4 10 R684-EA RN425-7-EA 300 25 13.8 0.359 G-5 10 R684-BU RN425-7-BU 300 25 15.0 0.219 G-6 10 R684-WA RN425-7-WA 300 25 37.5 0.003 G-7 10 R684 R684 400 25 25.3 0.040

Example 15: Preparation of Schisandra Fruit Organic Extract

A total of 20 g of Schisandra dried fruit was loaded into two 100 ml stainless steel tubes and extracted twice with organic 70% EtOH/water using an ASE 300 automatic extractor at 80 degrees and 1500 psi pressure. The extraction solution is automatically filtered and collected. The combined solution was evaporated to dryness by rotary evaporator to give crude 70% EtOH extract (9.65 g, 49.5%).

Similar results were obtained using the same procedure, but replacing the organic solvent with methanol or ethanol to provide methanol extract (ME) or ethanol extract (EE), ethanol: _H2O (7:3) extract, ethanol:H ₂ O (1:1) extract, ethanol:H ₂ O (3:7) extract and water extract.

Schisandra extract was prepared by extracting dried fruits with 70% ethanol/30% water (v/v). The extract was further processed to obtain an extract in powder form (Lot#) with not less than 2% total schisandrin, including schisandrin, schisandrin ester A, schisandrin A (deoxyschisandrin) and schisandrin B.

Example 16: HPLC Analysis and Quantification of Schisandra Extract

Four active marker compounds Schisandrin (lot #110857, National Institute for Food and Control, China), schisantherin A (lot #11529-200503, National Institute for Food and Control, China), Schisandrin A (deoxyschisandrin, lot # 110764-200107, National Institute for Food and Control, China) and schisandrin B (lot #110765-200508, National Institute for Food and Control, China) were identified in Schisandra extracts and compared with Schisandra reference standard material (lot #140217, National Institute for Food and Control, China) confirmed.

Active marker compounds were quantified by HPLC on a Hitachi HPLC system using a C18 reversed-phase column (Phenomenex, Luna C18, 10µm, 250 mm x 4.6 mm) at a UV wavelength of 250 nm by comparison with reference standard materials. The column was eluted with water and acetonitrile at a flow rate of 1 mL/min. Table 15 shows the gradient table for this example. The individual peaks were identified and integrated, and then the total content of the four compounds, including schisandrin, schisantherin A, schisandrin A, and schisandrin B, was calculated based on RSM, and the information is shown in Table 16.

Table 15: HPLC mobile phase gradient table for quantification of Schisandra chinensis extract time (min) _H2O (%) ACN (%) 0 40 60 10 20 80 25 0 100 30 0 100 30.1 40 60 35 40 60

Table 16: Schizandrin content in Schisandra extract sample code Schizandrin schisantherin A deoxyschisandrin Schisandrin B total schisandrin L531 0.03% 0.87% 0.07% 0.04% 1.01% L0498 1.16% 0.10% 0.23% 0.58% 2.07% L499 3.80% 0.69% 0.77% 1.84% 7.10%

Example 17: HPLC Quantification of Organic Acids in Schisandra Fruit Extract

The presence of malic acid, shikimic acid and citric acid in 70% EtOH extracts generated in-house from different collections has been confirmed and listed in Table 17. Quantitative analysis of organic acids by HPLC using a Hypersil GOLD aQ column (4.6x250mm, 5 µm) at 5 °C for 20 min under isocratic conditions with 50 mM potassium dihydrogen phosphate (pH adjusted to _2.8 with _H3PO4 ) as flow Phase, the flow rate is 0.7ml/min. Organic acids were detected using a UV detector at 205 nm and identified based on retention time by comparison with organic acid standards.

Table 17: HPLC quantification of organic acid content in Schisandra extract

Example 18: Artemisia and Schisandra Extracts in Different Combinations for Liver Protection in APAP and _CCl4 Models

Once lead plants such as Artemisia annua and Schisandra were selected, they were evaluated at different combination ratios of 4:1, 2:1, 1:1, 1:2 and 1:4 in the APAP and _CCl4- induced hepatotoxicity model Efficacy in liver protection. The combination of two plants is coded as "SA" by the first letter of each plant, that is, "S" is Schisandra, and "A" is Artemisia capillary. As shown in Table 18 below, while all blends showed some hepatoprotection, serum ALT levels were observed when mice were treated with a 2:1 ratio blend of Schisandra and Artemisia at a total dose of 400 mg/kg A reduction of 48.0% was measured, the most statistically significant protective effect. Similarly, in the _CCl4 model, when mice were treated with a 1:2 ratio blend of Schisandra and Artemisia at a total dose of 400 mg/kg, a measured 40.6% reduction in serum ALT levels was observed for The largest hepatoprotective effect with statistical significance. In both models, the survival rate at this particular rate is 100%.

Table 18: Efficacy of composition SA in APAP/CCl ₄ induced liver toxicity model

The highest hepatoprotective efficacy was observed when Schisandra and Artemisia were blended at 2S:1A (APAP model) and 1S:2A ( _CCl4 model). As a result, these ratios are considered to be selected.

Example 19: Preparation of Combination SAL Compositions

By using a ribbon blender (Ribbon blender) (Hankook P.M. EMG, Korea) at 30rpm to blend 320g Schisandra extract (lot #E1458), 263g Artemisia extract (lot#RN425-13), 377g Artemisia extract (lot #RN425-14) and 240 g of N931 (E1459 2% aloesin) for 1 hour to obtain a SAL combination (lot#RN425-1501) at a ratio of 1.17 kg for Schisandra:Artemisia:N931=4:8:3 weight, The intended SAL combination composition (lot#RN425-1501) was thus prepared.

Example 20: Evaluation of the hepatoprotective activity of a blend of Schisandra, Artemisia capillary and N931 in the APAP/CCl ₄ model

Two lead blend ratios of Schisandra chinensis and Artemisia captiva were selected at 2S:1A (APAP model) and 1S:2A ( _CCl4 model), and further hepatoprotective activity was obtained by adding a third lead component (Loesyn) , named SAL. The "L" stands for Loesyn. N931 was added at 10, 20 and 30% by weight to the 2S:1A combination and at 10, 20 and 25% by weight to the 1S:2A combination. The composition was tested in the APAP/ _CCl4 induced liver toxicity model. Mice were treated with the composition SAL at a dose of 400 mg/kg. Although all compositions of different ratios showed some degree of liver protection, as shown in Table 19, when mice were treated with SAL at a dose of 400 mg/kg at ratios of 106.7/213.3/80, the greatest decrease in serum ALT was observed ( 51.9%, P=0.01), so the protective effect is the largest. In this model, there is a 100% survival rate at this particular rate.

Similarly, although all compositions at different ratios showed some degree of liver protection, as shown in Table 19, serum ALT decreased the most (42.3%, P=0.01). In this model, there is a 100% survival rate at this particular rate.

Table 19: Efficacy of composition SAL in APAP/CCl ₄ induced liver toxicity model

Although various compositions showed hepatoprotective efficacy, the highest protection was observed when 20% by weight Loesyn was added to the 1S:2A ratio in both models to obtain the final 4S:8A:3L ratio of the composition SAL. As a result, the ratio 4S:8A:3L was considered the lead composition.

Example 21: Dose-response effects of compositions comprising Schisandra, Artemisia capillary and N931 in APAP and _CCl4 -induced hepatotoxicity models

Optimal doses of the composition SAL that would cause significant hepatoprotection were evaluated in APAP and CCl ₄ -induced models. Mice were orally gavaged the composition SAL at doses of 400mg/kg, 325mg/kg and 250mg/kg suspended in 10% Tween-20. The vehicle control group received vehicle solution only. As shown in Table 20, dose-related inhibition of serum ALT was observed with the composition in the APAP group. Suppression of 52.5% (p=0.001), 48.5% (p=0.012) and 34.6% (p=0.079) was observed in mice treated with doses of 400mg/kg, 325mg/kg and 250mg/kg SAL, respectively. Similarly, in the CCl ₄ group, a dose-related inhibition of serum ALT was observed for the composition. Suppression of 46.3% (p=0.003), 39.5% (p=0.007) and 29.9% (p=0.036) was observed in mice treated with doses of 400mg/kg, 325mg/kg and 250mg/kg SAL, respectively. All groups in both models had 100% survival. Composition SAL provided statistically significant (CCL4) protection from liver injury at dose levels as low as 250 mg/kg at a ratio of 1S:2A with 20% L.

Here we tested the efficacy of individual plants such as Schisandra, Artemisia and Loesyn at doses equal to the ratio of each plant in the composition SAL as they were at the highest tested dose (400 mg/kg) in the ratio 4S:8A:3L Appear. As shown in Table 20, an average of 20% inhibition and 70-80% survival of these plants was observed at the given doses.

Table 20: Dose-related hepatoprotection of the composition SAL in APAP/ _CCl4 -induced hepatotoxicity model

Example 22: Evaluation of Composition SAL Synergy

The benefit of combining Schisandra, Artemisia captiva and N931 in APAP and CCL4 models was assessed using the Colby equation (Colby, 1967). As shown in Table 21 below, the observed values in both models were greater than the expected hypothetical values (A+BC), suggesting a synergistic effect when the three components were formulated in specific ratios to produce SAL. The advantage of blending Schisandra, Artemisia and N931 was confirmed by its synergistic protection against liver damage caused by APAP and _CCl4 .

Table 21 : Unexpected synergistic activity of Schisandra, Artemisia annua and N931 in liver protection.

Example 23: Hepatoprotective activity of a SAL composition at a dose of 300 mg/kg relative to its individual components

Using the APAP and _CCl4- induced hepatotoxicity model, the hepatoprotective activity of the SAL composition at a dose of 300 mg/kg was compared against its individual components, using reduced serum ALT levels as a measure of efficacy. 10% Tween-20 was used as the carrier vehicle for all materials. Control mice received Tween-20 only. In addition to serum ALT, control, APAP/CCl ₄ , liver function panels of SAL such as T protein, T bilirubin, albumin, AST and bile acids were measured at T24.

Table 22: Serum ALT levels in APAP and CCl ₄ -induced liver toxicity model of composition SAL and individual components at a dose of 300 mg/kg

As seen in Tables 23 and 24, AST as a measure of efficacy, the composition (SAL) showed enhanced protection from liver injury (ie 60.6%) in the APAP model compared to vehicle. Statistically significant decreases of 47.1, 42.2, 42.0 and 16.6% in serum ALT were observed in mice treated with SAL, S (Schisandra), A (Artemisia) and L (N931 ), respectively, compared to the vehicle group. The lowest survival rate (50%) was observed for mice treated with Artemisia.

Confirming the results of the APAP model, the composition SAL at a dose of 300 mg/kg showed a greater hepatoprotective effect than each individual component in the _CCl4 model, using serum ALT as a measure of efficacy. Furthermore, using AST as a measure of efficacy, the composition (SAL) showed enhanced damage protection (ie, 32.5%) over vehicle. All groups had 100% survival in this model.

Table 23: Panel markers of liver function compared to vehicle-treated mice in the APAP model

As shown in Table 24, the composition SAL showed improved liver-related biomarkers such as bile acids, T. bilirubin, and T. protein in the APAP model compared to vehicle-treated APAP-positive mice. Similarly, statistically significant clearance of bile acids was observed in mice treated with the composition SAL in the _CCl4 model compared to the vehicle group.

Table 24: Panel markers of liver function compared to vehicle-treated mice in the _CCl4 model

Example 24: Efficacy Confirmation Study of Composition SAL in APAP and CCL4 Induced Hepatotoxicity Model

Demonstrating the superiority of the hepatoprotective activity of the composition SAL, confirmatory studies were performed using models of APAP and _CCl4- induced hepatotoxicity. Mice were orally gavaged with 400 mg/kg composition SAL. 10% Tween-20 was used as the carrier vehicle for all materials. Control mice received Tween-20 only. In addition to serum ALT, control, APAP/CCl ₄ , liver function panels of SAL such as T. protein, total bilirubin, direct and indirect bilirubin, albumin, globulin, AST, bile acid and ALP.

As shown in Tables 25 and 26 below, statistically significant suppression of serum ALT, AST, conjugated bilirubin and bile acids was observed in mice treated with the composition SAL. These inhibitions were 34.0%, 44.5%, 60.0% and 26.7% reduction compared to the vehicle treated group. Similarly, composition SAL showed a statistically significant reduction in serum ALT levels (44.0% reduction) and a strong trend toward reduction in AST (35.9% reduction) compared to vehicle-treated mice. Overall, the composition SAL provided greater protection from liver injury in various commonly used animal models, as shown in Table 27.

Table 25: Summary of liver function panel analyte levels in mice treated with SAL in the APAP-induced hepatotoxicity model.

Table 26: Summary of liver function panel analyte levels in mice treated with SAL in the CCl ₄ -induced liver toxicity model.

Table 27: Summary of percent change in liver function panel markers in the SAL group compared to vehicle-treated mice in the APAP/CCl ₄ model.

(+): ↓Reduced relative to APAP/CCl ₄ (+) vehicle

(-): ↑Increased relative to APAP/CCl ₄ (+) vehicle

Example 25: Effect of Composition SAL on Oxidative Stress Biomarkers in Liver Homogenates Collected from _CCl4 -Induced Hepatotoxicity Model

Additional confirmatory assays were performed using a _CCl4- induced hepatotoxicity model to assess the effect of the composition SAL in protecting the liver. Mice were orally gavaged with 400 mg/kg composition SAL. Use 10% Tween 20 as the carrier vehicle. Control mice received Tween 20 only. Liver tissue was collected immediately after necropsy and placed on dry ice until transferred to -80°C. The material was then shipped on dry ice to a contract laboratory (Brunswick Laboratories, 200 Turnpike Rd, MA 01772, USA) for final sample processing and biomarker analysis. Hepatic glutathione (GSH) and superoxide dismutase (SOD) were assessed.

Glutathione (GSH) is a key intracellular tripeptide thiol that helps protect cells from free radical damage by providing reducing equivalents to reduce lipid hydroperoxides. During this process, oxidized glutathione (GSSG) is formed as a reaction product. GSH levels have been used as an indicative biomarker of oxidants in the body and levels of oxidative stress in cells and tissues. In this assay, the sulfhydryl group of GSH reacts with DTNB (5,5'-dithio-bis-2-(nitrobenzoic acid)) to produce a yellow 5-mercapto-2-nitrobenzoic acid (TNB) product. The amount of GSH in biological samples was determined by measuring the absorbance of TNB at 410 nm.

Superoxide dismutase (SOD) is a metalloenzyme that catalyzes the dismutation of superoxide anion into molecular oxygen and hydrogen peroxide. SOD is considered to be one of the most important antioxidant enzymes in the body. The SOD assay is a colorimetric assay that utilizes tetrazolium salts to measure the disproportionation of superoxide radicals induced by xanthine oxidase and xanthine, and quantifies the amount of oxidase in a given sample by using a standard curve generated with SOD standards. SOD activity. One unit of SOD is defined as the amount of enzyme required to exhibit 50% disproportionation of superoxide radicals.

As shown in Table 28 below, the composition SAL supplemented depleted hepatic glutathione, in conjunction with increasing hepatic superoxide dismutase, using per gram protein levels of each biomarker tested. These findings, together with previously published liver function panel data, strongly suggest that the composition SAL has hepatoprotective activity against oxidative stress caused by CCL4-induced liver injury.

Table 28: Oxidative stress biomarker levels in liver homogenates of mice treated with the composition SAL

Example 26: Evaluation of Hepatoprotective Activity of Blends of Astragalus, Schisandra, and Artemisia captiva at Specific Ratios in a _CCl4- Induced Hepatotoxicity Model

The hepatoprotective activity of the combination consisting of two additional lead plant extracts was also evaluated in a _CCl4- induced mouse hepatotoxicity model. Astragalus Membranous was combined with Schisandra or Artemisia caprifolia in ratios of 1:1, 1:2, 2:1, 1:4 and 4:1. As shown in Table 29, only one ratio, 1:4, showed a statistically non-significant (34.1%) reduction in serum ALT when Astragalus was blended with Schisandra compared to vehicle-treated lesioned mice. In contrast, a higher degree of liver protection was observed when astragalus was combined with artemisia. A statistically significant 46.3% and 57.7% inhibition of serum ALT was observed for the 2:1 and 4:1 ratios of Astragalus:Artemisiae, respectively. There was 100% survival at all rates tested in this model.

Table 29: Data summary of serum ALT levels in mice in a CCL4-induced hepatotoxicity model treated with specific ratios of Astragalus, Schisandra, and Artemisiae

Accordingly, specific embodiments and methods of compounds and compositions for liver health management have been disclosed, including stereoisomers, pharmaceutically or nutraceutical acceptable salts, tautomers, glycosides and pro- Medicines, and related methods for improving and maintaining liver health. It will be apparent, however, to those skilled in the art that many more modifications than those already described can be made without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be limited except within the spirit disclosed herein. Furthermore, when interpreting the specification and claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprising" and "comprising" should be interpreted as referring to elements, components or steps in a non-exclusive manner, indicating that the mentioned elements, components or steps can be combined with other elements, components or steps not explicitly mentioned, Components or steps are present, utilized or combined together.

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Claims (38)

1. A composition for treating the liver and maintaining liver health comprising a mixture of plant extracts, wherein the plant extracts comprise at least one Artemisia extract, at least one Aloe Gel powder and at least one Schizandra extract. 2. A composition for the treatment and maintenance of liver health comprising a mixture of plant extracts derived from Artemisia extracts enriched in at least one polymer or biopolymer, enriched in Aloe vera gel powder of at least one chromone and Schisandra extract enriched in at least one lignan and organic acid. 3. The composition of claim 1, wherein the Artemisia extract and Schisandra extract are blended in a weight ratio of 4:1 to 1:4. 4. The composition of claim 1, wherein the Aloe vera gel powder is further blended with a mixture of Artemisia and Schisandra extracts at a weight percentage of about 5% to about 50%. 5. The composition according to claim 1, wherein the ratio of the mixture of Artemisia, Schisandra and Aloe leaf gel powders is 8:4:3. 6. The composition of claim 2, wherein the Artemisia extract comprises 0.01% to 99.9% of biopolymers with a molecular weight above 500. 7. The composition according to claim 1, wherein the Artemisia extract comprises Artemisia absinthium, Artemisia abrotanum L., Artemisia afra, Artemisia annua L), Artemisia arborescens, Artemisiaasiatica, Artemisia campestris, Artemisia deserti, Artemisiaiwayomogi, Artemisia ludoviciana, Artemisia vulgaris, Artemisiaoelandica, Artemisia princeps Pamp ), Artemisia sacrorum, Artemisia scoparia, Artemisia stelleriana, Artemisia frigidaWilld, Artemisia anethoides Mattf., Artemisia anethifolia Weber., Artemisia faurier Nakai, Origanum vulgare, Siphenostegia chinensis or any combination thereof. 8. The composition according to claim 1, wherein the Artemisia extract is selected from the group consisting of Artemisia absinthium, Artemisia abrotanum L., Artemisia afra, Artemisia annua L), Artemisia arborescens, Artemisiaasiatica, Artemisia campestris, Artemisia deserti, Artemisiaiwayomogi, Artemisia ludoviciana, Artemisia vulgaris, Artemisiaoelandica, Artemisia princeps Pamp), Artemisia sacrorum, Artemisia scoparia, Artemisia stelleriana, Artemisia frigidaWilld, Artemisia anethoides Mattf., Artemisia anethifolia Weber., Artemisia faurier Nakai, Origanum vulgare, Siphenostegia chinensis or any combination thereof. 9. The composition of claim 2, wherein the one or more biopolymers are extracted from Artemisia plants with water, methanol, ethanol, alcohol, water mixed solvents, or combinations thereof. 10. The composition according to claim 1, wherein said Aloe gel powder comprises Aloe arborescens, Aloe barbadensis, Aloe cremnophila, Aloeferox, Aloe saponin saponaria), true aloe (Aloe vera), Chinese aloe (Aloe vera var. chinensis) or combinations thereof. 11. The composition of claim 2, wherein the at least one chromone composition comprises from about 0.01% to about 100% of one or more chromones. 12. The composition according to claim 2, wherein said at least one chromone is selected from the group consisting of aloesin, aloesinol, aloe resin A, aloe resin B, aloe resin C, aloe resin D, aloe resin E or any combination thereof. 13. The composition of claim 2, wherein the chromone composition comprises from about 1% to about 4% aloesin, wherein the composition is substantially free of anthraquinones and wherein the aloe vera gel is derived from is isolated from a plant selected from Aloe vera or Aloe vera; and wherein said at least one chromone is isolated from Aloe vera or Aloe vera or any combination thereof. 14. The composition according to claim 1, wherein the Schisandra genus comprises Schisandra chinensis, Schisandra elongate, Schisandra glabra, Schisandra glaucescens, Schisandra henryi, Schisandra incarnate, Schisandra incarnate ( Schisandra lancifolia), Schisandra neglecta, Schisandra nigra, Schisandra propinqua, Schisandra pubescens, Schisandra repanda, Schisandra rubriflora, Schisandra rubrifolia, Schisandra sinensis, Schisandra sphaerandra, Schisandra sphenanthera, Schisandra tomentella, Schisandra tuberculata, Schisandra vestita, Schisandra viridis, Heqing Schisandra wilsoniana or combinations thereof. 15. The composition according to claim 2, wherein said at least one lignan isolated from an extract of the genus Schisandrin is Schizandrin, DeoxySchisandrin, γ-Schisandrin, Pseudo-γ-Schisandrin, Schizandrin B, Schizandrin C, Isschisandrin, Pregomisin, eoschizandrin, Schisandrin, Schisandrin A, Schisandrin B, Schisandrin Ester A, B, C, D, E, Safflower Schisandrin Ester, Schisandrin Acetate ( Schisanhenol acetdte), schisandrin B, schisandrin, gomisin A, B, C, D, E, F, G, H, J, N, O, R, S, T, U, epigomisin O, Angeloylgomisin H, O, Q, T, igloylgomisin H, P, angeloylisogomisin O, benzoyl-gomisin H, O, P, Q, benzoyl-isogomisin or its combination. 16. The composition of claim 2, wherein the at least one organic acid isolated from a Schisandra extract comprises malic acid, citric acid, shikimic acid, or combinations thereof. 17. The composition of claim 1, wherein the plant extract is derived from at least one plant part selected from the group consisting of stem, stem bark, trunk, trunk bark, branch, tuber, root, root bark, Shoots, seeds, rhizomes, flowers and other reproductive organs, leaves, other aerial parts or combinations thereof. 18. The composition of claim 2, wherein the plant extract is derived from at least one plant part selected from the group consisting of stem, stem bark, trunk, trunk bark, branch, tuber, root, root bark, Shoots, seeds, rhizomes, flowers and other reproductive organs, leaves, other aerial parts or combinations thereof. 19. The composition of claim 1, wherein the composition additionally comprises at least one hepatoprotective agent. 20. The composition according to claim 2, wherein said composition additionally comprises at least one hepatoprotective agent. 21. The composition according to claim 19, wherein the hepatoprotective agent comprises milk thistle, turmeric, Bupleurum, licorice, sage, mulberry, aurantium aurantium, agrimony, thorn, lyceum, citrus, plum, Plant powder or plant extract of yellow plum, Korea gim, dandelion, grape, grape seed, raspberry, camellia, green tea, krill oil, yeast, soybean; isolated and enriched silymarin, flavonoids, phospholipids, thios, pycnogenol Peel, Gelatin, Soy Lecithin, Pancreatin; Natural or Synthetic N-Acetyl Cysteine, Taurine, Riboflavin, Niacin, Pyridoxine, Folic Acid, Carotene, Vitamin A, Vitamin B2, B6 , B16, vitamin C, vitamin E, glutathione, branched-chain amino acids, selenium, copper, zinc, manganese, coenzyme Q10, L-arginine, L-glutamine, phosphatidylcholine, or combinations thereof. 22. The composition according to claim 20, wherein the hepatoprotective agent comprises milk thistle, turmeric, Bupleurum, licorice, sage, mulberry, aurantium aurantium, agrimony, thorn, lyceum, citrus, plum, Plant powder or plant extract of yellow plum, Korea gim, dandelion, grape, grape seed, raspberry, camellia, green tea, krill oil, yeast, soybean; isolated and enriched silymarin, flavonoids, phospholipids, thios, pycnogenol Peel, Gelatin, Soy Lecithin, Pancreatin; Natural or Synthetic N-Acetyl Cysteine, Taurine, Riboflavin, Niacin, Pyridoxine, Folic Acid, Carotene, Vitamin A, Vitamin B2, B6 , B16, vitamin C, vitamin E, glutathione, branched-chain amino acids, selenium, copper, zinc, manganese, coenzyme Q10, L-arginine, L-glutamine, phosphatidylcholine, or combinations thereof. 23. The composition according to claim 1, wherein said composition further comprises a pharmaceutically or healthcare acceptable carrier, diluent or excipient. 24. The composition according to claim 2, wherein said composition further comprises a pharmaceutically or healthcare acceptable carrier, diluent or excipient. 25. The composition of claim 1, wherein the composition comprises from about 0.5 weight percent (wt%) to about 90% by weight of the active ingredient of the mixture of plant extracts. 26. The composition of claim 2, wherein the composition comprises from about 0.5 weight percent (wt%) to about 90% by weight of the active ingredient of the mixture of plant extracts. 27. The composition according to claim 25, wherein said composition is formulated as tablet, hard capsule, soft gel capsule, powder, granule, liquid, tincture, sashay, ready-to-drink single dose or lozenge. 28. The composition of claim 26, wherein the composition is formulated as a tablet, hard capsule, soft gel capsule, powder, granule, liquid, tincture, sashay, ready-to-drink single dose or lozenge. 29. The composition of claim 1, wherein the composition is administered at a dose of 0.01 to 500 mg/kg animal body weight. 30. The composition of claim 2, wherein the composition is administered at a dose of 0.01 to 500 mg/kg animal body weight. 31. A method for maintaining liver function in mammals, minimizing liver cell damage, promoting healthy liver, protecting liver antioxidant integrity, neutralizing toxins, reducing free radicals that affect liver health, removing active oxygen species, reducing Oxidative Stress, Prevents Toxic Metabolic Formation, Improves Liver Detoxification Capacity and/or Function, Cleanses Liver, Restores Liver Structure, Protects Liver Cells from Toxins, Helps Liver Blood Flow and Circulation, Supports Liver Function, Strengthens and Soothes Liver, Calms and Nourishes the liver, relieves liver pain, removes harmful chemicals and organisms, supports metabolic processes in the liver, relieves liver discomfort, relieves fatty liver, improves liver detoxification, reduces liver enzymes, provides natural oxidants, increases SOD, increases GSH, reduces Liver cell peroxidation, reduce fatty acid accumulation, maintain healthy anti-inflammatory process, improve liver immune function, promote liver cell regeneration, improve liver renewal function, stimulate bile release, promote healthy bile flow, liver recovery, for overnutrition, overwork, A pharmaceutical composition for protecting the liver from excessive drinking, excessive aging, etc., wherein the pharmaceutical composition contains the composition of claim 1 as an active ingredient. 32. A method for maintaining liver function in mammals, minimizing liver cell damage, promoting healthy liver, protecting liver antioxidant integrity, neutralizing toxins, reducing free radicals affecting liver health, removing active oxygen species, reducing Oxidative Stress, Prevents Toxic Metabolic Formation, Improves Liver Detoxification Capacity and/or Function, Cleanses Liver, Restores Liver Structure, Protects Liver Cells from Toxins, Helps Liver Blood Flow and Circulation, Supports Liver Function, Strengthens and Soothes Liver, Calms and Nourishes the liver, relieves liver pain, removes harmful chemicals and organisms, supports metabolic processes in the liver, relieves liver discomfort, relieves fatty liver, improves liver detoxification, reduces liver enzymes, provides natural oxidants, increases SOD, increases GSH, reduces Liver cell peroxidation, reduce fatty acid accumulation, maintain healthy anti-inflammatory process, improve liver immune function, promote liver cell regeneration, improve liver renewal function, stimulate bile release, promote healthy bile flow, liver recovery, for overnutrition, overwork, A pharmaceutical composition for protecting the liver from excessive drinking, excessive aging, etc., wherein the pharmaceutical composition contains the composition of claim 2 as an active ingredient. 33. The pharmaceutical composition according to claim 31, wherein the liver disorder or disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease , drug-induced liver disease, cirrhosis, fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary ducts, Gilbert syndrome, jaundice or any other hepatotoxicity-related indication, and generally has acceptable toxicity to the patient, or any other hepatotoxicity-related indication, or any combination thereof. 34. The pharmaceutical composition according to claim 32, wherein the liver disorder or disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease , drug-induced liver disease, cirrhosis, fibrosis, liver failure, drug-induced liver failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary ducts, Gilbert syndrome, jaundice or any other hepatotoxicity-related indication, and generally has acceptable toxicity to the patient, or any other hepatotoxicity-related indication, or any combination thereof. 35. A method for maintaining liver function in mammals, minimizing liver cell damage, promoting healthy liver, protecting liver antioxidant integrity, neutralizing toxins, reducing free radicals affecting liver health, removing active oxygen species, reducing Oxidative Stress, Prevents Toxic Metabolic Formation, Improves Liver Detoxification Capacity and/or Function, Cleanses Liver, Restores Liver Structure, Protects Liver Cells from Toxins, Helps Liver Blood Flow and Circulation, Supports Liver Function, Strengthens and Soothes Liver, Calms and Nourishes the liver, relieves liver pain, removes harmful chemicals and organisms, supports metabolic processes in the liver, relieves liver discomfort, relieves fatty liver, improves liver detoxification, reduces liver enzymes, provides natural oxidants, increases SOD, increases GSH, reduces Liver cell peroxidation, reduce fatty acid accumulation, maintain healthy anti-inflammatory process, improve liver immune function, promote liver cell regeneration, improve liver renewal function, stimulate bile release, promote healthy bile flow, liver recovery, for overnutrition, overwork, A method for protecting the liver such as excessive drinking, excessive aging, etc., comprising administering an effective amount of the composition of claim 1. 36. A method for maintaining liver function in mammals, minimizing liver cell damage, promoting healthy liver, protecting liver antioxidant integrity, neutralizing toxins, reducing free radicals that affect liver health, removing reactive oxygen species, reducing Oxidative Stress, Prevents Toxic Metabolic Formation, Improves Liver Detoxification Capacity and/or Function, Cleanses Liver, Restores Liver Structure, Protects Liver Cells from Toxins, Helps Liver Blood Flow and Circulation, Supports Liver Function, Strengthens and Soothes Liver, Calms and Nourishes the liver, relieves liver pain, removes harmful chemicals and organisms, supports metabolic processes in the liver, relieves liver discomfort, relieves fatty liver, improves liver detoxification, reduces liver enzymes, provides natural oxidants, increases SOD, increases GSH, reduces Liver cell peroxidation, reduce fatty acid accumulation, maintain healthy anti-inflammatory process, improve liver immune function, promote liver cell regeneration, improve liver renewal function, stimulate bile release, promote healthy bile flow, liver recovery, for overnutrition, overwork, A method for protecting the liver from excessive drinking, excessive aging, etc., comprising administering an effective amount of the composition of claim 2. 37. The method of claim 35, wherein the liver condition or disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease, drug Liver disease caused by cirrhosis, fibrosis, hepatic failure, drug-induced hepatic failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary ducts, Gilbert's syndrome, jaundice or any Other hepatotoxicity-related indications, and generally have acceptable toxicity to the patient, or any other liver-related indications, or any combination thereof. 38. The method of claim 36, wherein the liver condition or disease is viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, alcoholic liver disease, fatty liver disease, steatosis, steatohepatitis, nonalcoholic fatty liver disease, drug Liver disease caused by cirrhosis, fibrosis, hepatic failure, drug-induced hepatic failure, metabolic syndrome, hepatocellular carcinoma, cholangiocarcinoma, primary biliary cirrhosis, capillary ducts, Gilbert's syndrome, jaundice or any Other hepatotoxicity-related indications, and generally have acceptable toxicity to the patient, or any other liver-related indications, or any combination thereof.