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However, the detailed molecular mechanism involved is unknown, and effective therapeutic approaches remain insufficient. In this study, we discovered that treatment with ginsenoside Rc can prevent the inflammatory response caused by APAP and oxidative stress in mouse primary hepatocytes MPHs , along with the corresponding changes in related genes. In vivo , Ginsenoside Rc administration remarkably attenuates APAP-induced hepatotoxicity, repairing liver damage and improving survival. Moreover, Ginsenoside Rc treatment modulates genes involved in APAP metabolism, leading to a decrease in NAPQI and resulting in the alleviation of fatal oxidative stress and inflammatory response after APAP exposure, along with the expression of their related indicators. Notably, due to the lack of FXR in mice and MPHs, ginsenoside Rc can no longer play its original protective role against hepatotoxicity and cell damage caused by APAP, and it is difficult to improve the corresponding survival rate and prevent hepatic apoptosis, NAPQI generation, fatal oxidative stress, and the inflammatory response induced by APAP and the expression of related genes. In summary, our results indicate that Ginsenoside Rc could act as an effective FXR activator and effectively regulate FXR-induced antioxidant stress and eliminate inflammation while also having an anti-apoptotic function. Acetaminophen APAP is an antipyretic analgesic that is widely used in clinical practice. It combines to form APAP adducts, causing mitochondria to lose their normal functions, produce reactive oxygen species ROS and release mitochondrial cell death factors, leading to liver necrosis Chen D. As the only approved antidote for AILI Acetaminophen-induced liver injury , N-acetyl-cysteine NAC can cause nausea and other adverse reactions, and its utility is limited to the early days of treatment. Later treatment with NAC may even damage liver regeneration Yin et al. Therefore, it is necessary to find a new and effective treatment method for acute liver injury caused by APAP. Reducing APAP-induced oxidative stress and inflammation may be an effective strategy. Bile acids regulate the bile acid balance, inflammation, and lipid and glucose metabolism by activating the nuclear receptor FXR and membrane G protein-coupled receptor TGR5. Cholestasis can lead to the accumulation of BAs in the liver. FXR is not only expressed in the liver, but also exists in the intestine to control the reabsorption of bile acids, acting as a key regulator of bile acid enterohepatic circulation Anakk et al. It also plays an essential role in the metabolism of xenobiotics Fiorucci et al. This mechanism can prevent bile acid overload and liver cell damage during cholestasis Bechmann et al. In addition, FXR combines with bound bile acids to induce fibroblast growth factor FGF to reduce the transcription of cytochrome P enzyme Cyp7a1 in hepatocytes, further inhibiting the de novo synthesis of bile acids Hartmann et al. Previous studies have shown that FXR and SHP strictly regulate the physiological concentration and homeostasis of bile acids through a multistep feedback loop, and ultimately inhibit cytochrome P CYP7A1 Anakk et al. Therefore, FXR may be a target protein mediating drug-induced liver injury and play an anti-inflammatory role to help inhibit the development of drug-induced liver injury. Ginseng, a precious medicinal material that has been widely used in Asian countries for thousands of years, can produce a variety of medicinaleffects in the field of disease treatment, including antitumor, antidiabetic, antifatigue, antioxidation, heart protection, and immune stimulation and neuroprotective effects. Ginsenoside is the main active ingredient responsible for its pharmacological effects Kim et al. Ginseng can also be used as a chemopreventive agent an adjuvant therapy Jeon et al. Previous research results have shown that ginsenoside Rc targets mitochondrial functions to increase the ATP content, remove free radicals and return to normal oxygen consumption levels. In addition, studies have found that ginsenoside Rc can stimulate and accelerate energy metabolism and fight oxidative damage, inflammation, cancer, aging, and metabolic diseases by activating SIRT1 Huang et al. This study can treat APAP-induced liver injury by intervening inflammation, oxidative stress, and liver regeneration, which has the characteristics of multi-pathway and multi-target, and can play a better role in liver protection and liver protection. At the same time, it was found that ginsenoside Rc had a preventive protective effect on APAP-induced liver injury, and its mechanism was related to anti-oxidative stress, anti-apoptosis of hepatocytes, inhibition of the expression of inflammation-related factors, and regulation of APAP metabolism and transport in vivo. And we will further study the protective effect of FXR nuclear receptor, a key target of liver metabolism regulation, on APAP-induced acute liver injury, acute hepatocyte injury, oxidative stress, and inflammatory response, identify key genes regulating antioxidant genes and explore new potential drug targets, and improve the related mechanism of FXR on liver protection. To provide ideas and basis for the efficacy study and drug development and utilization of ginsenoside Rc. Ginsenoside Rc CAS. No purity All the mice were housed in individually ventilated cages and were kept on a h light dark cycle at all times. All the animal experiments carried out were submitted to and approved by the Animal Ethics Committee of Guangzhou University of Traditional Chinese Medicine. The control group was given normal saline Control. The injection cycle was 10 days. The injection site was the abdominal cavity, and the control group did not undergo this operation. All mice were sacrificed 10 h after APAP injection. Fresh liver tissue from the mice was then extracted for further studies. In experiments conducted to test the survival rate, the time to death of mice within 72 h was recorded. Liang et al. After 6 h of cell incubation, a new culture base was formed, that is, configure various concentrations of ginsenoside Rc were configured, and the culture time was 24 h. Finally, the cells were washed three times with PBS, and the fluorescence emissions of the cells were observed by a fluorescence microscope. Then, the reactive oxygen species in the body were analyzed Liang et al. After death, liver tissue was extracted. Imaging was achieved with the aid of a fluorescence microscope Leica Microsystems Ltd. Immunofluorescence was performed according to current protocols. After being washed three times with PBS, sections were incubated with a secondary antibody Abclonal, Wuhan, China at room temperature for 40 min. Reverse transcription was accomplished using a high-capacity cDNA reverse transcription kit produced by Applied Biomaterials Canada. This was followed by an analysis with GraphPad Prism version 8. Moreover, TUNEL staining after high-dose Ginsenoside Rc treatment compared the number of red fluorescent label-positive apoptotic cells was the injury model group, showing a significant decrease. This indicated that Ginsenoside Rc could significantly improve the antioxidant defense system function of the damaged liver, alleviating oxidative stress injury. Interestingly, treatment with Ginsenoside Rc further significantly decreased the expression levels of these genes. Therefore, mice were injected with different doses of ginsenoside Rc daily for 10 days. As shown in Figures 2A—C , after the mice received ginsenoside Rc treatment, and then received APAP treatment, they were fully protected, and at the same time, the serum ALT and AST levels were significantly reduced, and lethality was significantly lower. Ginsenoside Rc alleviated hepatic damage in ALI mice by regulating oxidative stress. APAP overdose generates adducts with proteins in hepatocytes, which can lead to cell apoptosis. In the control injury model group, high-dose ginsenoside Rc treatment could significantly reduced the leverl of positive cell apoptosis marked by red fluorescence in TUNEL staining Figure 3A. It can be seen that ginsenoside Rc can effectively inhibit the inflammatory response induced by APAP-induced acute liver injury in mice. In order to further analyze the antagonism mechanism of ginsenoside Rc against ALI, we carried out a transcriptional analysis of liver tissue. In addition, we carried out a more in-depth docking analysis of ginsenoside Rc and FXR, and the data show that the hydrophobic interaction can lead to a greater binding affinity Figure 4C. In conclusion, this study concludes that FXR is likely to be a new candidate target for altered expression. The nucleus was stained with DAPI. However, mice treated with ginsenoside Rc can effectively reduce the damage caused by excessive APAP. We further detected its effect in vivo. Acetaminophen APAP , known as paracetamol, is commonly used as an analgesic, anti-inflammatory, and antipyretic drug Cooper et al. Ingestion of APAP above the recommended dose can seriously damage liver tissue and even cause acute liver failure. Many studies have concluded that the mechanism by which excessive APAP causes damage to hepatocytes is complicated but mainly involves oxidative stress, inflammatory cell infiltration, mitochondrial autophagy, and endoplasmic reticulum stress Yang et al. Therefore, further exploration of the pathological mechanism associated with APAP-induced liver injury is urgently needed so that new therapeutic drugs can be developed. Ginsenoside Rc is the main active component of ginseng and has become the main alternative for the treatment of liver diseases Lee et al. We and others have previously confirmed the protective effects of Ginsenoside Rc against hepatitis and hepatic steatosis Yang et al. However, whether and how Ginsenoside Rc affects acute liver injury is far from clear. APAP loses its activity by binding to sulfate and glucoside in the second stage of metabolism. With significant death of hepatocytes, oxidative stress and infectious inflammation in the liver are triggered Cao et al. Oxidative stress and inflammation, in turn, aggravate liver damage, forming a vicious cycle Elsayed et al. Studies have shown that APAP can cause oxidative stress in the mitochondria and produce ROS through the percolation of electrons from the transport chain Wang et al. There is an obvious positive relationship between the activity level of complex I and the degree of liver injury. Mitochondrial oxidative stress caused by APAP inevitably triggers cell death, which in turn produces an inflammatory response Geib et al. Oxidative stress in the mitochondria during the metabolic phase increases their permeability while releasing mitochondrial proteins which causing apoptosis of the factor AIF Shi et al. Mitochondrial proteins undergo nuclear translocation, which results in cell death and nuclear DNA fragmentation. Low levels of NAPQI promote the alleviation of liver cell apoptosis, oxidative stress, and the inflammatory response. Once formed, they decompose into hydrogen peroxide HO and oxygen in mitochondria or are converted to peroxynitrite ONOO- through a reaction mechanism with endogenous nitric oxide NO Ogino et al. These excess free radicals lead to GSH depletion, cause the accumulation of ONOO-, and form nitrotyrosine protein adducts, which eventually leads to mitochondrial DNA damage and hepatotoxicity Chau et al. However, the drug still has some defects, such as a narrow treatment window Lewis et al. Generally speaking, the adverse reactions of NAC are not life-threatening, but they include nausea, vomiting and allergic reactions. The detoxification effect of NAC is mainly effective 8 h before APAP poisoning, and then the treatment effect begins to decline obviously. Therefore, further research is needed on new drugs and potential targets that can treat APAP liver injury, especially for those patients who appear in the late stage of liver damage. Many studies on natural products extracted from foods have revealed a great deal of molecules that can be used to resist APAP hepatotoxicity Subramanya et al. GSH can participate in a variety of key biochemical reactions, and its function is to protect the sulfhydryl groups of key enzymatic proteins from oxidation and loss of activity, so that they can be utilized by cells and maintain normal energy metabolism. At the same time, the combination of sulfhydryl and free radicals in the body can promote the reduction of free radicals, and then convert them into acidic substances, thereby increasing the excretion rate of free radicals and reducing the damage done to key organs by free radicals. The early signal of apoptosis is often a decrease in the GSH content, and subsequent oxygen free radicals will accelerate apoptosis. Both chronic and acute liver disease are characterized by inflammation. However, the role of inflammation in liver disease is two-sided. On the one hand, inflammation can promote the removal of cell debris, which is conducive to the proliferation and repair of liver cells Chen et al. On the other hand, when numerous hepatocytes die, inflammation is produced, resulting in liver injury Fernandez-Checa et al. As the inflammatory reaction continues, cytokines are released to mediate the infiltration of inflammatory cells. The collected inflammatory cells can further kill hepatocytes over a short period of time, while long-term inflammation will induce the formation of liver fibrosis. Chayanupatkul and Schiano, Ultimately, a variety of inflammatory factors participate in the injury of liver tissue, either directly or indirectly. In addition, interleukin-1 IL-1 is also a strong pro-inflammatory factor. It can induce neutrophils and vascular endothelial cells to express adhesion molecules, trigger the secretion of other inflammatory factors, and participate in inflammatory responses Navaei-Alipour et al. Secondly, IL-6 has a wide range of biological activities, which can promote the proliferation and differentiation of B cells, leading to the production of antibodies, increasing the formation of immune complexes as well as causing an inflammatory reaction Navaei-Alipour et al. In conclusion, the excessive production of these inflammatory factors aggravates the damage done to liver pathological tissue. These elevated inflammatory factors promote the progression of the disease. FXR not only balances bile acids, but also has significant regulatory effects on lipid metabolism, glucose metabolism and other related links in the liver Molinaro and Marschall, It plays an important role in the development of chronic liver disease. Moreover, FXR forms a complex regulatory network through multiple signal pathways mediated by a cascade reaction signal pathway, G protein coupled receptor, cell surface receptor, and antigen receptor to protect the liver from damage due to pathogenic factors Chiang et al. It was also confirmed that FXR can ensure that intestinal barrier function is maintained, preventing the formation of gallstones and reducing liver cholestasis, which may be based on the regulation of related genes affecting bile acid detoxification and drug metabolism by FXR Norona et al. From the above results, it can be seen that FXR may also affect the metabolic pathways of xenobiotics. Similarly, another FXR agonist way is intended to treat nonalcoholic fatty liver and has also entered the clinical trial phase Zhang et al. The detailed experimental evidence is as follows: 1 Molecular docking results showed that Ginsenoside Rc and FXR are well docked. BSEP can reduce the solubility of bile acids and eventually lead to cholestasis and liver injury. The FXR-SHP axis can effectively regulate the metabolism of hepatic bile acids and lipids, liver immune inflammation, and tumor development. The most compelling finding is that Ginsenoside Rc did not significantly reduce the APAP-metabolic enzymes, oxidative stress, and inflammatory response when FXR was knocked out in vivo or vitro. Ginseng is used as a medicine and food worldwide. Many studies have confirmed that ginseng has pharmacological effects such as reducing the oxidative stress response, improving atherosclerosis, improving the osteoblast survival rate, and inhibiting tumor cell growth Sarhene et al. Furthermore, many studies have shown that ginseng can promote glucose and lipid metabolism and improve liver function Hou et al. Ginsenoside is the main effective substance contained in ginseng. Those mechanisms are related to the reduction of oxidative stress and inflammatory response. KLF16 is also a protein closely related to liver damage. In conclusion, our study presents for the first time reported that Ginsenoside Rc could act as an effective FXR activator and treatment of acetaminophen APAP overdose-induced liver injury by modulating FXR to produce anti-oxidative stress, anti-inflammatory, and anti-apoptotic functions. However, in this study, the in-depth mechanism of Ginsenoside Rc treating liver damage through FXR has not been further discussed such as APAP adduct protein, mitochondrial autophagy and oxidative stress, and a detailed molecular mechanism experiment will be carried out in the future. It works mainly by producing anti-inflammatory, antioxidant, and antiapoptotic effects. Our studies also confirmed that Ginsenoside Rc may be a promising compound for the treatment or relief of liver injury induced by APAP overdose. YZ contributed to the project management and experimental design. ZP contributed to the study design and acquisition and analysis of data. KT and YC contributed to the analysis and interpretation of data. GZ wrote the manuscript. All the authors critically revised the manuscript and approved the final version. YG is the guarantor of this work. This study was supported by the following funding sources: The Natural Science Foundation of China and , the Science and Technology Key Program of Guangzhou , and the science and innovation project of Guangzhou University of Chinese Medicine AZ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Keywords: ginsenoside Rc, FXR, acetaminophen, acute liver failure, inflammation, oxidative stress. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Ginsenoside Rc, as an FXR activator, alleviates acetaminophen-induced hepatotoxicity via relieving inflammation and oxidative stress. Introduction Acetaminophen APAP is an antipyretic analgesic that is widely used in clinical practice.

Atheroprotective role of vinpocetine: an old drug with new indication

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