Skip to Content
You are currently on the new version of our website. Access the old version .
MDPIMDPI
NutrientsNutrients
PDF
  • Systematic Review
  • Open Access

15 April 2024

The Role of Oxidative Stress in Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Preclinical Studies

,
and
1
Postgraduate Program in Biological Sciences, Federal University of Ouro Preto, Ouro Preto 35402-163, Brazil
2
Department of Biochemistry, Federal University of Alfenas, Alfenas 37130-001, Brazil
3
Nutrition School, Federal University of Ouro Preto, Ouro Preto 35400-000, Brazil
*
Authors to whom correspondence should be addressed.
Nutrients2024, 16(8), 1174;https://doi.org/10.3390/nu16081174
This article belongs to the Section Nutritional Epidemiology
Version Notes
Order Reprints

Abstract

Alcoholic Fatty Liver Disease (AFLD) is characterized by the accumulation of lipids in liver cells owing to the metabolism of ethanol. This process leads to a decrease in the NAD+/NADH ratio and the generation of reactive oxygen species. A systematic review and meta-analysis were conducted to investigate the role of oxidative stress in AFLD. A total of 201 eligible manuscripts were included, which revealed that animals with AFLD exhibited elevated expression of CYP2E1, decreased enzymatic activity of antioxidant enzymes, and reduced levels of the transcription factor Nrf2, which plays a pivotal role in the synthesis of antioxidant enzymes. Furthermore, animals with AFLD exhibited increased levels of lipid peroxidation markers and carbonylated proteins, collectively contributing to a weakened antioxidant defense and increased oxidative damage. The liver damage in AFLD was supported by significantly higher activity of alanine and aspartate aminotransferase enzymes. Moreover, animals with AFLD had increased levels of triacylglycerol in the serum and liver, likely due to reduced fatty acid metabolism caused by decreased PPAR-α expression, which is responsible for fatty acid oxidation, and increased expression of SREBP-1c, which is involved in fatty acid synthesis. With regard to inflammation, animals with AFLD exhibited elevated levels of pro-inflammatory cytokines, including TNF-a, IL-1β, and IL-6. The heightened oxidative stress, along with inflammation, led to an upregulation of cell death markers, such as caspase-3, and an increased Bax/Bcl-2 ratio. Overall, the findings of the review and meta-analysis indicate that ethanol metabolism reduces important markers of antioxidant defense while increasing inflammatory and apoptotic markers, thereby contributing to the development of AFLD.

1. Introduction

Alcohol is a prevalent chemical compound found in numerous beverages that are regularly consumed by populations worldwide. According to the latest 2023 report from the World Health Organization (WHO) [1], alcohol is a major factor in the development of around 200 diseases, and no amount of alcohol consumption is considered safe. One of the significant consequences of alcohol consumption is Alcoholic Fatty Liver Disease (AFLD), which is characterized by the excessive accumulation of triglycerides (TAG) and cholesterol in liver cells [2].
Ethanol can be metabolized through both oxidative and non-oxidative pathways, with the oxidative pathway being the predominant route. The key liver enzymes involved in ethanol detoxification are alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and Cytochrome P450 2E1 (CYP2E1). ADH and ALDH are activated by acute alcohol consumption, whereas chronic alcohol intake enhances the activity of CYP2E1 [2,3,4]. During these metabolic processes, three major factors contribute to toxicity: (1) acetaldehyde accumulation; (2) an alteration in the nicotinamide adenine dinucleotide (NAD)H/NAD+ ratio; and/or (3) generation of reactive oxygen species (ROS). These factors collectively result in a decrease in Peroxisomal Proliferator-Activated Receptor alpha (PPAR-alpha) and an increase in sterol regulatory element-binding protein 1 (SREBP-1). As a result, mechanisms for fatty acid export and oxidation decrease, while hepatic lipogenesis increases, leading to the accumulation of lipids in hepatic micro- and/or macrovesicles [2,4,5].
CYP2E1 activation exacerbates ROS production through the accumulation of reduced NADH in the mitochondria, triggering electron leakage. These ROS can attach to cellular proteins, creating pathways for the accumulation of fat droplets, and they can also trigger lipid peroxidation and protein carbonyl, worsening liver dysfunction and amplifying oxidative stress [6]. Compounding this scenario, the inhibition of antioxidant mechanisms further heightens intracellular oxidative stress. A pivotal player, the erythroid-derived nuclear factor 2 (NRF2), which is responsible for orchestrating the production of antioxidant enzymes like Superoxide Dismutase (SOD) and Catalase (CAT), becomes suppressed. This disturbance, coupled with compromised antioxidant defenses, fuels the production of pro-inflammatory cytokines by Kupffer cells. This, in turn, triggers local inflammation and leads to an increased presence of ROS within the liver tissue [2,7].
Although narrative reviews in the literature have mentioned the importance of oxidative stress in AFLD, a comprehensive systematic review and meta-analysis that consolidates primary studies investigating the relationship between ethanol metabolism and oxidative stress in AFLD is lacking. Our goal was to thoroughly examine the biochemical pathways involved in ethanol-related oxidative processes through a systematic review and meta-analysis, which is a widely recognized approach known for its high scientific rigor.

2. Materials and Methods

The protocol of this systematic review and meta-analysis was registered at the International Prospective Register of Systematic Reviews—PROSPERO [CRD42022350708] and was written based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8]. The guiding question of this research was: “What is the role of oxidative stress in the pathogenesis of alcoholic fatty liver disease?” The elaboration of this guiding question was structured in the PICOT search strategy; i.e., the population (P) to be studied, intervention (I), comparison (C), outcomes (O), and time point (T). In this project, (P) was rats/mice with AFLD, (I) was alcohol induction of AFLD, (C) was control rats/mice (healthy), (O) represented measurements of liver and lipid profiles, oxidative stress, inflammation, and apoptosis, and (T) was any point in time. Inclusion and exclusion criteria were defined to facilitate the selection of appropriate studies to answer the research question.

2.1. Inclusion Criteria

(1) The study design should be performed in rats and/or mice (all species, all sexes, all ages, and all weights); (2) the experimental design had to include AFLD (induced by alcohol/ethanol at any dose and time); (3) had to contain dosages of antioxidant enzymes (e.g.,: SOD, catalase, glutathione peroxidase, glutathione reductase) concomitantly with dosages of oxidative damage markers (e.g., thiobarbituric acid reactive species (TBARS), malondialdehyde (MDA), or protein carbonyl); and (4) had a control group for comparison with the AFLD group.

2.2. Exclusion Criteria

(1) Animals with co-morbidities; (2) animals with non-alcoholic fatty liver disease; (3) ex vivo; (4) in vitro; (5) in silico; (6) animals from the control group that have been exposed to a substance other than water, Phosphate Buffer Saline (PBS), methylcellulose, or inert substances; (7) studies without a separate control group; (8) case studies, cross-over studies, abstracts, case reports, letters to the editor, editorials, comments, or reviews; and (9) missing data necessary for extraction.

2.3. Search Strategy

A literature search was conducted up to 2 September 2022, using the Pubmed, Scopus, and LILACS electronic databases. The following keywords were used in the search strategy: ((((((((((((((“Alcoholic Fatty Liver Disease“[Title/Abstract]) OR (“Fatty liver alcoholic“[Title/Abstract])) OR (“Fatty liver alcoholic disease“[Title/Abstract])) OR (“Fatty liver ethanol disease“[Title/Abstract])) OR (“Alcohol-induced fatty liver disease“[Title/Abstract])) OR (“Ethanol induces fatty liver disease“[Title/Abstract])) OR (“Alcoholic Steatohepatitis“[Title/Abstract])) OR (“Ethanol induced hepatotoxicity“[Title/Abstract])) OR (“Alcohol induced hepatotoxicity“[Title/Abstract])) OR (“Steatohepatitis“[Title/Abstract])) OR (“Alcohol-associated liver disease“[Title/Abstract])) OR (“Alcoholic liver disease“[Title/Abstract])) OR (“Alcohol-induced liver disease“[Title/Abstract])) AND ((((((((((“Oxidative Stresses“[Title/Abstract]) OR (“Oxidative Stress“[Title/Abstract])) OR (“Oxidative Damage“[Title/Abstract])) OR (“Oxidative Stress Injury“[Title/Abstract])) OR (“Oxidative Injuries“[Title/Abstract])) OR (“Oxidative Cleavages“[Title/Abstract])) OR (“Oxidative DNA Damage“[Title/Abstract])) OR (“Oxidative Nitrative Stress“[Title/Abstract])) OR (“Redox Status“[Title/Abstract])) OR (“Redox Processes“[Title/Abstract]))) NOT ((((((“Non-Alcoholic Fatty Liver Disease“[Title/Abstract]) OR (“Nonalcoholic fatty liver disease“[Title/Abstract])) OR (“Non-Alcoholic Steatohepatitis“[Title/Abstract])) OR (“Nonalcoholic Steatohepatitis“[Title/Abstract])) OR (“Non-alcoholic liver disease“[Title/Abstract])) OR (“Nonalcoholic liver disease“[Title/Abstract])). The search was not restricted by date or language.

2.4. Study Selection

The primary literature search was carried out by two independent reviewers (ACSR and AKLA), where the title, author, year of publication, and DOI of each identified article were exported to Excel. The titles and abstracts of the retrieved records were then independently screened by two reviewers (ACSR and AKLA) to identify studies that potentially met the inclusion criteria. Those who met the eligibility criteria had their full texts scanned. Discrepancies that arose during any phases were resolved through consensus or the involvement of a third author (DCC). For manuscripts that met the inclusion criteria but had missing data, the authors were contacted once by email. If there was no response, the files were excluded.

2.5. Data Extraction

Data were independently extracted (ACSR and AKLA) based on the characteristics of the study (name of the author, year of publication, place where the study was conducted, funding, and conflict of interest), the characteristics of the animals (breeding, sex, size, and age), the characteristics of the study design to induce AFLD (alcohol concentration, time, and frequency of exposure), the sample number of each group (n) (control and AFLD), and the primary and secondary outcomes of interest (primary outcomes: dosage of antioxidant enzyme and oxidative damage; secondary outcomes: markers of liver damage, lipid profile, inflammation, apoptosis, lipid and glycemic metabolism, and liver histology). Through online meetings, both tables were compared between the two authors (ACSR and AKLA), and discrepancies were resolved through consensus or the involvement of a third author (DCC).
Then, the quantitative data of mean and standard deviation related to the primary and secondary outcomes of each included article were extracted independently (ACSR and AKLA). For data that were not expressed as a table, means and standard deviations were extracted from graphs using WebPlotDigitizer https://automeris.io/WebPlotDigitizer/ (accessed on 10 April 2024). As this tool has a high level of sensitivity (approximately 8–10 decimal places), small discrepancies can often occur in the last decimal places. Therefore, we opted to obtain an average for the extracted data, performed by ACSR and AKLA.
For each outcome, the most frequent measurement unit was selected, and all other units were converted to that unit for consistency. For those measurement units that were unique or could not be grouped with the others, the outcome was removed. In cases of doubt about measurements, typing errors, or any other problems, the authors were contacted once by email. If there was no response, that specific outcome was removed. Likewise, the tables were compared, and discrepancies were resolved between the two authors (ACSR and AKLA) or with the involvement of a third author (DCC).

2.6. Risk of Bias in Individual Studies

All included reports were critically analyzed using SYRCLE’s risk of bias tool for animal studies [9]. This tool assesses the methodological quality of preclinical studies and has ten entries related to six biases. For each group, there are specific questions:
(1)
Selection bias: Was the allocation sequence properly generated and applied? Were the groups similar at baseline or were they adjusted for confounders in the analysis? Was the allocation to the different groups properly concealed?
(2)
Performance bias: Were the animals randomly housed during the experiment? Were the caregivers and/or investigators blinded from knowledge of which intervention each animal received during the experiment?
(3)
Detection bias: Were animals selected at random for outcome assessment? Was the outcome advisor blinded?
(4)
Attrition bias: Were incomplete outcome data adequately addressed?
(5)
Reporting bias: Are reports of the study free of selective outcome reporting?
(6)
Other biases: Was the study apparently free of other problems that could result in a high risk of bias?
Both the reviewers (ACSR and AKLA) assessed each report for the risk of bias, answering the questions with yes (Y), no (N), or unclear (U). The results were compared, and disagreements were resolved through discussion or by consulting a third investigator (DCC).

2.7. Statistical Analysis

The sample size and mean ± standard deviation data extracted from the primary studies were plotted using the Review Manager (RevMan 5.3) software to generate the effective size. The random model was applied to estimate the pooled effects, the 95% confidence interval (95% CI) was used, and a p-value of <0.05 was considered statistically significant. The statistical heterogeneity among the studies was assessed using I2 statistics, and values of 25%, 50%, and 75% indicate low, moderate, and high heterogeneity, respectively. Assuming that there was some heterogeneity, subgroup analyses were carried out in categories (e.g.: liver × serum; mg/dL × mg/g). The standard mean difference (SMD) and in some cases, the mean difference (MD) were adopted. For analyses where there were more than 10 studies, funnel plots were produced.

3. Results

3.1. Literature Search

Initially, our search found 1348 articles in Scopus, 829 in Pubmed, and none in LILACS. Of these files, 777 were duplicates and were excluded. Therefore, 1400 records were filtered based on title and abstract. Files were excluded when they were reviews, book chapters, or event abstracts (n = 491); were not an AFLD model (n = 148); did not contain an in vivo study with rats and/or mice (n = 187); or did not contain antioxidant dosing concomitant with oxidative damage (n = 218). The full texts of 356 of these records were retrieved for further assessment. After the full texts were read, 133 articles were excluded because the animals had some type of comorbidity (n = 100); the control group received a substance that was not inert (n = 7); AFLD was induced by techniques other than orally or intragastrically (e.g., received ethanol intraperitoneally) (n = 23); and articles that were removed or portrayed in a newspaper (n = 3). After this analysis, 223 articles were potentially eligible for the review; however, 17 were excluded owing to missing data. Therefore, 206 files [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215] entered the systematic review, but 5 did not present outcomes that could be grouped with the others and were excluded from the meta-analysis. Figure 1 summarizes the entire selection process of articles that fit into this systematic review and meta-analysis.
Figure 1. Flow diagram of the study selection process for this systematic review and meta-analysis.

3.2. Characteristics of the Included Studies

A total of 206 [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215] eligible studies are illustrated in detail in Table 1, which includes studies published between 2000 and 2022. The animal species included mice [C57BL/6 (n = 69), Kunming (n = 19), ICR (n = 16), BALB/c (n = 9), Swiss (n = 2)] and rats [Wistar (n = 60), Sprague Dawley (n = 25), Albino (n = 3), did not declare the lineage (n = 2), Fisher (n = 1)]. Most studies used male animals (n = 169), followed by female (n = 16), both sexes (n = 8), or did not state the sex (n = 8). The weights of the mice ranged from 12 to 30 g, those of the rats were in the range of 100 to 350 g, and 46 studies did not state the weight. The youngest animals were 4 weeks old, the oldest were 17 weeks old, and 101 studies did not state the age.
Table 1. Data from primary articles used in the construction of the systematic review.
With regard to the induction of AFLD, there was significant variation in the concentration of ethanol used (ranging from absolute to 1% diluted in water), the methods of administering ethanol (including gavage, intragastric tube, in drinking water, and in the form of a Lieber-DeCarli diet), the doses administered (ranging from 1 mL/kg/bw to 15 mL/kg/bw or 1 g/kg/bw to 12 g/kg/bw), and the treatment durations (ranging from single doses to 24-week treatments).
In terms of the primary outcomes, the studies measured the activity of antioxidant enzymes, including SOD (n = 120), CAT (n = 84), GPx (n = 88), GR (n = 34), and GST (n = 20). The non-enzymatic antioxidant GSH (n = 118) and the GSH/GSSG ratio (n = 24) were also measured. Oxidative damage was assessed by measuring lipoperoxidation (n =158) and carbonylated protein (n = 11). For secondary outcomes, the studies evaluated liver damage by measuring ALT (n = 175) and AST (n = 156), and the lipid profile was assessed by measuring TAG (n = 112). Inflammation was assessed by measuring TNF-a (n = 66), IL-1β (n = 41), IL-6 (n = 43), and IL-10 (n = 7). Apoptosis was evaluated by measuring the Bax/Bcl-2 ratio (n = 13) and caspase 3 (n = 18). Enzymes that metabolize ethanol, such as CYP2E1, were also measured (n = 55). Histological analysis was performed to assess steatosis (n = 15) and inflammation (n = 14). Finally, transcription factors related to lipid and carbohydrate metabolism, including SREBP-1 (n = 16) and PPAR-a (n = 14), as well as antioxidant enzyme regulation, such as Nrf2 (n = 24), were also evaluated.
Table 1 shows the data extracted from the primary articles, including author name and year, study location, funding source, animal characteristics (lineage, sex, weight, age), the AFLD induction model, the number of animals in each group, and the outcomes of interest.

3.3. Parameters Analyzed in the Systematic Review and Meta-Analysis

The parameters chosen for extraction from the primary articles were based on those that validate the model of alcoholic steatosis, such as liver damage and lipid profile, but also on those that analyzed the markers of oxidative stress (the focus of the present work), inflammation, and cell death. Combining these parameters offers compelling evidence regarding the liver’s condition in response to ethanol metabolism. Each of these factors is elaborated upon below.

3.3.1. Liver Damage

Typically, ALT (alanine aminotransferase) and AST (aspartate aminotransferase) are present in the liver and are involved in protein metabolism, so there are low levels in the bloodstream. However, when there is liver damage, these enzymes commonly leak into the bloodstream and lead to an increase in their quantification in serum/plasma. Thus, measuring this activity is a good tool for understanding liver damage. Accordingly, we extracted data on ALT and AST activity from primary studies eligible for systematic review and meta-analysis in order to understand the state of liver damage in animals from the AFLD and control groups.
A total of 175 manuscripts evaluated the activity of ALT in serum/plasma (U/L). It is possible to observe through the SMD that there is an increase in the activity of this enzyme in AFLD groups compared with control groups (SMD: 3.51, 95% CI 3.21, 3.81, p < 0.00001). There was also high heterogeneity among the studies (I2 = 84%) (Supplementary Figure S1). With regard to AST, a total of 156 articles were included in the analysis, and these articles were heterogeneous among themselves (I2 = 85%). Similarly, an increase in AST activity was observed in AFLD groups compared with control groups (SMD: 3.56, 95% CI 3.24, 3.89, p < 0.00001) (Supplementary Figure S2).

3.3.2. Lipid Profile

Triacylglycerol (TAG)
The body of literature shows that ethanol metabolism leads to dysregulation of the lipid profile, especially of TAG; therefore, this systematic review and meta-analysis aimed to analyze TAG levels in animals with or without AFLD. A total of 112 articles eligible for our study quantified TAG in serum/plasma (50 measured in mmol/L and 27 in mg/dL) and liver (36 measured in mmol/g and 39 in mg/g). Subgroup analysis was adopted, namely liver and serum/plasma, but there was high heterogeneity among the studies (I2 = 82%). It was evident that there was an increase in TAG levels in AFLD groups compared with control groups, both in the liver and in the plasma. This effect was noted for both the subgroup analysis and the overall analysis (SMD: 2.91, 95% CI 2.63, 3.19, p < 0.00001) (Supplementary Figure S3).
Sterol Regulatory Element-Binding Transcription Factor 1c (SREBP-1c)
SREBP-1c triggers the activation of a group of genes that play a significant role in glucose metabolism and the production of fatty acids. Thus, its activation can contribute to AFLD. In order to prove whether there is evidence of this contribution to AFLD, this systematic review included the extraction of data on SREBP-1c protein expression from primary articles. Through analysis of 16 studies (all measuring protein expression), it was evident that there is an increase in the expression of this transcription factor in AFLD groups compared with control groups (MD: 1.40, 95% CI 0.76, 2.03, p < 0.00001) (Supplementary Figure S4).
Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α)
The activation of PPAR-α triggers a cascade of biological actions, including the uptake, utilization, and breakdown of fatty acids. Upregulating genes that are involved in fatty acid transport, binding, activation, and peroxisomal and mitochondrial fatty acid β-oxidation facilitate this process. Given the importance of PPAR-α in lipid metabolism, this systematic review included analysis of 14 manuscripts that quantified the expression of this transcription factor. There was a reduction of PPAR-α in AFLD groups compared with control groups (MD: −0.53, 95% CI −0.72, −0.35, p < 0.00001) (Supplementary Figure S5).
Histological Analysis of the Liver
A total of 15 articles analyzed the presence of hepatic steatosis, 5 of them through fatty accumulation and 10 through measurement of the steatosis score. There was an increase in the histological grade in AFLD groups compared with control groups (SMD: 4.33, 95% CI 2.92, 5.73, p < 0.00001) (Supplementary Figure S6).

3.3.3. Ethanol Metabolism through Cytochrome P450 2E (CYP2E1)

It is well established that CYP2E1 is one of the pathways involved in ethanol metabolism, and this pathway has a direct association with oxidative stress. Therefore, this meta-analysis included examination of 55 primary studies that investigated CYP2E1 expression (n = 48) and activity (11 measured in nmol/min/mg and 3 in ng/mg) in the livers of animals with or without AFLD. According to a forest plot, it was clear that there was an increase in the expression and activity of CYP2E1 in the animals of AFLD groups compared with control groups. This profile was maintained for individual subgroups and the overall analysis (SMD: 3.73, 95% CI 3.22, 4.24, p < 0.00001) (Supplementary Figure S7).

3.3.4. Oxidative Stress Biomarkers

In order to verify if there is increased oxidative stress in animals with AFLD, this meta-analysis included an evaluation of primary articles that analyzed antioxidant defense (SOD, CAT, GPx, GR, GST, GSH, and GSH/GSSG ratio) and oxidative damage (lipid peroxidation and carbonyl protein). The effect of ethanol metabolism for each parameter is described below.
Antioxidant Profile in AFLD
  • Superoxide Dismutase (SOD)
Liver SOD activity (U/mg) in animals was measured in 120 studies, which demonstrated a significant decrease in AFLD groups compared with control groups (MD of −1.77; 95% CI −1.83, −1.71; p < 0.00001), with statistically significant heterogeneity (p < 0.00001, I2 = 88%) (Figure 2).
Figure 2. Evidence of decreased superoxide dismutase (SOD) activity in liver tissue. The forest plot indicates lower SOD activity in the livers of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls (p < 0.05 for each). 95% Cl: confidence interval.
  • Catalase (CAT)
The CAT activity in the liver was assessed in 84 studies, which mainly used two different units of measurement (70 used U/mg and 14 used nmol/min/mg). The results showed significant reduction in CAT activity in AFLD groups compared with control groups in the subgroups and the overall analysis (SMD of −3.34; 95% CI −3.85, −2.84; I2 = 88%) (Figure 3).
Figure 3. Forest plot showing the decrease in catalase (CAT) activity in liver tissue from animals with alcoholic fatty liver disease (AFLD) compared with healthy controls (p < 0.05 for each). The 95% confidence interval is also shown.
  • Glutathione Peroxidase (GPx)
GPx activity in the liver of animals was assessed in 88 articles, which used two units of measurement, U/mg (n = 72) and nmol/min/mg (n = 16). The studies showed high heterogeneity (I2 = 88%, p < 0.00001). When statistical analysis was performed, a reduction in GPx activity was observed in AFLD groups for both subgroups and the overall analysis (SMD: −3.26, 95% CI −3.74, −2.78, p < 0.00001) (Figure 4).
Figure 4. Forest plot showing glutathione peroxidase (GPx) activity in liver tissue. There is evidence of decreased GPx activity in the liver tissue of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls (p < 0.05). 95% Cl: confidence interval.
  • Glutathione Reductase (GR)
A total of 34 eligible studies quantified GR activity (22 measured in U/mg and 12 in µmol/mg/min). High heterogeneity was evident among the studies, with I2 values of 87%. The results also showed a reduction in GR activity in AFLD groups compared with control groups (SMD: −2.87, 95% Cl −3.58, −2.16) (Figure 5).
Figure 5. Forest plot showing the results of combining studies that analyzed glutathione reductase (GR) activity in the liver. Animals with alcoholic fatty liver disease (AFLD) had lower GR activity compared with healthy controls (p < 0.05). 95% Cl: confidence interval.
  • Glutathione Transferase (GST)
Analysis of GST activity was performed in 20 studies, which mainly used the measurements units U/mg (n = 10) and µol/mg (n = 10). There was a reduction in GST activity in AFLD groups compared with control groups (SMD: −1.74; 95% Cl −2.85, −0.63, p = 0.002). The studies showed high heterogeneity, with I2 = 91% (Figure 6).
Figure 6. The evidence suggests a decrease in glutathione transferase (GST) activity in the liver tissue of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls. This is supported by the forest plot, which shows a significant reduction in GST activity (p < 0.05 for each), with 95% confidence intervals (Cl) reported.
  • Reduced Glutathione (GSH)
A total of 118 manuscripts analyzed GSH, of which 102 used µmol/mg and 16 used mg/g. There was high heterogeneity among the studies included in this analysis (I2 = 84%, p ˂ 0.00001). It was evident that there was a reduction of GSH in AFLD groups compared with control groups in both subgroups and the overall analysis (SMD −3.20, 95% CI −3.55, −2.85, p ˂ 0.00001) (Figure 7).
Figure 7. The evidence suggests a decrease in reduced glutathione (GSH) in the liver tissue of animals with alcoholic fatty liver disease (AFLD) compared with healthy controls. This is supported by the forest plot, which shows a significant reduction in GSH (p < 0.05 for each), with 95% confidence intervals (Cl) reported.
  • Reduced Glutathione (GSH)/Oxidized Glutathione (GSSG) Ratio
A total of 24 articles included GSH/GSSG ratio analysis. The results showed a significant reduction in GSH compared with GSSG in AFLD groups, with a MD of −5.09 (95% CI −6.28, −3.91, p ˂ 0.00001). These findings provide evidence that ethanol consumption leads to increased glutathione oxidation (Figure 8).
Figure 8. Analysis of the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in the livers of rats with AFLD and control groups. The forest plot shows that the AFLD groups had reduced GSH/GSSG ratios compared with the control group (p < 0.05 for each), with 95% confidence intervals (Cl) reported.
  • Factor 2 Related to Erythroid Nuclear Factor 2 (Nrf2)
A total of 24 manuscripts analyzed the expression of Nrf2, with high heterogeneity among the studies (I2 = 99%). The MD of −0.23 and 95% CI −0.41, −0.04, showed that there was a reduction in the expression of this transcription factor in AFLD groups compared with control groups (Supplementary Figure S8).
Oxidative Damage in AFLD
  • Lipid Peroxidation
With regard to lipid peroxidation, 158 articles included analyses of Thiobarbituric Acid Reactive Substances (TBARS), Malondialdehyde (MDA), Lipoperoxidation (LPO), and Lipid Hydroperoxides (LOOH). The data from these articles were combined, and the units were converted to nmol/mg. The results demonstrate that there was an increase in peroxidation in AFLD groups compared with control groups (SMD: 3.85, 95% CI 3.52, 4.19, p ˂ 0.00001). There was high heterogeneity among the articles (I2 = 86%, p ˂ 0.00001) (Figure 9).
Figure 9. Analysis of lipid peroxidation in the livers of rats with AFLD and healthy controls. The forest plot shows that AFLD groups had increased lipid peroxidation compared with control groups (p < 0.05 for each), with 95% confidence intervals (Cl) reported.
  • Carbonylated Protein
A total of 11 articles analyzed protein carbonyl in the livers of animals with AFLD or healthy controls. There was high heterogeneity among the studies (I2 = 85%), although all were converted to the same measurement unit (nmol/mg). When statistically analyzed, it was evident that there was a greater amount of carbonyl protein in AFLD groups compared with control groups (MD: 4.02, 95% CI 3.03, 5.00, p ˂ 0.00001) (Figure 10).
Figure 10. Analysis of protein carbonyl in the livers of rats with AFLD and healthy controls. The forest plot shows that AFLD groups had increased protein carbonyl levels compared with control groups (p < 0.05 for each), with 95% confidence intervals (Cl) reported.

3.3.5. Inflammation in AFLD

Tumor Necrosis Factor-α (TNF-α)
A total of 66 manuscripts focused on TNF-α. Among these, 50 assessed the effect of TNF-α on the liver, with 14 of them using pg/mL and the remaining 36 using pg/mg for measurements. In addition, 19 manuscripts evaluated TNF-α levels in serum/plasma, and all measurements were taken in pg/mL. Thus, the analysis was carried out using two subgroups, with an increase of TNF-α being evidenced in all subgroups of the AFLD group. When the subgroups were analyzed together, it was possible to confirm the increase in TNF-α in the AFLD group (SMD: 3.81, 95% CI 3.29, 4.34, p ˂ 0.00001) (Supplementary Figure S9).
Interleukin 1 beta (IL-1β)
A total of 41 articles quantified IL-1β in the liver (10 in pg/mL and 23 in pg/mg) and 9 in serum/plasma (pg/mL). Thus, we performed the analysis using two subgroups. The forest plot shows that IL-1β increased in AFLD groups compared with control groups for both liver and serum/plasma. The SMD was 3.69, 95% CI 3.03, 4.35, p ˂ 0.00001 (Supplementary Figure S10).
Interleukin-6 (IL-6)
A total of 43 manuscripts measured IL-6; of these, 32 performed the analysis in the liver (10 measured it in pg/mL and 22 in pg/mg), and 13 performed it in serum/plasma (pg/mL). Although the analysis was conducted in two subgroups, the heterogeneity among the studies was high (I2 = 88%, p ˂ 0.00001). With regard to the effects, it was possible to observe an increase in IL-6 levels in AFLD groups compared with control groups for both liver and serum/plasma (SMD: 4.79, 95% CI 3.99, 5.60, p ˂ 0.00001) (Supplementary Figure S11).
Interleukin-10 (IL-10)
Seven manuscripts measured IL-10; of these, four performed the analysis in the liver (measured it in pg/mg), and three performed it in serum (pg/mL). Although the analysis was conducted using three subgroups, the heterogeneity among the studies was high (I2 = 89%, p ˂ 0.00001). With regard to the effects, it was possible to observe that there was no difference between the AFLD and control groups, neither in the subgroup analysis nor in the overall analysis (SMD: −0.32, 95% CI −1.69, 1.06, p = 0.65) (Supplementary Figure S12).
Histological Analysis of the Liver
Fourteen articles examined the presence of inflammation in liver histological slides, with 4 measuring the number of inflammatory cells and 10 using an inflammation score. Statistical analysis revealed a greater degree of inflammation in AFLD groups compared with control groups (SMD: 2.27, 95% CI 1.37, 3.17, p ˂ 0.00001) (Supplementary Figure S13).

3.3.6. Apoptosis in AFLD

Caspase-3
Eighteen manuscripts analyzed caspase-3 in the liver of animals with or without AFLD. Of these, 14 performed protein expression and 4 measured activity (pmol/mg/min). There was high heterogeneity among the studies (I2 = 83%). With regard to the effects, it was observed that AFLD groups exhibited increased caspase-3 expression and activity compared with control groups. This suggests an increased occurrence of cell death following ethanol consumption. (SMD: 5.58, 95% CI 4.22, 6.94, p ˂ 0.00001) (Supplementary Figure S14).
BCL-2-Associated Protein X (BAX)/B-Cell CLL/Lymphoma 2 (BCL-2) Ratio
A total of 13 articles quantified the Bax/Bcl-2 ratio. There was moderate heterogeneity among the studies (I2 = 65%). With regard to the statistical analysis, there was a significant increase in Bax/Bcl-2 ratios in AFLD groups compared with control groups (MD: 2.50, 95% CI 1.74, 3.26, p ˂ 0.00001) (Supplementary Figure S15). These data suggest that the utilization of ethanol triggers cell death in hepatocytes.

3.3.7. Risk of Bias in Individual Studies

In our systematic review, we employed the SYRCLE scale, as described in the Materials and Methods section, to assess the risk of bias for each primary study. A comprehensive set of 206 manuscripts was included in our analysis. Upon evaluation, we noted that there was a moderate risk of bias, as evidenced by the questions receiving responses of Unclear (1337 = 64.9%), Yes (630 = 30.6%), and No (93 = 4.4%) (Table 2).
Table 2. Risk of bias in the included studies.
In addition, for all the analyzed parameters (including liver damage, lipid profile, oxidative stress, inflammation, and apoptosis) we conducted a risk analysis using more than 10 articles to identify publication bias. Our findings revealed considerable asymmetry in the funnel plot, as none conformed to the typical funnel shape, indicating potential bias in the publication of primary articles (see Supplementary Figure S16).

4. Discussion

To the best of our knowledge, this systematic review and meta-analysis is the first to provide a summary of the effects of ethanol metabolism on oxidative stress and examine the evidence of its impact on AFLD. Here, we used a compilation of 206 primary studies with rats and/or mice that induced AFLD with oral ethanol and measured different parameters related to pathological conditions of AFLD. The results indicated an increase in liver damage alongside alterations in the lipid profile. These data demonstrate an established model of AFLD that reflects an increase in oxidative stress and inflammatory processes and stimulates the death of hepatocytes by apoptotic processes.
It is known that ethanol metabolism in the liver involves oxidation reactions. Initially, ALD converts ethanol to acetaldehyde, generating NADH from NAD+ as an electron acceptor. In cases of high ethanol levels or chronic consumption, the microsomal ethanol oxidant system CYP2E1 contributes to acetaldehyde production. Subsequently, ALDH converts acetaldehyde to acetate, utilizing NAD+ and producing NADH. The decrease in the NAD+/NADH ratio from ethanol metabolism alters the body’s homeostasis and generates serious disturbances [216]. Indeed, this review and meta-analysis showed that animals in the ALFD groups had higher CYP2E1 expression compared with control groups. This was also reflected in increased liver damage, as shown by an increase in ALT and AST activity.
Alcohol intake has been found to impact lipid metabolism through the increased expression of lipogenic genes (such as SREBP-1c and its target genes) and inhibition of genes involved in fatty acid oxidation (for example, PPAR and its target genes) [4,186]. These processes lead to several outcomes. First, increased acetyl-CoA-carboxylase and ATP citrate lyase activity, which contribute to fatty acid and TAG synthesis. Second, there is a concurrent reduction in the activity of lipoprotein lipase, which is the key enzyme responsible for TAG hydrolysis. Third, there is an increase in the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a key enzyme in the mevalonate pathway and cholesterol synthesis. Fourth, cholesterol accumulates, as evidenced by elevated levels of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), while high-density lipoprotein (HDL) levels decrease [217]. These changes collectively contribute to the dysregulation of lipid metabolism and have implications for AFLD [6,186]. These characteristics were corroborated by our systematic review and meta-analysis, which revealed an elevation in both serum/plasma and liver TAG levels. Furthermore, our findings demonstrated a decrease in PPAR-α expression accompanied by an increase in SREBP-1c levels. These alterations collectively contributed to the notable presence of micro and macro fat vesicles within the hepatic histological sections of the examined experimental subjects.
The reoxidation of NADH to NAD+ in mitochondria has been associated with the leakage of electrons from the mitochondrial respiratory chain and subsequent production of ROS, thereby contributing to increased oxidative stress [7]. Normally, in a healthy liver, acetaldehyde is rapidly metabolized to acetate by ALDH. However, in individuals with chronic alcohol consumption, the ALDH pathway becomes overwhelmed and produces reactive aldehydes and lipid hydroperoxides. These harmful compounds can form adducts with DNA and proteins, contributing to hepatocyte damage and inflammation and exacerbating the negative effects of alcohol on the liver [2]. Notably, there is also CYP2E1-dependent ROS production, which has been shown to inhibit PPAR-mediated fatty acid oxidation genes and contribute to the oxidation of cellular components [218].
Under normal circumstances, the body depends on various endogenous antioxidant defense enzymes, including GR, SOD, CAT, and GPx, to neutralize the harmful effects of free radicals. However, individuals with AFLD undergo excessive production of free radicals and macromolecule oxidation induced by ethanol metabolism. This hampers the efficiency of the antioxidant defense system, exacerbating oxidative stress and thereby intensifying the overall pathogenesis of AFLD [6,219]. In addition, in AFLD, the transcription factor Nrf2 is impaired [220]. Under normal conditions, NRF2 is bound to KEAP1 and is degraded by the proteasome. However, during oxidative stress, ROS or electrophiles modify KEAP1, disrupting its binding to NRF2. This allows NRF2 to translocate to the nucleus and activate antioxidant response elements, leading to genetic transactivation [221].
This systematic review and meta-analysis confirmed the deleterious effects of ethanol metabolism. The evidence clearly indicated the presence of oxidative stress, as evidenced by a marked decline in antioxidant defense, including reduced levels of SOD, CAT, GPx, GR, GST, GSH, GSH/GSSG ratios, and Nrf2 transcription factor. In addition, we observed an elevated level of lipid peroxidation, as reflected by increased TBARS, MDA, LOOH, and protein carbonylation.
Studies have also shown that ROS contributes significantly to the development of ethanol-induced inflammation. One factor linking inflammation to oxidative stress is the depletion of mitochondrial GSH owing to CYP2E1 activation, which impairs hepatocyte tolerance to pro-inflammatory cytokines such as TNF-α and IL-1β [2]. Oxidative stress caused by ethanol or acetaldehyde alters mitochondrial membrane permeability and transition potential. This leads to the release of cytochrome c and other pro-apoptotic factors, stimulating the intrinsic pathway of apoptosis and, consequently, the death of hepatocytes. These typical characteristics of AFLD were observed in this meta-analysis and were evident from the marked increase in pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and the heightened degree of inflammation observed in hepatic slides from animals with ALFD. We also observed upregulation in caspase-3 and Bax/Bcl2, which contributed to the hepatocyte death process. Ethanol metabolism appears to generate a vicious cycle between fat accumulation, oxidative stress, inflammation, and hepatocyte death, thereby contributing to AFLD.

5. Conclusions

This comprehensive review and meta-analysis effectively consolidated evidence regarding the adverse effects of oxidative stress on AFLD, yielding informative results detailing the wide range of systemic complications associated with the condition. The data indicate that ethanol metabolism in animals with AFLD disrupts the redox system, rendering liver cells more susceptible to inflammation and cell death.
It is essential to acknowledge that considerable statistical heterogeneity was observed across most of the outcomes reported in the meta-analysis, and the primary studies were preclinical. The primary articles also demonstrated a high risk of publication bias and a moderate risk of bias overall. However, we emphasize that this review and meta-analysis represent a significant milestone, providing robust data on the impact of oxidative stress on AFLD and offering clarity on the underlying biochemical mechanisms driving this disease.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu16081174/s1, Supplementary Figure S1: Forest plot showing the alanine aminotransferase (ALT) activity in the serum/plasma from animals with or without AFLD. It is possible to observe that there was an increase in ALT activity in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S2: Forest plot showing the aspartate aminotransferase (AST) activity in the serum/plasma from animals with or without AFLD. It is possible to observe that there was an increase in AST activity in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S3: Forest plot showing the Triacylglycerol (TAG) levels in the serum/plasma and liver from animals with or without AFLD. It is possible to observe that there was an increase in TAG in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S4: Forest plot showing the Sterol regulatory element binding transcription factor 1c (SREBP-1c) expression in the liver from animals with or without AFLD. It is possible to observe that there was an increase in SREBP-1c expression in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S5: Forest plot showing the Peroxisome Proliferator Activated Receptor Alpha (PPAR-α) expression in the liver from animals with or without AFLD. It is possible to observe that there was a decrease in PPAR-α expression in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S6: Forest plot showing the steatosis profile in liver slices from animals with or without AFLD. It is possible to observe that there was an increase in histology steatosis in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S7: Forest plot showing the Cytochrome P450 2E (CYP2E1) expression and activity in liver from animals with or without AFLD. It is possible to observe that there was an increase in both CYP2E1 expression and activity in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S8: Forest plot showing Factor 2 related to erythroid nuclear factor 2 (Nrf2) analysis in liver from animals with or without AFLD. It is possible to observe that there was a reduction in Nrf2 expression in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S9: Forest plot showing Tumor Necrosis Factor-α (TNF-α) analysis in liver and serum/plasma from animals with or without AFLD. The analysis was carried out in two subgroups, where an increase in TNF-α can be observed in both liver and serum/plasma from the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S10: Forest plot showing Interleukin 1 beta (IL-1β) analysis in liver and serum/plasma from animals with or without AFLD. The analysis was carried out in two subgroups, where an increase in IL-1β can be observed in both liver and serum/plasma from the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S11: Forest plot showing Interleukin 6 (IL-6) analysis in liver and serum/plasma from animals with or without AFLD. The analysis was carried out in two subgroups, where an increase in IL-6 can be observed in both liver and serum/plasma from the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S12: Forest plot showing Interleukin 10 (IL-10) analysis in liver and serum from animals with or without AFLD. The analysis was carried out in two subgroups, and there was no difference between the AFLD and control group. 95% Cl: confidence interval. Supplementary Figure S13: Forest plot showing the inflammation profile in liver slices from animals with or without AFLD. It is possible to observe that there was an increase in histology inflammation in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S14: Forest plot showing caspase-3 expression and activity in liver from animals with or without AFLD. The analysis indicated increase in caspase-3 from AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S15: Forest plot showing Bax/Bcl-2 ratio in liver from animals with or without AFLD. An increase in Bax/Bcl-2 ratio can be observed in the AFLD group (p < 0.05). 95% Cl: confidence interval. Supplementary Figure S16: Funnel plot for the assessment of publication bias.

Author Contributions

A.C.S.R.: performed all stages of the systematic review and meta-analysis and wrote the draft and final version. A.K.d.L.A.: performed all stages of the systematic review and meta-analysis. D.C.C.: supervised the study and corrected the final version. All authors have read and agreed to the published version of the manuscript.

Funding

Pró-reitoria de Pesquisa, Pós-graduação e Inovação (PROPPI); Federal University of Ouro Preto; Federal University of Alfenas; Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. World Health Organization—WHO. No Level of Alcohol Consumption Is Safe for Our Health. Available online: https://www.who.int/europe/news/item/04-01-2023-no-level-of-alcohol-consumption-is-safe-for-our-health (accessed on 10 February 2023).
  2. Salete-Granado, D.; Carbonell, C.; Puertas-Miranda, D.; Vega-Rodríguez, V.J.; García-Macia, M.; Herrero, A.B.; Marcos, M. Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications. Antioxidants 2023, 12, 1425. [Google Scholar] [CrossRef] [PubMed]
  3. Zima, T.; Fialová, L.; Mestek, O.; Janebová, M.; Crkovská, J.; Malbohan, I.; Stípek, S.; Mikulíková, L.; Popov, P. Oxidative stress, metabolism of ethanol and alcohol-related diseases. J. Biomed. Sci. 2001, 8, 59–70. [Google Scholar] [CrossRef] [PubMed]
  4. You, M.; Fischer, M.; Deeg, M.A.; Crabb, D.W. Ethanol Induces Fatty Acid Synthesis Pathways by Activation of Sterol Regulatory Element-Binding Protein (SREBP). J. Biol. Chem. 2002, 277, 29342–29347. [Google Scholar] [CrossRef] [PubMed]
  5. Tan, H.K.; Yates, E.; Lilly, K.; Dhanda, A.D. Oxidative Stress in Alcohol-Related Liver Disease. World J. Hepatol. 2020, 12, 332–349. [Google Scholar] [CrossRef] [PubMed]
  6. Lívero, F.A.R.; Acco, A. Molecular Basis of Alcoholic Fatty Liver Disease: From Incidence to Treatment. Hepatol. Res. 2016, 46, 111–123. [Google Scholar] [CrossRef] [PubMed]
  7. Diesinger, T.; Buko, V.; Lautwein, A.; Dvorsky, R.; Belonovskaya, E.; Lukivskaya, O.; Naruta, E.; Kirko, S.; Andreev, V.; Buckert, D. Drug Targeting CYP2E1 for the Treatment of Early-Stage Alcoholic Steatohepatitis. PLoS ONE 2020, 15, e0235990. [Google Scholar] [CrossRef] [PubMed]
  8. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. J. Clin. Epidemiol. 2021, 134, 178–189. [Google Scholar] [CrossRef] [PubMed]
  9. Hooijmans, C.R.; Rovers, M.M.; De Vries, R.B.M.; Leenaars, M.; Ritskes-Hoitinga, M.; Langendam, M.W. SYRCLE’s Risk of Bias Tool for Animal Studies. BMC Med. Res. Methodol. 2014, 14, 43. [Google Scholar] [CrossRef]
  10. Abdelhamid, A.M.; Elsheakh, A.R.; Abdelaziz, R.R.; Suddek, G.M. Empagliflozin Ameliorates Ethanol-Induced Liver Injury by Modulating NF-ΚB/Nrf-2/PPAR-γ Interplay in Mice. Life Sci. 2020, 256, 117908. [Google Scholar] [CrossRef] [PubMed]
  11. Abdelhamid, A.M.; Elsheakh, A.R.; Suddek, G.M.; Abdelaziz, R.R. Telmisartan Alleviates Alcohol-Induced Liver Injury by Activation of PPAR-γ/ Nrf-2 Crosstalk in Mice. Int. Immunopharmacol. 2021, 99, 107963. [Google Scholar] [CrossRef] [PubMed]
  12. Al-Rejaie, S.S. Effect of Oleo-Gum-Resin on Ethanol-Induced Hepatotoxicity in Rats. J. Med. Sci. 2012, 12, 1–9. [Google Scholar] [CrossRef]
  13. Atef, M.M.; Hafez, Y.M.; Alshenawy, H.A.; Emam, M.N. Ameliorative Effects of Autophagy Inducer, Simvastatin on Alcohol-Induced Liver Disease in a Rat Model. J. Cell Biochem. 2019, 120, 7679–7688. [Google Scholar] [CrossRef] [PubMed]
  14. Bae, D.; Kim, J.; Lee, S.Y.; Choi, E.J.; Jung, M.A.; Jeong, C.S.; Na, J.R.; Kim, J.J.; Kim, S. Hepatoprotective Effects of Aqueous Extracts from Leaves of Dendropanax Morbifera Leveille against Alcohol-Induced Hepatotoxicity in Rats and in Vitro Anti-Oxidant Effects. Food Sci. Biotechnol. 2015, 24, 1495–1503. [Google Scholar] [CrossRef]
  15. Balasubramaniyan, V.; Sailaja, J.K.; Nalini, N. Role of Leptin on Alcohol-Induced Oxidative Stress in Swiss Mice. Pharmacol. Res. 2003, 47, 211–216. [Google Scholar] [CrossRef] [PubMed]
  16. Baranisrinivasan, P.; Elumalai, E.K.; Sivakumar, C.; Therasa, S.V.; David, E. Hepatoprotective Effect of Enicostemma Littorale Blume and Eclipta Alba during Ethanol Induced Oxidative Stress in Albino Rats. Int. J. Pharmacol. 2009, 5, 268–272. [Google Scholar] [CrossRef]
  17. Bardag-Gorce, F.; Oliva, J.; Lin, A.; Li, J.; French, B.A.; French, S.W. Proteasome Inhibitor up Regulates Liver Antioxidative Enzymes in Rat Model of Alcoholic Liver Disease. Exp. Mol. Pathol. 2011, 90, 123–130. [Google Scholar] [CrossRef] [PubMed]
  18. Bedi, O.; Bariwal, J.; Kumar, P.; Bhakuni, G.S. Hepatoprotective Activity of Morin and its Semi-Synthetic Derivatives Against Alcohol Induced Hepatotoxicity in Rats. Indian J. Physiol. Pharmacol. 2017, 61, 175–190. [Google Scholar]
  19. Bharrhan, S.; Koul, A.; Chopra, K.; Rishi, P. Catechin Suppresses an Array of Signalling Molecules and Modulates Alcohol-Induced Endotoxin Mediated Liver Injury in a Rat Model. PLoS ONE 2011, 6, e20635. [Google Scholar] [CrossRef] [PubMed]
  20. Bisht, P.; Chandrashekhara, S.; Das, K.; Tribedi, S. Effect of Cultural Condition on Evaluation of Hepatoprotective Activity of Methanolic Bark Extract of Anogeissus Latifolia on Ethanol-Induced Hepatotoxicity. Asian J. Pharm. Clin. Res. 2018, 11, 247–252. [Google Scholar] [CrossRef]
  21. Bispo, V.S.; Dantas, L.S.; Chaves Filho, A.B.; Pinto, I.F.D.; da Silva, R.P.; Otsuka, F.A.M.; Santos, R.B.; Santos, A.C.; Trindade, D.J.; Matos, H.R. Reduction of the DNA Damages, Hepatoprotective Effect and Antioxidant Potential of the Coconut Water, Ascorbic and Caffeic Acids in Oxidative Stress Mediated by Ethanol. An. Acad. Bras. Cienc. 2017, 89, 1095–1109. [Google Scholar] [CrossRef]
  22. Buko, V.; Kuzmitskaya, I.; Kirko, S.; Belonovskaya, E.; Naruta, E.; Lukivskaya, O.; Shlyahtun, A.; Ilyich, T.; Zakreska, A.; Zavodnik, I. Betulin Attenuated Liver Damage by Prevention of Hepatic Mitochondrial Dysfunction in Rats with Alcoholic Steatohepatitis. Physiol. Int. 2019, 106, 323–334. [Google Scholar] [CrossRef] [PubMed]
  23. Bulle, S.; Reddyvari, H.; Reddy Vaddi, D.; Pannuru, P.; Nch, V. Therapeutic potential of P. santalinus against alcohol-induced histo-pathological changes and oxidative damage in heart and lungs. Int. J. Res. Pharm. Sci. 2015, 6, 30–311. [Google Scholar]
  24. Cao, Y.W.; Jiang, Y.; Zhang, D.Y.; Wang, M.; Chen, W.S.; Su, H.; Wang, Y.T.; Wan, J.B. Protective Effects of Penthorum Chinense Pursh against Chronic Ethanol-Induced Liver Injury in Mice. J. Ethnopharmacol. 2015, 161, 92–98. [Google Scholar] [CrossRef]
  25. Chandra, R.; Aneja, R.; Rewal, C.; Konduri, R.; Dass, S.K.; Agarwal, S. An opium alkaloid-papaverine ameliorates ethanol-induced hepatotoxicity: Diminution of oxidative stress. Indian J. Clin. Biochem. 2000, 15, 155–160. [Google Scholar] [CrossRef]
  26. Chang, Y.Y.; Liu, Y.C.; Kuo, Y.H.; Lin, Y.L.; Wu, Y.H.S.; Chen, J.W.; Chen, Y.C. Effects of Antrosterol from Antrodia Camphorata Submerged Whole Broth on Lipid Homeostasis, Antioxidation, Alcohol Clearance, and Anti-Inflammation in Livers of Chronic-Alcohol Fed Mice. J. Ethnopharmacol. 2017, 202, 200–207. [Google Scholar] [CrossRef] [PubMed]
  27. Chang, B.Y.; Kim, H.J.; Kim, T.Y.; Kim, S.Y. Enzyme-Treated Zizania Latifolia Extract Protects against Alcohol-Induced Liver Injury by Regulating the Nrf2 Pathway. Antioxidants 2021, 10, 960. [Google Scholar] [CrossRef]
  28. Chaturvedi, P.; George, S.; John, A. Preventive and Protective Effects of Wild Basil in Ethanol-Induced Liver Toxicity in Rats. Br. J. Biomed. Sci. 2007, 64, 10–12. [Google Scholar] [CrossRef]
  29. Chavan, T.; Ghadge, A.; Karandikar, M.; Pandit, V.; Ranjekar, P.; Kulkarni, O.; Kuvalekar, A.; Mantri, N. Activity of Satwa against Alcohol Injury in rats. Altern. Ther. Health Med. 2017, 23, 34–40. [Google Scholar]
  30. Chen, Y.L.; Peng, H.C.; Tan, S.W.; Tsai, C.Y.; Huang, Y.H.; Wu, H.Y.; Yang, S.C. Amelioration of Ethanol-Induced Liver Injury in Rats by Nanogold Flakes. Alcohol 2013, 47, 467–472. [Google Scholar] [CrossRef] [PubMed]
  31. Chen, Y.; Singh, S.; Matsumoto, A.; Manna, S.K.; Abdelmegeed, M.A.; Golla, S.; Murphy, R.C.; Dong, H.; Song, B.J.; Gonzalez, F.J.; et al. Chronic Glutathione Depletion Confers Protection against Alcohol-Induced Steatosis: Implication for Redox Activation of AMP-Activated Protein Kinase Pathway. Sci. Rep. 2016, 6, 29743. [Google Scholar] [CrossRef] [PubMed]
  32. Cheng, D.; Kong, H. The Effect of Lycium Barbarum Polysaccharide on Alcohol-Induced Oxidative Stress in Rats. Molecules 2011, 16, 2542–2550. [Google Scholar] [CrossRef] [PubMed]
  33. Chiu, P.Y.; Lam, P.Y.; Leung, H.Y.; Leong, P.K.; Ma, C.W.; Tang, Q.T.; Ko, K.M. Co-Treatment with Shengmai San-Derived Herbal Product Ameliorates Chronic Ethanol-Induced Liver Damage in Rats. Rejuvenation Res. 2011, 14, 17–23. [Google Scholar] [CrossRef] [PubMed]
  34. Chu, J.; Yan, R.; Wang, S.; Li, G.; Kang, X.; Hu, Y.; Lin, M.; Shan, W.; Zhao, Y.; Wang, Z.; et al. Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease. Front. Pharmacol. 2021, 12, 668708. [Google Scholar] [CrossRef] [PubMed]
  35. Colantoni, A.; Paglia, N.L.; De Maria, N.; Emanuele, M.A.; Emanuele, N.V.; Idilman, R.; Harig, J.; Van Thiel, D.H. Influence of Sex Hormonal Status on Alcohol-Induced Oxidative Injury in Male and Female Rat Liver. Alcohol. Clin. Exp. Res. 2000, 24, 1467–1473. [Google Scholar] [PubMed]
  36. Cui, Y.; Ye, Q.; Wang, H.; Li, Y.; Xia, X.; Yao, W.; Qian, H. Aloin Protects against Chronic Alcoholic Liver Injury via Attenuating Lipid Accumulation, Oxidative Stress and Inflammation in Mice. Arch. Pharmacal Res. 2014, 37, 1624–1633. [Google Scholar] [CrossRef] [PubMed]
  37. Cui, Y.; Ye, Q.; Wang, H.; Li, Y.; Yao, W.; Qian, H. Hepatoprotective Potential of Aloe Vera Polysaccharides against Chronic Alcohol-Induced Hepatotoxicity in Mice. J. Sci. Food Agric. 2014, 94, 1764–1771. [Google Scholar] [CrossRef] [PubMed]
  38. Das, S.K.; Vasudevan, D.M. Effect of Lecithin in the Treatment of Ethanol Mediated Free Radical Induced Hepatotoxicity. Indian J. Clin. Biochem. 2006, 21, 62–69. [Google Scholar] [CrossRef]
  39. Das, S.K.; Mukherjee, S.; Vasudevan, D.M. Effects of Long Term Ethanol Consumption Mediated Oxidative Stress on Neovessel Generation in Liver. Toxicol. Mech. Methods 2012, 22, 375–382. [Google Scholar] [CrossRef] [PubMed]
  40. De Souza, C.E.A.; Stolf, A.M.; Dreifuss, A.A.; Lívero, F.R.; Gomes, L.O.; Petiz, L.; Beltrame, O.; Dittrich, R.L.; Telles, J.E.Q.; Cadena, S.M. Characterization of an Alcoholic Hepatic Steatosis Model Induced by Ethanol and High-Fat Diet in Rats. Braz. Arch. Biol. Technol. 2015, 58, 367–378. [Google Scholar] [CrossRef]
  41. Develi, S.; Evran, B.; Kalaz, E.B.; Koçak-Toker, N.; Erata, G.Ö. Protective Effect of Nigella Sativa Oil against Binge Ethanol-Induced Oxidative Stress and Liver Injury in Rats. Chin. J. Nat. Med. 2014, 12, 495–499. [Google Scholar] [CrossRef] [PubMed]
  42. Dou, X.; Shen, C.; Wang, Z.; Li, S.; Zhang, X.; Song, Z. Protection of Nicotinic Acid against Oxidative Stress-Induced Cell Death in Hepatocytes Contributes to Its Beneficial Effect on Alcohol-Induced Liver Injury in Mice. J. Nutr. Biochem. 2013, 24, 1520–1528. [Google Scholar] [CrossRef] [PubMed]
  43. Du, S.-Y.; Zhang, Y.-L.; Bai, R.-X.; Ai, Z.-L.; Xie, B.-S.; Yang, H.-Y. Lutein Prevents Alcohol-Induced Liver Disease in Rats by Modulating Oxidative Stress and Inflammation. Int. J. Clin. Exp. Med. 2015, 8, 8785–8793. [Google Scholar] [PubMed]
  44. Duryee, M.J.; Dusad, A.; Hunter, C.D.; Kharbanda, K.K.; Bruenjes, J.D.; Easterling, K.C.; Siebler, J.C.; Thiele, G.M.; Chakkalakal, D.A. N-Acetyl Cysteine Treatment Restores Early Phase Fracture Healing in Ethanol-Fed Rats. Alcohol Clin. Exp. Res. 2018, 42, 1206–1216. [Google Scholar] [CrossRef] [PubMed]
  45. Feng, R.; Chen, J.H.; Liu, C.H.; Xia, F.B.; Xiao, Z.; Zhang, X.; Wan, J.B. A Combination of Pueraria Lobata and Silybum Marianum Protects against Alcoholic Liver Disease in Mice. Phytomedicine 2019, 58, 152824. [Google Scholar] [CrossRef] [PubMed]
  46. Galligan, J.J.; Smathers, R.L.; Shearn, C.T.; Fritz, K.S.; Backos, D.S.; Jiang, H.; Franklin, C.C.; Orlicky, D.J.; MacLean, K.N.; Petersen, D.R. Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease. J. Toxicol. 2012, 2012, 207594. [Google Scholar] [CrossRef] [PubMed]
  47. Gao, L.; Yuan, J.; Cheng, Y.; Chen, M.; Zhang, G.; Wu, J. Selenomethionine-Dominated Selenium-Enriched Peanut Protein Ameliorates Alcohol-Induced Liver Disease in Mice by Suppressing Oxidative Stress. Foods 2021, 10, 2979. [Google Scholar] [CrossRef] [PubMed]
  48. George, S.; Chaturvedi, P. A comparative study of the antioxidant properties of two different species of Ocimum of southern Africa on alcohol-induced oxidative stress. J. Med. Food. 2009, 12, 1154–1158. [Google Scholar] [CrossRef] [PubMed]
  49. Gustot, T.; Lemmers, A.; Moreno, C.; Nagy, N.; Quertinmont, E.; Nicaise, C.; Franchimont, D.; Louis, H.; Devière, J.; Le Moine, O. Differential Liver Sensitization to Toll-like Receptor Pathways in Mice with Alcoholic Fatty Liver. Hepatology 2006, 43, 989–1000. [Google Scholar] [CrossRef] [PubMed]
  50. Han, X.; Liu, J.; Bai, Y.; Hang, A.; Lu, T.; Mao, C. An Iridoid Glycoside from Cornus Officinalis Balances Intestinal Microbiome Disorder and Alleviates Alcohol-Induced Liver Injury. J. Funct. Foods 2021, 82, 104488. [Google Scholar] [CrossRef]
  51. Hao, L.; Sun, Q.; Zhong, W.; Zhang, W.; Sun, X.; Zhou, Z. Mitochondria-Targeted Ubiquinone (MitoQ) Enhances Acetaldehyde Clearance by Reversing Alcohol-Induced Posttranslational Modification of Aldehyde Dehydrogenase 2: A Molecular Mechanism of Protection against Alcoholic Liver Disease. Redox Biol. 2018, 14, 626–636. [Google Scholar] [CrossRef] [PubMed]
  52. Hao, L.; Zhong, W.; Sun, X.; Zhou, Z. TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice. Front. Pharmacol. 2021, 12, 709002. [Google Scholar] [CrossRef] [PubMed]
  53. Hasanein, P.; Seifi, R. Beneficial effects of rosmarinic acid against alcohol-induced hepatotoxicity in rats. Can. J. Physiol. Pharmacol. 2018, 96, 32–37. [Google Scholar] [CrossRef] [PubMed]
  54. He, Y.; Xia, F.; Nan, M.; Li, L.; Wang, X.; Zhang, Y. Regulation of Bcl-2 and the NF-KB Signaling Pathway by Succinyl Rotundic Acid in Livers of Rats with Alcoholic Hepatitis. Int. J. Agric. Biol. 2021, 25, 730–734. [Google Scholar] [CrossRef]
  55. Hsu, J.Y.; Lin, H.H.; Hsu, C.C.; Chen, B.C.; Chen, J.H. Aqueous Extract of Pepino (Solanum Muriactum Ait) Leaves Ameliorate Lipid Accumulation and Oxidative Stress in Alcoholic Fatty Liver Disease. Nutrients 2018, 10, 931. [Google Scholar] [CrossRef] [PubMed]
  56. Hu, B.; Jiang, W.; Yang, Y.; Xu, W.; Liu, C.; Zhang, S.; Qian, H.; Zhang, W. Gut-Liver Axis Reveals the Protective Effect of Exopolysaccharides Isolated from Sporidiobolus Pararoseus on Alcohol-Induced Liver Injury. J. Funct. Foods 2021, 87, 104737. [Google Scholar] [CrossRef]
  57. Huang, Q.H.; Xu, L.Q.; Liu, Y.H.; Wu, J.Z.; Wu, X.; Lai, X.P.; Li, Y.C.; Su, Z.R.; Chen, J.N.; Xie, Y.L. Polydatin Protects Rat Liver against Ethanol-Induced Injury: Involvement of CYP2E1/ROS/Nrf2 and TLR4/NF- B P65 Pathway. Evid. Based Complement. Alternat. Med. 2017, 2017, 7953850. [Google Scholar] [CrossRef] [PubMed]
  58. Ilaiyaraja, N.; Khanum, F. Amelioration of Alcohol-Induced Hepatotoxicity and Oxidative Stress in Rats by Acorus Calamus. J. Diet Suppl. 2011, 8, 331–345. [Google Scholar] [CrossRef] [PubMed]
  59. Jayaraman, J.; Veerappan, M.; Namasivayam, N. Potential Beneficial Effect of Naringenin on Lipid Peroxidation and Antioxidant Status in Rats with Ethanol-Induced Hepatotoxicity. J. Pharm. Pharmacol. 2009, 61, 1383–1390. [Google Scholar] [CrossRef] [PubMed]
  60. Jiang, Z.; Chen, C.; Wang, J.; Xie, W.; Wang, M.; Li, X.; Zhang, X. Purple Potato (Solanum tuberosum L.) Anthocyanins Attenuate Alcohol-Induced Hepatic Injury by Enhancing Antioxidant Defense. J. Nat. Med. 2016, 70, 45–53. [Google Scholar] [CrossRef] [PubMed]
  61. Jiang, X.; Lin, D.; Shao, H.; Yang, X. Antioxidant Properties of Komagataeibacter Hansenii CGMCC 3917 and Its Ameliorative Effects on Alcohol-Induced Liver Injury in Mice. CYTA J. Food 2019, 17, 355–364. [Google Scholar] [CrossRef]
  62. Jin, D.C.; Jeong, S.W.; Park, P.S. Effects of Green Tea Extract on Acute Ethanol-Induced Hepatotoxicity in Rats. J. Korean Soc. Food Sci. Nutr. 2010, 39, 343–349. [Google Scholar] [CrossRef]
  63. Jose, S.P.; Mohanan, R.; Sandya, S.; Asha, S.; Krishnakumar, I.M. A Novel Powder Formulation of Coconut Inflorescence Sap Inhibits Alcoholic Liver Damage by Modulating Inflammatory Markers, Extracellular Matrix Metalloproteinase, and Oxidative Stress. J. Food Biochem. 2018, 42, e12543. [Google Scholar] [CrossRef]
  64. Kanbak, G.; Inal, M.; Bayçu, C. Ethanol-Induced Hepatotoxicity and Protective Effect of Betaine. Cell Biochem. Funct. 2001, 19, 281–285. [Google Scholar] [CrossRef] [PubMed]
  65. Kanchana, G.; Jayapriya, K. Antioxidant Effect of Livomap, a Polyherbal Formulation on Ethanol Induced Hepatotoxicity in Albino Wistar Rats. J. Appl. Pharm. Sci. 2013, 3, 52–56. [Google Scholar] [CrossRef]
  66. Kang, X.; Zhong, W.; Liu, J.; Song, Z.; McClain, C.J.; Kang, Y.J.; Zhou, Z. Zinc Supplementation Reverses Alcohol-Induced Steatosis in Mice through Reactivating Hepatocyte Nuclear Factor-4α and Peroxisome Proliferator-Activated Receptor-α. Hepatology 2009, 50, 1241–1250. [Google Scholar] [CrossRef] [PubMed]
  67. Kang, H.; Kim, M.B.; Park, Y.K.; Lee, J.Y. A Mouse Model of the Regression of Alcoholic Hepatitis: Monitoring the Regression of Hepatic Steatosis, Inflammation, Oxidative Stress, and NAD+ Metabolism upon Alcohol Withdrawal. J. Nutr. Biochem. 2022, 99, 108852. [Google Scholar] [CrossRef] [PubMed]
  68. Kaviarasan, S.; Sundarapandiyan, R.; Anuradha, C.V. Epigallocatechin Gallate, a Green Tea Phytochemical, Attenuates Alcohol-Induced Hepatic Protein and Lipid Damage. Toxicol. Mech. Methods 2008, 18, 645–652. [Google Scholar] [CrossRef] [PubMed]
  69. Khanal, T.; Choi, J.H.; Hwang, Y.P.; Chung, Y.C.; Jeong, H.G. Saponins Isolated from the Root of Platycodon Grandiflorum Protect against Acute Ethanol-Induced Hepatotoxicity in Mice. Food Chem.Toxicol. 2009, 47, 530–535. [Google Scholar] [CrossRef] [PubMed]
  70. Kim, S.J.; Park, J.G.; Lee, S.M. Protective Effect of Heme Oxygenase-1 Induction against Hepatic Injury in Alcoholic Steatotic Liver Exposed to Cold Ischemia/Reperfusion. Life Sci. 2012, 90, 169–176. [Google Scholar] [CrossRef] [PubMed]
  71. Kim, D.; Kim, G.W.; Lee, S.H.; Han, G.D. Ligularia Fischeri Extract Attenuates Liver Damage Induced by Chronic Alcohol Intake. Pharm. Biol. 2016, 54, 1465–1473. [Google Scholar] [CrossRef] [PubMed]
  72. Kumar, D.; Dwivedi, D.K.; Lahkar, M.; Jangra, A. Hepatoprotective Potential of 7,8-Dihydroxyflavone against Alcohol and High-Fat Diet Induced Liver Toxicity via Attenuation of Oxido-Nitrosative Stress and NF-ΚB Activation. Pharmacol. Rep. 2019, 71, 1235–1243. [Google Scholar] [CrossRef] [PubMed]
  73. Lai, J.R.; Ke, B.J.; Hsu, Y.W.; Lee, C.L. Dimerumic Acid and Deferricoprogen Produced by Monascus purpureus Attenuate Liquid Ethanol Diet-Induced Alcoholic Hepatitis via Suppressing NF-ΚB Inflammation Signalling Pathways and Stimulation of AMPK-Mediated Lipid Metabolism. J. Funct. Foods 2019, 60, 103393. [Google Scholar] [CrossRef]
  74. Lee, M.; Kim, Y.; Yoon, H.G.; You, Y.; Park, J.; Lee, Y.H.; Kim, S.; Hwang, K.; Lee, J.; Jun, W. Prevention of Ethanol-Induced Hepatotoxicity by Fermented Curcuma Longa L. in C57BL/6 Mice. Food Sci. Biotechnol. 2014, 23, 925–930. [Google Scholar] [CrossRef]
  75. Lee, J.Y.; An, Y.J.; Kim, J.W.; Choi, H.K.; Lee, Y.H. Effect of Angelica Keiskei Koidzumi Extract on Alcohol-Induced Hepatotoxicity in Vitro and in Vivo. J. Korean Soc. Food Sci. Nutr. 2016, 45, 1391–1397. [Google Scholar] [CrossRef]
  76. Lee, Y.J.; Hsu, J.D.; Lin, W.L.; Kao, S.H.; Wang, C.J. Upregulation of Caveolin-1 by Mulberry Leaf Extract and Its Major Components, Chlorogenic Acid Derivatives, Attenuates Alcoholic Steatohepatitis: Via Inhibition of Oxidative Stress. Food Funct. 2017, 8, 397–405. [Google Scholar] [CrossRef] [PubMed]
  77. Lee, H.Y.; Nam, Y.; Choi, W.S.; Kim, T.W.; Lee, J.; Sohn, U.D. The Hepato-Protective Effect of Eupatilin on an Alcoholic Liver Disease Model of Rats. Korean J. Physiol. Pharmacol. 2020, 24, 385–394. [Google Scholar] [CrossRef] [PubMed]
  78. Lee, D.H.; Lee, J.S.; Lee, I.H.; Hong, J.T. Therapeutic Potency of Fermented Field Water in Ethanol-Induced Liver Injury. RSC Adv. 2020, 10, 1544–1551. [Google Scholar] [CrossRef] [PubMed]
  79. Lee, Y.J.; Tsai, M.C.; Lin, H.T.; Wang, C.J.; Kao, S.H. Aqueous Mulberry Leaf Extract Ameliorates Alcoholic Liver Injury Associating with Upregulation of Ethanol Metabolism and Suppression of Hepatic Lipogenesis. Evid. Comp. Alt. Med. 2021, 2021, 6658422. [Google Scholar] [CrossRef] [PubMed]
  80. Li, Y.; Gao, C.; Shi, Y.; Tang, Y.; Liu, L.; Xiong, T.; Du, M.; Xing, M.; Yao, P. Carbon Monoxide Alleviates Ethanol-Induced Oxidative Damage and Inflammatory Stress through Activating P38 MAPK Pathway. Toxicol. Appl Pharmacol. 2013, 273, 53–58. [Google Scholar] [CrossRef] [PubMed]
  81. Li, B.; Zhu, L.; Wu, T.; Zhang, J.; Jiao, X.; Liu, X.; Wang, Y.; Meng, X. Effects of Triterpenoid from Schisandra Chinensis on Oxidative Stress in Alcohol-Induced Liver Injury in Rats. Cell Biochem. Biophys. 2015, 71, 803–811. [Google Scholar] [CrossRef] [PubMed]
  82. Li, Y.; Chen, M.; Xu, Y.; Yu, X.; Xiong, T.; Du, M.; Sun, J.; Liu, L.; Tang, Y.; Yao, P. Iron-Mediated Lysosomal Membrane Permeabilization in Ethanol-Induced Hepatic Oxidative Damage and Apoptosis: Protective Effects of Quercetin. Oxid. Med. Cell Longev. 2016, 2016, 4147610. [Google Scholar] [CrossRef] [PubMed]
  83. Li, L.; Wu, Y.; Yin, F.; Feng, Q.; Dong, X.; Zhang, R.; Yin, Z.; Luo, L. Fructose 1, 6-Diphosphate Prevents Alcohol-Induced Liver Injury through Inhibiting Oxidative Stress and Promoting Alcohol Metabolism in Mice. Eur. J. Pharmacol. 2017, 815, 274–281. [Google Scholar] [CrossRef] [PubMed]
  84. Li, D.; Sun, L.; Yang, Y.; Wang, Z.; Yang, X.; Guo, Y. Preventive and Therapeutic Effects of Pigment and Polysaccharides in Lycium Barbarum on Alcohol-Induced Fatty Liver Disease in Mice. CYTA J. Food 2018, 16, 938–949. [Google Scholar] [CrossRef]
  85. Li, B.; Mao, Q.; Zhou, D.; Luo, M.; Gan, R.; Li, H.; Huang, S.; Saimaiti, A.; Shang, A.; Li, H. Effects of Tea against Alcoholic Fatty Liver Disease by Modulating Gut Microbiota in Chronic Alcohol-Exposed Mice. Foods 2021, 10, 1232. [Google Scholar] [CrossRef] [PubMed]
  86. Li, B.Y.; Li, H.Y.; Zhou, D.D.; Huang, S.Y.; Luo, M.; Gan, R.Y.; Mao, Q.Q.; Saimaiti, A.; Shang, A.; Li, H. Bin Effects of Different Green Tea Extracts on Chronic Alcohol Induced-Fatty Liver Disease by Ameliorating Oxidative Stress and Inflammation in Mice. Oxid. Med. Cell Longev. 2021, 2021, 5188205. [Google Scholar] [CrossRef] [PubMed]
  87. Li, H.; Shi, J.; Zhao, L.; Guan, J.; Liu, F.; Huo, G.; Li, B. Lactobacillus Plantarum KLDS1.0344 and Lactobacillus Acidophilus KLDS1.0901 Mixture Prevents Chronic Alcoholic Liver Injury in Mice by Protecting the Intestinal Barrier and Regulating Gut Microbiota and Liver-Related Pathways. J. Agric. Food Chem. 2021, 69, 183–197. [Google Scholar] [CrossRef] [PubMed]
  88. Li, B.Y.; Mao, Q.Q.; Gan, R.Y.; Cao, S.Y.; Xu, X.Y.; Luo, M.; Li, H.Y.; Li, H. Bin Protective Effects of Tea Extracts against Alcoholic Fatty Liver Disease in Mice via Modulating Cytochrome P450 2E1 Expression and Ameliorating Oxidative Damage. Food Sci. Nutr. 2021, 9, 5626–5640. [Google Scholar] [CrossRef] [PubMed]
  89. Lian, L.H.; Wu, Y.L.; Song, S.Z.; Wan, Y.; Xie, W.X.; Li, X.; Bai, T.; Ouyang, B.Q.; Nan, J.X. Gentiana Manshurica Kitagawa Reverses Acute Alcohol-Induced Liver Steatosis through Blocking Sterol Regulatory Element-Binding Protein-1 Maturation. J. Agric. Food Chem. 2010, 58, 13013–13019. [Google Scholar] [CrossRef] [PubMed]
  90. Lin, C.P.; Chuang, W.C.; Lu, F.J.; Chen, C.Y. Anti-Oxidant and Anti-Inflammatory Effects of Hydrogen-Rich Water Alleviate Ethanol-Induced Fatty Liver in Mice. World J. Gastroenterol. 2017, 23, 4920–4934. [Google Scholar] [CrossRef] [PubMed]
  91. Lin, T.A.; Ke, B.J.; Cheng, S.C.; Lee, C.L. Red Quinoa Bran Extract Prevented Alcoholic Fatty Liver Disease via Increasing Antioxidative System and Repressing Fatty Acid Synthesis Factors in Mice Fed Alcohol Liquid Diet. Molecules 2021, 26, 6973. [Google Scholar] [CrossRef] [PubMed]
  92. Liu, J.; Wang, X.; Liu, R.; Liu, Y.; Zhang, T.; Fu, H.; Hai, C. Oleanolic Acid Co-Administration Alleviates Ethanol-Induced Hepatic Injury via Nrf-2 and Ethanol-Metabolizing Modulating in Rats. Chem. Biol. Interact. 2014, 221, 88–98. [Google Scholar] [CrossRef] [PubMed]
  93. Liu, J.; Wang, X.; Peng, Z.; Zhang, T.; Wu, H.; Yu, W.; Kong, D.; Liu, Y.; Bai, H.; Liu, R.; et al. The Effects of Insulin Pre-Administration in Mice Exposed to Ethanol: Alleviating Hepatic Oxidative Injury through Anti-Oxidative, Anti-Apoptotic Activities and Deteriorating Hepatic Steatosis through SRBEP-1c Activation. Int. J. Biol. Sci. 2015, 11, 569–586. [Google Scholar] [CrossRef] [PubMed]
  94. Liu, J.; He, H.; Wang, J.; Guo, X.; Lin, H.; Chen, H.; Jiang, C.; Chen, L.; Yao, P.; Tang, Y. Oxidative Stress-Dependent Frataxin Inhibition Mediated Alcoholic Hepatocytotoxicity through Ferroptosis. Toxicology 2020, 445, 152584. [Google Scholar] [CrossRef] [PubMed]
  95. Liu, S.X.; Liu, H.; Wang, S.; Zhang, C.L.; Guo, F.F.; Zeng, T. Diallyl Disulfide Ameliorates Ethanol-Induced Liver Steatosis and Inflammation by Maintaining the Fatty Acid Catabolism and Regulating the Gut-Liver Axis. Food Chem. Toxicol. 2022, 164, 113108. [Google Scholar] [CrossRef] [PubMed]
  96. Liu, J.; Kong, D.; Ai, D.; Xu, A.; Yu, W.; Peng, Z.; Peng, J.; Wang, Z.; Liu, R.; Li, W.; et al. Insulin Resistance Enhances Binge Ethanol-Induced Liver Injury through Promoting Oxidative Stress and up-Regulation CYP2E1. Life Sci. 2022, 303, 120681. [Google Scholar] [CrossRef] [PubMed]
  97. Lu, K.H.; Tseng, H.C.; Liu, C.T.; Huang, C.J.; Chyuan, J.H.; Sheen, L.Y. Wild Bitter Gourd Protects against Alcoholic Fatty Liver in Mice by Attenuating Oxidative Stress and Inflammatory Responses. Food Funct. 2014, 5, 1027–1037. [Google Scholar] [CrossRef] [PubMed]
  98. Lu, C.; Xu, W.; Zhang, F.; Jin, H.; Chen, Q.; Chen, L.; Shao, J.; Wu, L.; Lu, Y.; Zheng, S. Ligustrazine Prevents Alcohol-Induced Liver Injury by Attenuating Hepatic Steatosis and Oxidative Stress. Int. Immunopharmacol. 2015, 29, 613–621. [Google Scholar] [CrossRef] [PubMed]
  99. Lu, N.S.; Chiu, W.C.; Chen, Y.L.; Peng, H.C.; Shirakawa, H.; Yang, S.C. Fish Oil Up-Regulates Hepatic Autophagy in Rats with Chronic Ethanol Consumption. J. Nutr. Biochem. 2020, 77, 108314. [Google Scholar] [CrossRef] [PubMed]
  100. Ma, J.; Liu, X.Y.; Noh, K.H.; Kim, M.J.; Song, Y.S. Protective Effects of Persimmon Leaf and Fruit Extracts against Acute Ethanol-Induced Hepatotoxicity. J. Food Sci. Nutr. 2007, 12, 202–208. [Google Scholar] [CrossRef]
  101. Madushani Herath, K.H.I.N.; Bing, S.J.; Cho, J.; Kim, A.; Kim, G.; Kim, J.S.; Kim, J.B.; Doh, Y.H.; Jee, Y. Sasa Quelpaertensis Leaves Ameliorate Alcohol-Induced Liver Injury by Attenuating Oxidative Stress in HepG2 Cells and Mice. Acta Histochem. 2018, 120, 477–489. [Google Scholar] [CrossRef] [PubMed]
  102. Mai, B.; Han, L.; Zhong, J.; Shu, J.; Cao, Z.; Fang, J.; Zhang, X.; Gao, Z.; Xiao, F. Rhoifolin Alleviates Alcoholic Liver Disease In Vivo and In Vitro via Inhibition of the TLR4/NF-ΚB Signaling Pathway. Front. Pharmacol. 2022, 13, 878898. [Google Scholar] [CrossRef] [PubMed]
  103. Maimaitimin, K.; Jiang, Z.; Aierken, A.; Shayibuzhati, M.; Zhang, X. Hepatoprotective Effect of Alhagi sparsifolia against Alcoholic Liver Injury in Mice. Braz. J. Pharm. Sci. 2018, 54, e17732. [Google Scholar] [CrossRef]
  104. Mallikarjuna, K.; Sahitya Chetan, P.; Sathyavelu Reddy, K.; Rajendra, W. Ethanol Toxicity: Rehabilitation of Hepatic Antioxidant Defense System with Dietary Ginger. Fitoterapia 2008, 79, 174–178. [Google Scholar] [CrossRef] [PubMed]
  105. Mandal, S.; Nelson, V.K.; Mukhopadhyay, S.; Bandhopadhyay, S.; Maganti, L.; Ghoshal, N.; Sen, G.; Biswas, T. 14-Deoxyandrographolide Targets Adenylate Cyclase and Prevents Ethanol-Induced Liver Injury through Constitutive NOS Dependent Reduced Redox Signaling in Rats. Food Chem. Toxicol. 2013, 59, 236–248. [Google Scholar] [CrossRef] [PubMed]
  106. Mehanna, E.T.; Ali, A.S.A.; El-Shaarawy, F.; Mesbah, N.M.; Abo-Elmatty, D.M.; Aborehab, N.M. Anti-Oxidant and Anti-Inflammatory Effects of Lipopolysaccharide from Rhodobacter sphaeroides against Ethanol-Induced Liver and Kidney Toxicity in Experimental Rats. Molecules 2021, 26, 7437. [Google Scholar] [CrossRef] [PubMed]
  107. Meng, X.; Tang, G.Y.; Zhao, C.N.; Liu, Q.; Xu, X.Y.; Cao, S.Y. Hepatoprotective Effects of Hovenia Dulcis Seeds against Alcoholic Liver Injury and Related Mechanisms Investigated via Network Pharmacology. World J. Gastroenterol. 2020, 26, 3432–3446. [Google Scholar] [CrossRef] [PubMed]
  108. Miana, J.B.; Gómez-Cambronero, L.; Lloret, A.; Pallardó, F.V.; Del Olmo, J.; Escudero, A.; Rodrigo, J.M.; Pellíin, A.; Via, J.R.; Viña, J.; et al. Mitochondrial Oxidative Stress and CD95 Ligand: A Dual Mechanism for Hepatocyte Apoptosis in Chronic Alcoholism. Hepatology 2002, 35, 1205–1214. [Google Scholar] [CrossRef] [PubMed]
  109. Ming, L.; Qi, B.; Hao, S.; Ji, R. Camel Milk Ameliorates Inflammatory Mechanisms in an Alcohol-Induced Liver Injury Mouse Model. Sci. Rep. 2021, 11, 22811. [Google Scholar] [CrossRef] [PubMed]
  110. Mohan, R.; Jose, S.; Sukumaran, S.; Asha, S.; Sheethal, S.; John, G.; Krishnakumar, I.M. Curcumin-Galactomannosides Mitigate Alcohol-Induced Liver Damage by Inhibiting Oxidative Stress, Hepatic Inflammation, and Enhance Bioavailability on TLR4/MMP Events Compared to Curcumin. J. Biochem. Mol. Toxicol. 2019, 33, e22315. [Google Scholar] [CrossRef] [PubMed]
  111. Nagappan, A.; Jung, D.Y.; Kim, J.H.; Lee, H.; Jung, M.H. Gomisin N Alleviates Ethanol-Induced Liver Injury through Ameliorating Lipid Metabolism and Oxidative Stress. Int. J. Mol. Sci. 2018, 19, 2601. [Google Scholar] [CrossRef]
  112. Nie, W.; Du, Y.Y.; Xu, F.R.; Zhou, K.; Wang, Z.M.; Al-Dalali, S.; Wang, Y.; Li, X.M.; Ma, Y.H.; Xie, Y. Oligopeptides from Jinhua Ham Prevent Alcohol-Induced Liver Damage by Regulating Intestinal Homeostasis and Oxidative Stress in Mice. Food Funct. 2021, 12, 10053–10070. [Google Scholar] [CrossRef]
  113. Nie, W.; Xu, F.; Zhou, K.; Yang, X.; Zhou, H.; Xu, B. Stearic Acid Prevent Alcohol-Induced Liver Damage by Regulating the Gut Microbiota. Food Res. Int. 2022, 155, 111095. [Google Scholar] [CrossRef] [PubMed]
  114. Oh, S.I.; Lee, M.S.; Kim, C.I.; Song, K.Y.; Park, S.C. Aspartate Modulates the Ethanol-Induced Oxidative Stress and Glutathione Utilizing Enzymes in Rat Testes. Exp. Mol. Med. 2002, 34, 47–52. [Google Scholar] [CrossRef] [PubMed][Green Version]
  115. Osaki, K.; Arakawa, T.; Kim, B.; Lee, M.; Jeong, C.; Kang, N. Hepatoprotcetive Effects of Oyster (Crassostrea Gigas) Extract in a Rat Model of Alcohol-Induced Oxidative Stress. J. Korean Soc. Food Sci. Nutr. 2016, 45, 805–811. [Google Scholar] [CrossRef]
  116. Panda, V.; Ashar, H.; Srinath, S. Antioxidant and Hepatoprotective Effect of Garcinia Indica Fruit Rind in Ethanolinduced Hepatic Damage in Rodents. Interdiscip. Toxicol. 2012, 5, 207–213. [Google Scholar] [CrossRef] [PubMed]
  117. Panda, V.; Kharat, P.; Sudhamani, S. Hepatoprotective Effect of the Macrotyloma Uniflorum Seed (Horse Gram) in Ethanol-Induced Hepatic Damage in Rats. J. Biol. Act. Prod. Nat. 2015, 5, 178–191. [Google Scholar]
  118. Pari, L.; Suresh, A. Effect of Grape (Vitis vinifera L.) Leaf Extract on Alcohol Induced Oxidative Stress in Rats. Food Chem. Toxicol. 2008, 46, 1627–1634. [Google Scholar] [CrossRef] [PubMed]
  119. Park, H.Y.; Ha, S.K.; Eom, H.; Choi, I. Narirutin Fraction from Citrus Peels Attenuates Alcoholic Liver Disease in Mice. Food Chem. Toxicol. 2013, 55, 637–644. [Google Scholar] [CrossRef] [PubMed]
  120. Park, S.Y.; Ahn, G.; Um, J.H.; Han, E.J.; Ahn, C.B.; Yoon, N.Y.; Je, J.Y. Hepatoprotective Effect of Chitosan-Caffeic Acid Conjugate against Ethanol-Treated Mice. Exp. Toxicol. Pathol. 2017, 69, 618–624. [Google Scholar] [CrossRef] [PubMed]
  121. Park, S.Y.; Fernando, I.P.S.; Han, E.J.; Kim, M.J.; Jung, K.; Kang, D.S.; Ahn, C.B.; Ahn, G. In Vivo Hepatoprotective Effects of a Peptide Fraction from Krill Protein Hydrolysates against Alcohol-Induced Oxidative Damage. Mar. Drugs 2019, 17, 690. [Google Scholar] [CrossRef] [PubMed]
  122. Patere, S.N.; Majumdar, A.S.; Saraf, M.N. Exacerbation of Alcohol-Induced Oxidative Stress in Rats by Polyunsaturated Fatty Acids and Iron Load. Indian J. Pharm. Sci. 2011, 73, 152–158. [Google Scholar] [PubMed]
  123. Peng, H.C.; Chen, Y.L.; Chen, J.R.; Yang, S.S.; Huang, K.H.; Wu, Y.C.; Lin, Y.H.; Yang, S.C. Effects of Glutamine Administration on Inflammatory Responses in Chronic Ethanol-Fed Rats. J. Nutr. Biochem. 2011, 22, 282–288. [Google Scholar] [CrossRef] [PubMed]
  124. Peng, H.C.; Chen, Y.L.; Yang, S.Y.; Ho, P.Y.; Yang, S.S.; Hu, J.T.; Yang, S.C. The Antiapoptotic Effects of Different Doses of β-Carotene in Chronic Ethanol-Fed Rats. Hepatobiliary Surg. Nutr. 2013, 2, 132–141. [Google Scholar] [PubMed]
  125. Pi, A.; Jiang, K.; Ding, Q.; Lai, S.; Yang, W.; Zhu, J.; Guo, R.; Fan, Y.; Chi, L.; Li, S. Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice. Front. Pharmacol. 2021, 12, 752148. [Google Scholar] [CrossRef] [PubMed]
  126. Prathibha, P.; Rejitha, S.; Harikrishnan, R.; Das, S.S.; Abhilash, P.A.; Indira, M. Additive Effect of Alpha-Tocopherol and Ascorbic Acid in Combating Ethanol-Induced Hepatic Fibrosis. Redox Rep. 2013, 18, 36–46. [Google Scholar] [CrossRef] [PubMed]
  127. Qi, N.; Liu, C.; Yang, H.; Shi, W.; Wang, S.; Zhou, Y.; Wei, C.; Gu, F.; Qin, Y. Therapeutic Hexapeptide (PGPIPN) Prevents and Cures Alcoholic Fatty Liver Disease by Affecting the Expressions of Genes Related with Lipid Metabolism and Oxidative Stress. Oncotarget 2017, 8, 88079–88093. [Google Scholar] [CrossRef] [PubMed][Green Version]
  128. Qu, L.; Zhu, Y.; Liu, Y.; Yang, H.; Zhu, C.; Ma, P.; Deng, J.; Fan, D. Protective Effects of Ginsenoside Rk3 against Chronic Alcohol-Induced Liver Injury in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis. Food Chem. Toxicol. 2019, 126, 277–284. [Google Scholar] [CrossRef] [PubMed]
  129. Rabelo, A.C.S.; de Pádua Lúcio, K.; Araújo, C.M.; de Araújo, G.R.; de Amorim Miranda, P.H.; Carneiro, A.C.A.; de Castro Ribeiro, É.M.; de Melo Silva, B.; de Lima, W.G.; Costa, D.C. Baccharis Trimera Protects against Ethanol Induced Hepatotoxicity in Vitro and in Vivo. J. Ethnopharmacol. 2018, 215, 1–13. [Google Scholar] [CrossRef]
  130. Rejitha, S.; Prathibha, P.; Indira, M. Amelioration of Alcohol-Induced Hepatotoxicity by the Administration of Ethanolic Extract of Sida Cordifolia Linn. Brit. J. Nutr. 2012, 108, 1256–1263. [Google Scholar] [CrossRef] [PubMed]
  131. Roede, J.R.; Stewart, B.J.; Petersen, D.R. Decreased Expression of Peroxiredoxin 6 in a Mouse Model of Ethanol Consumption. Free Radic. Biol. Med. 2008, 45, 1551–1558. [Google Scholar] [CrossRef] [PubMed]
  132. Roede, J.R.; Orlicky, D.J.; Fisher, A.B.; Petersen, D.R. Overexpression of Peroxiredoxin 6 Does Not Prevent Ethanol-Mediated Oxidative Stress and May Play a Role in Hepatic Lipid Accumulation. J. Pharmacol. Exp. Ther. 2009, 330, 79–88. [Google Scholar] [CrossRef] [PubMed]
  133. Rong, S.; Zhao, Y.; Bao, W.; Xiao, X.; Wang, D.; Nussler, A.K.; Yan, H.; Yao, P.; Liu, L. Curcumin Prevents Chronic Alcohol-Induced Liver Disease Involving Decreasing ROS Generation and Enhancing Antioxidative Capacity. Phytomedicine 2012, 19, 545–550. [Google Scholar] [CrossRef] [PubMed]
  134. Ronis, M.J.J.; Butura, A.; Sampey, B.P.; Shankar, K.; Prior, R.L.; Korourian, S.; Albano, E.; Ingelman-Sundberg, M.; Petersen, D.R.; Badger, T.M. Effects of N-Acetylcysteine on Ethanol-Induced Hepatotoxicity in Rats Fed via Total Enteral Nutrition. Free Radic. Biol. Med. 2005, 39, 619–630. [Google Scholar] [CrossRef] [PubMed]
  135. Ronis, M.J.; Korourian, S.; Blackburn, M.L.; Badeaux, J.; Badger, T.M. The Role of Ethanol Metabolism in Development of Alcoholic Steatohepatitis in the Rat. Alcohol 2010, 44, 157–169. [Google Scholar] [CrossRef] [PubMed]
  136. Samuhasaneeto, S.; Thong-Ngam, D.; Kulaputana, O.; Suyasunanont, D.; Klaikeaw, N. Curcumin Decreased Oxidative Stress, Inhibited Nf-k b Activation, and Improved Liver Pathology in Ethanol-Induced Liver Injury in Rats. J. Biomed. Biotechnol. 2009, 2009, 981963. [Google Scholar] [CrossRef] [PubMed]
  137. Saravanan, N.; Rajasankar, S.; Nalini, N. Antioxidant Effect of 2-Hydroxy-4-Methoxy Benzoic Acid on Ethanol-Induced Hepatotoxicity in Rats. J. Pharm. Pharmacol. 2010, 59, 445–453. [Google Scholar] [CrossRef] [PubMed]
  138. Saravanan, N.; Nalini, N. Antioxidant Effect of Hemidesmus Indicus on Ethanol-Induced Hepatotoxicity in Rats. J. Med. Food 2007, 10, 675–682. [Google Scholar] [CrossRef] [PubMed]
  139. Sathiavelu, J.; Senapathy, G.J.; Devaraj, R.; Namasivayam, N. Hepatoprotective Effect of Chrysin on Prooxidant-Antioxidant Status during Ethanol-Induced Toxicity in Female Albino Rats. J. Pharm. Pharmacol. 2009, 61, 809–817. [Google Scholar] [CrossRef] [PubMed]
  140. Senthilkumar, R.; Sengottuvelan, M.; Nalini, N. Protective Effect of Glycine Supplementation on the Levels of Lipid Peroxidation and Antioxidant Enzymes in the Erythrocyte of Rats with Alcohol-Induced Liver Injury. Cell Biochem. Funct. 2004, 22, 123–128. [Google Scholar] [CrossRef] [PubMed]
  141. Shankari, S.G.; Karthikesan, K.; Jalaludeen, A.M.; Ashokkumar, N.; Ashokkumar, N.; Patill, S.; Brid, S. Hepatoprotective effect of morin on ethanol-induced hepatotoxicity in rats. J. Basic Clin. Physiol. Pharmacol. 2010, 21, 277–294. [Google Scholar] [CrossRef] [PubMed]
  142. Shearn, C.T.; Backos, D.S.; Orlicky, D.J.; Smathers-McCullough, R.L.; Petersen, D.R. Identification of 5′ AMP-Activated Kinase as a Target of Reactive Aldehydes during Chronic Ingestion of High Concentrations of Ethanol. J. Biol. Chem. 2014, 289, 15449–15462. [Google Scholar] [CrossRef] [PubMed]
  143. Shenbagam, M.; Nalini, N. Dose Response Effect of Rutin a Dietary Antioxidant on Alcohol-Induced Prooxidant and Antioxidant Imbalance—A Histopathologic Study. Fundam. Clin. Pharmacol. 2011, 25, 493–502. [Google Scholar] [CrossRef] [PubMed]
  144. Shi, X.; Zhao, Y.; Ding, C.; Wang, Z.; Ji, A.; Li, Z.; Feng, D.; Li, Y.; Gao, D.; Zhou, J. Salvianolic Acid A Alleviates Chronic Ethanol-Induced Liver Injury via Promotion of β-Catenin Nuclear Accumulation by Restoring SIRT1 in Rats. Toxicol. Appl. Pharmacol. 2018, 350, 21–31. [Google Scholar] [CrossRef] [PubMed]
  145. Smathers, R.L.; Galligan, J.J.; Shearn, C.T.; Fritz, K.S.; Mercer, K.; Ronis, M.; Orlicky, D.J.; Davidson, N.O.; Petersen, D.R. Susceptibility of L-FABP -/- Mice to Oxidative Stress in Early-Stage Alcoholic Liver. J. Lipid. Res. 2013, 54, 1335–1345. [Google Scholar] [CrossRef] [PubMed]
  146. Sönmez, M.F.; Narin, F.; Akkuş, D.; Türkmen, A.B. Melatonin and Vitamin C Ameliorate Alcohol-Induced Oxidative Stress and ENOS Expression in Rat Kidney. Ren. Fail 2012, 34, 480–486. [Google Scholar] [CrossRef] [PubMed]
  147. Song, Z.; Deaciuc, I.; Song, M.; Lee, D.Y.W.; Liu, Y.; Ji, X.; McClain, C. Silymarin Protects against Acute Ethanol-Induced Hepatotoxicity in Mice. Alcohol Clin. Exp. Res. 2006, 30, 407–413. [Google Scholar] [CrossRef] [PubMed]
  148. Song, X.; Liu, Z.; Zhang, J.; Zhang, C.; Dong, Y.; Ren, Z.; Gao, Z.; Liu, M.; Zhao, H.; Jia, L. Antioxidative and Hepatoprotective Effects of Enzymatic and Acidic-Hydrolysis of Pleurotus geesteranus Mycelium Polysaccharides on Alcoholic Liver Diseases. Carbohydr. Polym. 2018, 201, 75–86. [Google Scholar] [CrossRef] [PubMed]
  149. Song, Y.; Wu, X.; Yang, D.; Fang, F.; Meng, L.; Liu, Y.; Cui, W. Protective Effect of Andrographolide on Alleviating Chronic Alcoholic Liver Disease in Mice by Inhibiting Nuclear Factor Kappa B and Tumor Necrosis Factor Alpha Activation. J. Med. Food 2020, 23, 409–415. [Google Scholar] [CrossRef]
  150. Song, X.; Sun, W.; Cui, W.; Jia, L.; Zhang, J. A Polysaccharide of PFP-1 from: Pleurotus Geesteranus Attenuates Alcoholic Liver Diseases via Nrf2 and NF-ΚB Signaling Pathways. Food Funct. 2021, 12, 4591–4605. [Google Scholar] [CrossRef] [PubMed]
  151. Arumugam, S.; Srinivasan, P.; Manikandaselvi, S.; Thinagarbabu, R. Protective effect and antioxidant role of Achyranthus aspera, L. against ethanol-induced oxidative stress in rats. Int. J. Pharm. Pharm. Sci. 2012, 4 (Suppl. 3), 280–284. [Google Scholar]
  152. Sun, Q.; Zhong, W.; Zhang, W.; Zhou, Z. Defect of Mitochondrial Respiratory Chain Is a Mechanism of ROS Overproduction in a Rat Model of Alcoholic Liver Disease: Role of Zinc Deficiency. Am. J. Physiol. Gastrointest. Liver Physiol. 2016, 310, 205–214. [Google Scholar] [CrossRef]
  153. Tahir, M.; Rehman, M.U.; Lateef, A.; Khan, R.; Khan, A.Q.; Qamar, W.; Ali, F.; O’Hamiza, O.; Sultana, S. Diosmin Protects against Ethanol-Induced Hepatic Injury via Alleviation of Inflammation and Regulation of TNF-α and NF-ΚB Activation. Alcohol 2013, 47, 131–139. [Google Scholar] [CrossRef] [PubMed]
  154. Tan, P.; Liang, H.; Nie, J.; Diao, Y.; He, Q.; Hou, B.; Zhao, T.; Huang, H.; Li, Y.; Gao, X.; et al. Establishment of an Alcoholic Fatty Liver Disease Model in Mice. Am. J. Drug Alcohol Abuse 2017, 43, 61–68. [Google Scholar] [CrossRef] [PubMed]
  155. Tang, Y.; Gao, C.; Xing, M.; Li, Y.; Zhu, L.; Wang, D.; Yang, X.; Liu, L.; Yao, P. Quercetin Prevents Ethanol-Induced Dyslipidemia and Mitochondrial Oxidative Damage. Food Chem. Toxicol. 2012, 50, 1194–1200. [Google Scholar] [CrossRef] [PubMed]
  156. Tang, C.C.; Lin, W.L.; Lee, Y.J.; Tang, Y.C.; Wang, C.J. Polyphenol-Rich Extract of Nelumbo Nucifera Leaves Inhibits Alcohol-Induced Steatohepatitis via Reducing Hepatic Lipid Accumulation and Anti-Inflammation in C57BL/6J Mice. Food Funct. 2014, 5, 678–687. [Google Scholar] [CrossRef] [PubMed]
  157. Tang, Y.; Li, Y.; Yu, H.; Gao, C.; Liu, L.; Xing, M.; Yao, P. Quercetin Attenuates Chronic Ethanol Hepatotoxicity: Implication of “Free” Iron Uptake and Release. Food Chem. Toxicol. 2014, 67, 131–138. [Google Scholar] [CrossRef] [PubMed]
  158. Tang, X.; Wei, R.; Deng, A.; Lei, T. Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice. Nutrients 2017, 9, 1000. [Google Scholar] [CrossRef] [PubMed]
  159. Tao, Z.; Zhang, L.; Wu, T.; Fang, X.; Zhao, L. Echinacoside Ameliorates Alcohol-Induced Oxidative Stress and Hepatic Steatosis by Affecting SREBP1c/FASN Pathway via PPARα. Food Chem. Toxicol. 2021, 148, 111956. [Google Scholar] [CrossRef] [PubMed]
  160. Valansa, A.; Tietcheu Galani, B.R.; Djamen Chuisseu, P.D.; Tontsa Tsamo, A.; Ayissi Owona, V.B.; Yanou Njintang, N. Natural Limonoids Protect Mice from Alcohol-Induced Liver Injury. J. Basic Clin. Physiol. Pharmacol. 2020, 31, 20190271. [Google Scholar] [CrossRef] [PubMed]
  161. Varghese, J.; James, J.V.; Sagi, S.; Chakraborty, S.; Sukumaran, A.; Ramakrishna, B.; Jacob, M. Decreased Hepatic Iron in Response to Alcohol May Contribute to Alcohol-Induced Suppression of Hepcidin. Brit. J. Nutr. 2016, 115, 1978–1986. [Google Scholar] [CrossRef] [PubMed]
  162. Velvizhi, S.; Nagalashmi, T.; Essa, M.M.; Dakshayani, K.B.; Subramanian, P. Effects of alpha-ketoglutarate on lipid peroxidation and antioxidant status during chronic ethanol administration in Wistar rats. Pol. J. Pharmacol. 2002, 54, 231–236. [Google Scholar] [PubMed]
  163. Wang, C.; Li, X.; Wang, H.; Xie, Q.; Xu, Y. Notch1-Nuclear Factor ΚB Involves in Oxidative Stress-Induced Alcoholic Steatohepatitis. Alcohol Alcohol. 2014, 49, 10–16. [Google Scholar] [CrossRef] [PubMed]
  164. Wang, Z.; Su, B.; Fan, S.; Fei, H.; Zhao, W. Protective Effect of Oligomeric Proanthocyanidins against Alcohol-Induced Liver Steatosis and Injury in Mice. Biochem. Biophys. Res. Commun. 2015, 458, 757–762. [Google Scholar] [CrossRef] [PubMed]
  165. Wang, H.; Zhang, Y.; Bai, R.; Wang, M.; Du, S. Baicalin Attenuates Alcoholic Liver Injury through Modulation of Hepatic Oxidative Stress, Inflammation and Sonic Hedgehog Pathway in Rats. Cell. Physiol. Biochem. 2016, 39, 1129–1140. [Google Scholar] [CrossRef] [PubMed]
  166. Wang, X.; Liu, M.; Zhang, C.; Li, S.; Yang, Q.; Zhang, J.; Gong, Z.; Han, J.; Jia, L. Antioxidant Activity and Protective Effects of Enzyme-Extracted Oudemansiella Radiata Polysaccharides on Alcohol-Induced Liver Injury. Molecules 2018, 23, 481. [Google Scholar] [CrossRef] [PubMed]
  167. Wang, G.; Fu, Y.; Li, J.; Li, Y.; Zhao, Q.; Hu, A.; Xu, C.; Shao, D.; Chen, W. Aqueous Extract of Polygonatum sibiricum Ameliorates Ethanol-Induced Mice Liver Injury via Regulation of the Nrf2/ARE Pathway. J. Food Biochem. 2021, 45, e13537. [Google Scholar] [CrossRef] [PubMed]
  168. Wang, X.; Chang, X.; Zhan, H.; Zhang, Q.; Li, C.; Gao, Q.; Yang, M.; Luo, Z.; Li, S.; Sun, Y. Curcumin and Baicalin Ameliorate Ethanol-Induced Liver Oxidative Damage via the Nrf2/HO-1 Pathway. J. Food Biochem. 2020, 44, e13425. [Google Scholar] [CrossRef] [PubMed]
  169. Wang, Z.D.; Zhang, Y.; Dai, Y.D.; Ren, K.; Han, C.; Wang, H.X.; Yi, S.Q. Tamarix Chinensis Lour Inhibits Chronic Ethanol-Induced Liver Injury in Mice. World J. Gastroenterol. 2020, 26, 1286–1297. [Google Scholar] [CrossRef]
  170. Wang, W.; Zhong, G.Z.; Long, K.B.; Liu, Y.; Liu, Y.Q.; Xu, A.L. Silencing MiR-181b-5p Upregulates PIAS1 to Repress Oxidative Stress and Inflammatory Response in Rats with Alcoholic Fatty Liver Disease through Inhibiting PRMT1. Int. Immunopharmacol. 2021, 101, 108151. [Google Scholar] [CrossRef] [PubMed]
  171. Wang, X.; Yu, H.; Xing, R.; Li, P. Hepatoprotective Effect of Oyster Peptide on Alcohol-Induced Liver Disease in Mice. Int. J. Mol. Sci. 2022, 23, 8081. [Google Scholar] [CrossRef]
  172. Wang, X.; Wang, Y.; Liu, Y.; Cong, P.; Xu, J.; Xue, C. Hepatoprotective Effects of Sea Cucumber Ether-Phospholipids against Alcohol-Induced Lipid Metabolic Dysregulation and Oxidative Stress in Mice. Food Funct. 2022, 13, 2791–2804. [Google Scholar] [CrossRef] [PubMed]
  173. Wang, R.; Mu, J. Arbutin Attenuates Ethanol-Induced Acute Hepatic Injury by the Modulation of Oxidative Stress and Nrf-2/HO-1 Signaling Pathway. J. Biochem. Mol. Toxicol. 2021, 35, e22872. [Google Scholar] [CrossRef] [PubMed]
  174. Wei, J.; Huang, Q.; Huang, R.; Chen, Y.; Lv, S.; Wei, L.; Liang, C.; Liang, S.; Zhuo, L.; Lin, X. Asiatic Acid from Potentilla Chinensis Attenuate Ethanol-Induced Hepatic Injury via Suppression of Oxidative Stress and Kupffer Cell Activation. Biol. Pharm. Bull. 2013, 36, 1980–1989. [Google Scholar] [CrossRef] [PubMed]
  175. Wu, X.; Wang, Y.; Jia, R.; Fang, F.; Liu, Y.; Cui, W. Computational and Biological Investigation of the Soybean Lecithin-Gallic Acid Complex for Ameliorating Alcoholic Liver Disease in Mice with Iron Overload. Food Funct. 2019, 10, 5203–5214. [Google Scholar] [CrossRef]
  176. Wu, C.; Liu, J.; Tang, Y.; Li, Y.; Yan, Q.; Jiang, Z. Hepatoprotective Potential of Partially Hydrolyzed Guar Gum against Acute Alcohol-Induced Liver Injury in Vitro and Vivo. Nutrients 2019, 11, 963. [Google Scholar] [CrossRef] [PubMed]
  177. Xia, T.; Zhang, J.; Yao, J.; Zhang, B.; Duan, W.; Xia, M.; Song, J.; Zheng, Y.; Wang, M. Shanxi Aged Vinegar Prevents Alcoholic Liver Injury by Inhibiting CYP2E1 and NADPH Oxidase Activities. J. Funct. Foods 2018, 47, 575–584. [Google Scholar] [CrossRef]
  178. Xiao, J.; Wang, J.; Xing, F.; Han, T.; Jiao, R.; Liong, E.C.; Fung, M.L.; So, K.F.; Tipoe, G.L. Zeaxanthin Dipalmitate Therapeutically Improves Hepatic Functions in an Alcoholic Fatty Liver Disease Model through Modulating MAPK Pathway. PLoS ONE 2014, 9, e95214. [Google Scholar] [CrossRef]
  179. Xiao, J.; Zhang, R.; Huang, F.; Liu, L.; Deng, Y.; Ma, Y.; Wei, Z.; Tang, X.; Zhang, Y.; Zhang, M. Lychee (Litchi chinensis Sonn.) Pulp Phenolic Extract Confers a Protective Activity against Alcoholic Liver Disease in Mice by Alleviating Mitochondrial Dysfunction. J. Agric. Food Chem. 2017, 65, 5000–5009. [Google Scholar] [CrossRef]
  180. Xiao, J.; Wu, C.; He, Y.; Guo, M.; Peng, Z.; Liu, Y.; Liu, L.; Dong, L.; Guo, Z.; Zhang, R.; et al. Rice Bran Phenolic Extract Confers Protective Effects against Alcoholic Liver Disease in Mice by Alleviating Mitochondrial Dysfunction via the PGC-1α-TFAM Pathway Mediated by MicroRNA-494-3p. J. Agric. Food Chem. 2020, 68, 12284–12294. [Google Scholar] [CrossRef]
  181. Xu, J.J.; Li, H.D.; Wu, M.F.; Zhu, L.; Du, X.S.; Li, J.J.; Li, Z.; Meng, X.M.; Huang, C.; Li, J. 3-B-RUT, a Derivative of RUT, Protected against Alcohol-Induced Liver Injury by Attenuating Inflammation and Oxidative Stress. Int. Immunopharmacol. 2021, 95, 107471. [Google Scholar] [CrossRef]
  182. Yalçinkaya, S.; Ünlüçerçi, Y.; Uysal, M. Methionine-Supplemented Diet Augments Hepatotoxicity and Prooxidant Status in Chronically Ethanol-Treated Rats. Exp. Toxicol. Pathol. 2007, 58, 455–459. [Google Scholar] [CrossRef] [PubMed]
  183. Yan, S.L.; Yin, M.C. Protective and Alleviative Effects from 4 Cysteine-Containing Compounds on Ethanol-Induced Acute Liver Injury through Suppression of Oxidation and Inflammation. J. Food Sci. 2007, 72, S511–S515. [Google Scholar] [CrossRef] [PubMed]
  184. Yang, P.; Wang, Z.; Zhan, Y.; Wang, T.; Zhou, M.; Xia, L.; Yang, X.; Zhang, J. Endogenous A1 Adenosine Receptor Protects Mice from Acute Ethanol-Induced Hepatotoxicity. Toxicology 2013, 309, 100–106. [Google Scholar] [CrossRef] [PubMed]
  185. Yang, C.; Liao, A.M.; Cui, Y.; Yu, G.; Hou, Y.; Pan, L.; Chen, W.; Zheng, S.; Li, X.; Ma, J.; et al. Wheat Embryo Globulin Protects against Acute Alcohol-Induced Liver Injury in Mice. Food Chem. Toxicol. 2021, 153, 112240. [Google Scholar] [CrossRef] [PubMed]
  186. Yang, Y.; Zhou, Z.; Liu, Y.; Xu, X.; Xu, Y.; Zhou, W.; Chen, S.; Mao, J. Non-Alcoholic Components in Huangjiu as Potential Factors Regulating the Intestinal Barrier and Gut Microbiota in Mouse Model of Alcoholic Liver Injury. Foods 2022, 11, 1537. [Google Scholar] [CrossRef]
  187. Yao, P.; Li, K.; Song, F.; Zhou, S.; Sun, X.; Zhang, X.; Nüssler, A.K.; Liu, L. Heme Oxygenase-1 Upregulated by Ginkgo Biloba Extract: Potential Protection against Ethanol-Induced Oxidative Liver Damage. Food Chem. Toxicol. 2007, 45, 1333–1342. [Google Scholar] [CrossRef] [PubMed]
  188. Yeh, W.J.; Tsai, C.C.; Ko, J.; Yang, H.Y. Hylocereus Polyrhizus Peel Extract Retards Alcoholic Liver Disease Progression by Modulating Oxidative Stress and Inflammatory Responses in C57Bl/6 Mice. Nutrients 2020, 12, 3884. [Google Scholar] [CrossRef] [PubMed]
  189. Yoon, S.J.; Koh, E.J.; Kim, C.S.; Zee, O.P.; Kwak, J.H.; Jeong, W.J.; Kim, J.H.; Lee, S.M. Agrimonia Eupatoria Protects against Chronic Ethanol-Induced Liver Injury in Rats. Food Chem. Toxicol. 2012, 50, 2335–2341. [Google Scholar] [CrossRef] [PubMed]
  190. You, Y.; Yoo, S.; Yoon, H.G.; Park, J.; Lee, Y.H.; Kim, S.; Oh, K.T.; Lee, J.; Cho, H.Y.; Jun, W. In Vitro and in Vivo Hepatoprotective Effects of the Aqueous Extract from Taraxacum Officinale (Dandelion) Root against Alcohol-Induced Oxidative Stress. Food Chem. Toxicol. 2010, 48, 1632–1637. [Google Scholar] [CrossRef] [PubMed]
  191. You, Y.; Liu, Y.L.; Ai, Z.Y.; Wang, Y.S.; Liu, J.M.; Piao, C.H.; Wang, Y.H. Lactobacillus Fermentum KP-3-Fermented Ginseng Ameliorates Alcohol-Induced Liver Disease in C57BL/6N Mice through the AMPK and MAPK Pathways. Food Funct. 2020, 11, 9801–9809. [Google Scholar] [CrossRef]
  192. Yu, Y.; Tian, Z.Q.; Liang, L.; Yang, X.; Sheng, D.D.; Zeng, J.X.; Li, X.Y.; Shi, R.Y.; Han, Z.P.; Wei, L.X. Babao Dan Attenuates Acute Ethanol-Induced Liver Injury via Nrf2 Activation and Autophagy. Cell Biosci. 2019, 9, 80. [Google Scholar] [CrossRef] [PubMed]
  193. Lu, R.; Yu, R.-J.; Yang, C.; Wang, Q.; Xuan, Y.; Wang, Z.; He, Z.; Xu, Y.; Kou, L.; Zhao, Y.-Z.; et al. Evaluation of the Hepatoprotective Effect of Naringenin Loaded Nanoparticles against Acetaminophen Overdose Toxicity. Drug Deliv. 2022, 29, 3256–3269. [Google Scholar] [CrossRef] [PubMed]
  194. Yuan, R.; Tao, X.; Liang, S.; Pan, Y.; He, L.; Sun, J.; Wenbo, J.; Li, X.; Chen, J.; Wang, C. Protective Effect of Acidic Polysaccharide from Schisandra Chinensis on Acute Ethanol-Induced Liver Injury through Reducing CYP2E1-Dependent Oxidative Stress. Biomed. Pharmacother. 2018, 99, 537–542. [Google Scholar] [CrossRef] [PubMed]
  195. Yuan, H.; Duan, S.; Guan, T.; Yuan, X.; Lin, J.; Hou, S.; Lai, X.; Huang, S.; Du, X.; Chen, S. Vitexin Protects against Ethanol-Induced Liver Injury through Sirt1/P53 Signaling Pathway. Eur. J. Pharmacol. 2020, 873, 173007. [Google Scholar] [CrossRef] [PubMed]
  196. Zahid, M.; Arif, M.; Rahman, M.A.; Mujahid, M. Hepatoprotective and Antioxidant Activities of Annona Squamosa Seed Extract against Alcohol-Induced Liver Injury in Sprague Dawley Rats. Drug Chem. Toxicol. 2020, 43, 588–594. [Google Scholar] [CrossRef] [PubMed]
  197. Zeng, T.; Zhang, C.L.; Song, F.Y.; Zhao, X.L.; Yu, L.H.; Zhu, Z.P.; Xie, K.Q. The Activation of HO-1/Nrf-2 Contributes to the Protective Effects of Diallyl Disulfide (DADS) against Ethanol-Induced Oxidative Stress. Biochim. Biophys. Acta Gen. Subj. 2013, 1830, 4848–4859. [Google Scholar] [CrossRef] [PubMed]
  198. Zhang, J.; Xue, J.; Wang, H.; Zhang, Y.; Xie, M. Osthole Improves Alcohol-Induced Fatty Liver in Mice by Reduction of Hepatic Oxidative Stress. Phytother. Res. 2011, 25, 638–643. [Google Scholar] [CrossRef] [PubMed]
  199. Zhang, P.; Ma, D.; Wang, Y.; Zhang, M.; Qiang, X.; Liao, M.; Liu, X.; Wu, H.; Zhang, Y. Berberine Protects Liver from Ethanol-Induced Oxidative Stress and Steatosis in Mice. Food Chem. Toxicol. 2014, 74, 225–232. [Google Scholar] [CrossRef] [PubMed]
  200. Zhang, P.; Qiang, X.; Zhang, M.; Ma, D.; Zhao, Z.; Zhou, C.; Liu, X.; Li, R.; Chen, H.; Zhang, Y. Demethyleneberberine, a Natural Mitochondria-Targeted Antioxidant, Inhibits Mitochondrial Dysfunction, Oxidative Stress, and Steatosis in Alcoholic Liver Disease Mouse Model. J. Pharmacol. Exp. Ther. 2015, 352, 139–147. [Google Scholar] [CrossRef]
  201. Zhang, L.; Meng, B.; Li, L.; Wang, Y.; Zhang, Y.; Fang, X.; Wang, D. Boletus aereus Protects against Acute Alcohol-Induced Liver Damage in the C57BL/6 Mouse via Regulating the Oxidative Stress-Mediated NF-ΚB Pathway. Pharm. Biol. 2020, 58, 905–914. [Google Scholar] [CrossRef] [PubMed]
  202. Zhang, Y.; Zhao, S.; Fu, Y.; Yan, L.; Feng, Y.; Chen, Y.; Wu, Y.; Deng, Y.; Zhang, G.; Chen, Z.; et al. Computational Repositioning of Dimethyl Fumarate for Treating Alcoholic Liver Disease. Cell Death Dis. 2020, 11, 641. [Google Scholar] [CrossRef] [PubMed]
  203. Zhang, W.; Yang, J.; Liu, J.; Long, X.; Zhang, X.; Li, J.; Hou, C. Red Yeast Rice Prevents Chronic Alcohol-Induced Liver Disease by Attenuating Oxidative Stress and Inflammatory Response in Mice. J. Food Biochem. 2021, 45, e13672. [Google Scholar] [CrossRef] [PubMed]
  204. Zhao, J.; Chen, H.; Li, Y. Protective Effect of Bicyclol on Acute Alcohol-Induced Liver Injury in Mice. Eur. J. Pharmacol. 2008, 586, 322–331. [Google Scholar] [CrossRef] [PubMed]
  205. Zhao, L.; Zhang, N.; Yang, D.; Yang, M.; Guo, X.; He, J.; Wu, W.; Ji, B.; Cheng, Q.; Zhou, F. Protective Effects of Five Structurally Diverse Flavonoid Subgroups against Chronic Alcohol-Induced Hepatic Damage in a Mouse Model. Nutrients 2018, 10, 1754. [Google Scholar] [CrossRef]
  206. Zhao, L.; Mehmood, A.; Soliman, M.M.; Iftikhar, A.; Iftikhar, M.; Aboelenin, S.M.; Wang, C. Protective Effects of Ellagic Acid Against Alcoholic Liver Disease in Mice. Front. Nutr. 2021, 8, 744520. [Google Scholar] [CrossRef] [PubMed]
  207. Zhao, H.; Liu, S.; Zhao, H.; Liu, Y.; Xue, M.; Zhang, H.; Qiu, X.; Sun, Z.; Liang, H. Protective Effects of Fucoidan against Ethanol-Induced Liver Injury through Maintaining Mitochondrial Function and Mitophagy Balance in Rats. Food Funct. 2021, 12, 3842–3854. [Google Scholar] [CrossRef] [PubMed]
  208. Zheng, Y.; Cui, J.; Chen, A.H.; Zong, Z.M.; Wei, X.Y. Optimization of Ultrasonic-Microwave Assisted Extraction and Hepatoprotective Activities of Polysaccharides from Trametes orientalis. Molecules 2019, 24, 147. [Google Scholar] [CrossRef] [PubMed]
  209. Zheng, L.Y.; Zou, X.; Wang, Y.L.; Zou, M.; Ma, F.; Wang, N.; Li, J.W.; Wang, M.S.; Hung, H.Y.; Wang, Q. Betulinic Acid-Nucleoside Hybrid Prevents Acute Alcohol -Induced Liver Damage by Promoting Anti-Oxidative Stress and Autophagy. Eur. J. Pharmacol. 2022, 914, 174686. [Google Scholar] [CrossRef] [PubMed]
  210. Zhou, Z.; Sun, X.; Kang, Y.J. Metallothionein Protection against Alcoholic Liver Injury through Inhibition of Oxidative Stress. Exp. Biol. Med. 2002, 227, 214–222. [Google Scholar] [CrossRef]
  211. Zhou, J.; Zhang, J.; Wang, C.; Qu, S.; Zhu, Y.; Yang, Z.; Wang, L. Açaí (Euterpe Oleracea Mart.) Attenuates Alcohol-Inducedliver Injury in Rats by Alleviating Oxidative Stressand Inflammatory Response. Exp. Ther. Med. 2018, 15, 166–172. [Google Scholar] [PubMed]
  212. Zhou, J.; Zhang, N.; Zhao, L.; Wu, W.; Zhang, L.; Zhou, F.; Li, J. Astragalus Polysaccharides and Saponins Alleviate Liver Injury and Regulate Gut Microbiota in Alcohol Liver Disease Mice. Foods 2021, 10, 2688. [Google Scholar] [CrossRef] [PubMed]
  213. Zhou, J.; Zhang, N.; Zhao, L.; Soliman, M.M.; Wu, W.; Li, J.; Zhou, F.; Zhang, L. Protective Effects of Honey-Processed Astragalus on Liver Injury and Gut Microbiota in Mice Induced by Chronic Alcohol Intake. J. Food Qual. 2022, 2022, 5333691. [Google Scholar] [CrossRef]
  214. Zhu, S.; Ma, L.; Wu, Y.; Ye, X.; Zhang, T.; Zhang, Q.; Rasoul, L.M.; Liu, Y.; Guo, M.; Zhou, B.; et al. FGF21 Treatment Ameliorates Alcoholic Fatty Liver through Activation of AMPK-SIRT1 Pathway. Acta Biochim. Biophys. Sin. 2014, 46, 1041–1048. [Google Scholar] [CrossRef] [PubMed]
  215. Zhu, Z.; Zhou, W.; Yang, Y.; Wang, K.; Li, F.; Dang, Y. Quantitative Profiling of Oxylipin Reveals the Mechanism of Pien-Tze-Huang on Alcoholic Liver Disease. Evid. Based Complement Alternat. Med. 2021, 2021, 9931542. [Google Scholar] [CrossRef]
  216. Xie, N.; Zhang, L.; Gao, W.; Huang, C.; Huber, P.E.; Zhou, X.; Li, C.; Shen, G.; Zou, B. NAD+ Metabolism: Pathophysiologic Mechanisms and Therapeutic Potential. Signal Transduct. Target Ther. 2020, 5, 227. [Google Scholar] [CrossRef] [PubMed]
  217. Bougarne, N.; Weyers, B.; Desmet, S.J.; Deckers, J.; Ray, D.W.; Staels, B.; De Bosscher, K. Molecular Actions of PPARα in Lipid Metabolism and Inflammation. Endocr. Rev. 2018, 39, 760–802. [Google Scholar] [CrossRef]
  218. Namachivayam, A.; Gopalakrishnan, A.V. A Review on Molecular Mechanism of Alcoholic Liver Disease. Life Sci. 2021, 274, 119328. [Google Scholar] [CrossRef] [PubMed]
  219. Shen, Y.; Huang, H.; Wang, Y.; Yang, R.; Ke, X. Antioxidant Effects of Se-Glutathione Peroxidase in Alcoholic Liver Disease. J. Trace Elem. Med. Biol. 2022, 74, 127048. [Google Scholar] [CrossRef] [PubMed]
  220. Sun, J.; Fu, J.; Li, L.; Chen, C.; Wang, H.; Hou, Y.; Xu, Y.; Pi, J. Nrf2 in Alcoholic Liver Disease. Toxicol. Appl. Pharmacol. 2018, 357, 62–69. [Google Scholar] [CrossRef] [PubMed]
  221. Bae, T.; Hallis, S.P.; Kwak, M.-K. Hypoxia, Oxidative Stress, and the Interplay of HIFs and NRF2 Signaling in Cancer. Exp. Mol. Med. 2024, 56, 501–514. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Article Metrics

Citations

Article Access Statistics

Journal Statistics
Multiple requests from the same IP address are counted as one view.
Gut Microbiome—How Does Two-Month Consumption of Fiber-Enriched Rolls Change Microbiome in Patients Suffering from MASLD?
Previous
Sex-Specific Effects of Dietary Factors on Sarcopenic Obesity in Korean Elderly: A Nationwide Cross-Sectional Study
Next