Panax ginseng C. A. Meyer as a potential therapeutic agent for organ fibrosis disease

Each organ has its own function, maintaining the normal operation of life. However, due to certain known or unknown etiologies, the appearance of organ fibrosis disease (OFD) will suddenly break this steady state. Besides the etiologies that it is hard to diagnose correctly, patients with OFD often fail to show the corresponding clinical symptoms in time, which creates difficulties for exact treatment. OFD mainly includes liver fibrosis (LF), pulmonary fibrosis (PF), myocardial fibrosis (MF), and renal fibrosis (RF), which is the initial process of serious tissue damage, organ necrosis, and major fatal diseases, dramatically shortening the lives of folks. Tissue or organ fibrosis is the leading cause of disability and death in many diseases. Statistics have shown that approximately 45% of the individuals who died of various diseases could be attributed to the results of tissue fiber hyperplasia in the developed countries [1], and even around the whole globe, organ failure caused by fibrotic diseases accounted for at least one-third of all deaths. When the tissues or organs are seriously destroyed for any unpredictable reasons, such as irritant, virus, radiation, and the damage is repetitive or exceed the self-repair capacity of cells, the entire process of OFD is initiated. Different organs have analogous fibrotic mechanism. Generally, during chronic injury, epithelial or endothelial cells secrete cytokines, for instance, tumor necrosis factor and interleukin (IL). Under this stimulation, fibroblasts will be activated and gradually transformed into myofibroblasts. After that, myofibroblasts composed of multiple sources, such as epithelial-mesenchymal transition (EMT) and resident fibroblast transformation, will abnormally proliferate and finally lead to the massive deposit of extracellular matrix (ECM), which further promote the development of fibrogenesis. Meanwhile, immune cells will produce cytokines such as transforming growth factor β1 (TGF-β)1, up-regulating the activity of myofibroblasts and boosting collagen synthesis (Fig. 1). In response to injury, the increase of fibrous connective tissue and interstitial cells and the decrease of parenchymal cells reveal the reasons of the destruction of organ structure and function [2, 3]. It may be easy to eliminate the scars appear on the skin, but in liver, lung, heart, kidney, or other internal organs, the scars cannot be easily healed. Therefore, determining suitable remedies for patients with OFD are necessary.

Panax ginseng C. A. Meyer is a household medicinal plant belonging to Araliaceae. “Panax” means all diseases can be cured in Greek, implicating the vital medicinal effect of P. ginseng. As an excellent preventive and therapeutic herb, P. ginseng has been applied medicinally for centuries in various diseases such as cancer, Alzheimer’s disease, cognitive deficit and pulmonary disease [4‐7]. It can also be regarded as a tonic and functional food to improve physical function and exercise capacity or a dietary supplement to neutralize the toxic and ameliorate unexpected side effects after chemotherapy [8]. Moreover, different types of P. ginseng such as sun-dried ginseng, white ginseng and red ginseng exhibit different therapeutic potential.

Recently, researches have revealed the curative effect of P. ginseng on severe late-stage disease. However, the systematic summary of P. ginseng for fibrosis, the inevitable stage of disease deterioration, is still insufficient. Here, this review aims at integrating the studies of P. ginseng therapy for fibrosis from main organs. Notably, holistic medication can maximum exert the therapeutic potential of herbal medicine through the synergistic action of multi-component [9], so we primarily focus on ginseng extract and its derived formulas, but also consider ginseng bioactive compounds so as to further comprehensively develop the application of P. ginseng as an effective agent in the treatment of fibrotic diseases.

Many appropriate remedies have been carried out to fibrosis intervention. Surgery can be used to remove local lesions, but not diffuse fibrosis. Also, organ transplantation is applicable for advanced fibrotic individuals. Unfortunately, it often shows high probability of organ rejection and serious complications [10]. Expelling the pathogeny is one of the most efficient approaches in treating fibrosis. After alcohol withdrawal, the clinical performance and histopathological characteristics of patient will be evidently improved, which means the control of fibrosis in liver [11].

Drug therapy has always been regarded as the dominant intervention for OFD. However, there is still no synthetic drug that can completely avoid side effects while exerting efficacy throughout the treatment process. Oral administration of pirfenidone (PFD) and nintedanib (NDB), the mainstream synthetic drugs for fibrosis, often induces hypersensitivity, nausea, fatigue, or other adverse reactions and significantly increase aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, implying liver function damage. PF patients may experience repeated diarrhea and gastrointestinal disorders after taking NDB, resulting in premature therapy discontinuation [12]. For hepatic fibrosis caused by schistosomiasis, praziquantel has a limitation that it often causes abdominal pain and can hardly kill immature worms at a specified dose [13]. Tenofovir and entecavir, the resultful antiviral drugs recommended by World Health Organization (WHO), act on hepatic fibrosis caused by hepatitis B virus, whereas lactic acidosis may be developed in patients with impaired liver function during therapy [14]. Calcium channel blocker, angiotensin type 1 receptor antagonist and angiotensin converting enzyme inhibitor also has unpredictable side effect in the treatment of MF [15, 16].

Most of the methods of treating fibrosis have two nonnegligible issues: toxicity and unpleasant side effects. Conversely, natural products have received attention as a better strategy for fibrosis due to its particular advantages of “green therapy” [17]. Herbal medicine was generally exploited to charm away fibrosis with satisfactory results long ago, especially in Korea, Japan, and China [18, 19]. Cheap and easily available herbs instead of synthetic drugs are used as alternative medicine in underdeveloped areas to basically guarantee fibrosis treatment. Fuzheng Huayu, a herbal medicine preparations which has finished Phase II clinical trials authorized by the U.S. Food and Drug Administration, has been proven to lighten LF by reducing α-smooth muscle actin (α-SMA) expression, activating liver natural killer cells and producing interferon-gamma [20]. Similarly, Si-Miao-Yong-An decoction (SMYAD) can restrain serine-threonine kinase Akt (AKT) and p38 mitogen-activated protein kinase (MAPK) pathway expression to dramatically reverse MF [21]. Additionally, small molecule compounds also provide vital therapeutic clues in OFD [22]. The potential of anti-inflammatory and anti-fibrosis of hesperidin derivative (HD) has been confirmed, which is based on regulating liver injury markers and depending on hedgehog-Glioma associated oncogene-1 signaling [23]. With the hepatoprotective effect, baicalin can decrease the levels of hyaluronic acid and procollagen type III in CCl₄ model [24]. Paeoniflorin has a capacity to relieve the severity of IPF and control collagen synthesis through modulating TGF-β/Smad pathway [25]. Triptolide has an outstanding effectiveness in PF induced by paraquat through adjusting the EMT progression of epithelial cells [26]. Crocin is able to suppress the inflammation and oxidative stress in isoprenaline-induced MF by triggering toll-like receptor (TLR) 4 and nuclear factor kappa B (NF-κB) signaling [27]. Astragaloside IV or its sapogenin cycloastragenol can be a candidate ingredient of fibrosis, which is linked to the inhibition of NLRP3 inflammasome [28].

Long-term use of synthetic drug always leads to irreversible organ injury. However, more and more studies suggested that phytotherapy preserves organ function with few side effects and satisfying results. P. ginseng, the king of herbs, have been extensively investigated by Asian scholars. Ancient oriental healers decocted the root of P. ginseng with pure water as ginseng extract to cure a broad spectrum of diseases. They believed that this kind of natural and conventional method will give full play to the best nourishing effect of P. ginseng. Moreover, “Du Shen Tang”, a traditional decoction that uses P. ginseng alone and many classical formulas that combines P. ginseng with other adjuvant herbs were developed. So far, the compound containing various types of P. ginseng such as sun died, red and white ginseng obtained by the simplest preparation method has been confirmed can be available to treat OFD. Moreover, not only can ginseng extract and its formulas show a positive therapeutic effect on skin fibrosis that appears outside, but also it has a certain effect in internal organ such as liver, lung, heart and kidney [29].

Most of drug discovery paid more attention to the treatment of advanced disease, for instance, cirrhosis and uremia, which can hardly be cured fundamentally. But often overlooked is that, organ fibrosis is a necessary process for the development of most diseases. If it can be suppressed or reversed as much as possible, the serious condition will be alleviated or even resolved.

Many differences distinguish synthetic drugs and herbal medicines, from treatment cost to adverse reactions. Notably, only about 10% terrestrial plants have been studied in pharmacology, further indicating the prospect of herbal medicine in the discovery of anti-fibrosis [75]. With the irreplaceable medicinal value and obvious therapeutic effect, P. ginseng plays an increasingly significant role in the fibrotic prevention and rehabilitation and has proverbially been utilized to increase longevity. As an advantage to apply expediently, P. ginseng can be used independently or in combination with multiple herbs as herbal compounds, exhibiting multi-component or multi-herb combination characterizes, respectively. Whether ginseng extract or formulas, their therapeutic effect on the main organ fibrosis has been confirmed. Furthermore, saponin and polysaccharide or other monomers of ginseng exert anti-fibrosis actions by regulating fibrotic-related signal transduction pathways, which involves multiple mechanisms such as enhancing the self-healing ability of damaged cells, inhibiting fibroblast activation, promoting myofibroblast apoptosis and regulating inflammatory response. Although there may be more targets for the treatment of fibrosis in ginseng extract or formulas, a complex system of treatment, it is not as generally recognized as the ginseng monomers which have the clear structure.

It is universal believed P. ginseng can act as a dietary supplement or medicine to intervene disease progression. Meanwhile, synthetic drug or natural product combined with P. ginseng may be more advantageous than using them alone in fibrosis treatment [76]. Worth noting that drug combination has been proved to be clinical efficacy, especially in China where the integrated traditional and western medicine is widely used to treat fibrosis. Cooperation of the advantages may become one of the appropriate therapeutic methods for OFD. However, it is difficult to thoroughly determine the mechanism of drug combination, which attributes to the interaction of a wide range of complex components. In addition, P. ginseng can also alleviate the fibrosis caused by synthetic drugs such as omeprazole in the process of treating other diseases, although further clinical researches are needed to confirmed whether there will always be beneficial drug interactions. What matter is that patients may experience temporary stomach upset, insomnia, hypertension, or other mild adverse effects after taking an inappropriate dose of ginseng.

Overall, the preliminary experimental evidence in vivo and in vitro supported the therapeutic potential of P. ginseng in different organs fibrosis, which has a bearing on anti-inflammation, antioxidant and regulating TGF-β/SMAD pathway. However, in order to better apply P. ginseng in the clinical practice of OFD and promote the modern development of traditional Chinese medicine represented by ginseng in the treatment of fibrosis, further convincing evidence of the relationship between the all-round mechanisms and the anti-fibrotic activity of P. ginseng requires to be provided.