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. 2023 Mar 8;15(2):222–230. doi: 10.1016/j.chmed.2022.08.011

Pharmacological importance of Kunxian Capsule in clinical applications and its adverse effects: A review

Ruijiao Ma a,b,1, Maharajan Kannan a,b,1, Kaiyan Zhuang a,b, Qing Xia a,b, Dong Sun c, Pengfei Tu d, Taiping Fan e, Kechun Liu a,b, Yun Zhang a,b,⁎
PMCID: PMC10230640  PMID: 37265775

Abstract

Kunxian Capsule (KX) is a popular Chinese patent medicine for the treatment of rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus, Henoch-Schönlein purpura, ankylosing spondylitis, psoriatic arthritis and eczema. However, there is scarcity of comprehensive information on the significance of KX in the clinical application and its side effects. Hence, it is aimed to provide a review of the significance of KX, with a focus on the pharmacological effects, clinical applications, and its adverse reactions. This review was based on the published literatures in PubMed, China National Knowledge Infrastructure and WanFang database. The articles were collected by two independent authors with no time limits applied until November 30, 2022. The search term includes Kunxian Capsule and/or clinical effect, pharmacology, disease, therapy, adverse effects and quality control. KX has been shown to be effective in the treatment of autoimmune arthritis by inhibiting inflammatory responses and inducing apoptosis. Many studies suggest that KX has anti-inflammatory and analgesic properties that aid in the improvement of joint functions. KX dispels wind, removes dampness, invigorates the kidneys, and promotes blood circulation, thereby curing various diseases. However, studies also suggest KX-related adverse reactions in multiple systems. Overall, this review highlights the scientific basis of KX in curing or preventing various diseases and provides novel insights for further research and clinical applications.

Keywords: adverse effects, autoimmune disease, Chinese patent medicine, Kunxian Capsule, rheumatoid arthritis

1. Introduction

Kunxian Capsule (KX) is a Chinese patent medicine consists of four herbal components. It appears light brown to brown granules and powders with a bitter taste. KX helps in invigorating kidneys, promoting blood circulation, dispelling wind, removing dampness, inhibiting inflammation, and alleviating pain (Xue et al., 2016). KX is an immune system regulator that has been widely used in treating autoimmune and inflammatory diseases (Chen, Zhang, & Xing, 2022, Li et al., 2016). It is commonly used to treat rheumatoid arthritis (RA), nephrotic syndrome (NS), systemic lupus erythematosus (SLE), and Henoch-Schönlein purpura (HSP) (Zhang & Yi, 2014). Besides, the intervention of KX also showed curative effects on ankylosing spondylitis (AS), psoriatic arthritis (PsA) and eczema (Sohn et al., 2011, Saunes et al., 2012, Scotti et al., 2018, Hao et al., 2021). Although the clinical significance has been extensively studied, the comprehensive role of KX in treating various diseases has received scant attention. For instance, a recent network and pharmacology-based study reviewed the pharmacological mechanism of KX only in RA treatment (Tang, Zhang, Li, Xie, & Huang, 2020). Hence, this review aims to provide the clinical significance of KX in treatment of RA, NS, SLE, HSP, AS, PsA and eczema. Besides, the role of bioactive compounds present in herbal components of KX and their molecular mechanisms were discussed. Finally, the adverse reactions of KX during the clinical treatment were also reviewed.

A literature survey was conducted across databases such as China National Knowledge Infrastructure (CNKI), WanFang database and PubMed. The articles were collected by two independent authors with no time limits applied until November 30, 2022. The search term includes Kunxian Capsule and/or clinical effect, pharmacology, disease, therapy, adverse effects and quality control. In total, 293 articles were collected in both English and Chinese language versions. While, in this review, 24 articles were included and their findings were discussed. The remaining literature was ignored due to repetition or being not relevant for this review.

2. Composition, pharmacological effects and quality control of KX

There are four main herbs in KX, namely Tripterygium wilfordii Hook. F. (Kunming Leigongteng in Chinese) [Tripterygium hypoglaucum (H. Lév.) Hutch (Kunming Shanhaitang in Chinese)], Epimedium brevicornu Maxim (Yinyanghuo in Chinese), Cuscuta chinensis Lam (Tusizi in Chinese), and Lycium barbarum L. (Ningxia Gouqi in Chinese) (Tang, Zhang, Li, Xie, & Huang, 2020). The details of each herb and its uses were listed in Table 1. Besides, the importance of KX in clinical application was shown in Fig. 1.

Table 1.

Composition and usages of KX.

Botanical origins Families Chinese names Pharmaceutical parts Usages References
Tripterygium wilfordii Hook. F. Celastraceae Kunming Shanhaitang Roots Treats autoimmune and inflammatory
diseases, cancer, cadaveric kidney transplants, and Crohn disease.		 Goldbach-Mansky et al., 2009, Chang et al., 2021
Epimedium brevicornu Maxim. Berberidaceae Yinyanghuo Aerial parts Treats osteoporosis and sexual dysfunction Huang et al., 2018)
Lycium barbarum L. Solanaceae Ningxia Gouqi Fruits Used to treat abdominal pain, blurred vision, fatigue, dizziness, infertility, and headache. Gao, Wei, Wang, Gao, & Chen, 2017, Hao, Wang, Zhao, & Li, 2020
Cuscuta chinensis Lam. Convolvulaceae Tusizi Seeds Nourish the liver and kidneys, treat impotence and improves eyesight. Zhang et al., 2020
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Fig. 1.

Fig. 1

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Overview of KX composition in treating various diseases.

2.1. T. wilfordii

T. wilfordii is a traditional Chinese medicine (TCM) with potential immunosuppressive effects and has been reported to treat RA (Bao & Dai, 2011). In TCM and Chinese allopathic medicine, the root extracts of T. hypoglaucum have shown promising treating effects against autoimmune and inflammatory diseases, cancer, cadaveric kidney transplants, and Crohn's disease (Goldbach-Mansky, Fleischmann, Silverfield, & Kempf, 2009). THH can dispel wind, remove dampness, promote blood circulation, relax muscles and joints, reduce heat, and remove toxic materials.

2.2. E. brevicornu

The clinical importance of Epimedium was first recorded in the Shennong’s Herbal Atlas from 221 BCE to 220 CE. The aerial part of Epimedium spp. has been used to treat osteoporosis and sexual dysfunction (Huang et al., 2018). E. brevicornu is a TCM tonic that can enhance immune function, strengthen bones and tendons, replenish the kidneys, enhance gonadal function, and treat RA (Guo, Wang, & Gao, 2018, Xue et al., 2016). The main active ingredients of Epimedium are glycosides, which have been proven to improve the phagocytosis rate and phagocytosis index of peritoneal macrophages, promote spleen lymphocyte transformation, enhance natural killer cell activity, and improve immune function in mice (Li, Jin, & Guo, 2002). A recent study has revealed the osteogenic potential of epimedin A, B, and C from E. brevicornu extracts (Guo, Wang, & Gao, 2018). The potential effects of Epimedium in treating osteoporosis have resulted in widespread usage of this plant in many TCM formulas (Hao et al., 2021).

2.3. L. barbarum

L. barbarum, a plant belongs to Solanaceae family, while its fruit is commonly known as 'Goji' in China and or 'wolfberry' in western countries (Hao, Wang, Zhao, & Li, 2020). It can nourish the liver and kidneys and replenish vital essence to improve eyesight (Zhu, 2005). In TCM, L. barbarum has been used to treat various diseases such as abdominal pain, fatigue, dizziness, infertility, and headache. The immunoregulative and anti-apoptotic properties of L. barbarum have suggested that it is acting as an anti-aging agent (Gao, Wei, Wang, Gao, & Chen, 2017). It inhibits carbon tetrachloride-induced hepatic lipid peroxidation, reduces alanine aminotransferase (ALT), and promotes liver recovery. Moreover, it promotes lipolysis, inhibits fat accumulation, and prevents fatty liver formation. A recent study found that L. barbarum could also promote osteoblast proliferation and differentiation, suggesting its potential clinical importance in treating bone diseases (Zhang, Zheng, & Yuan, 2019).

2.4. C. chinensis

Cuscutae Semen is the dried seeds of C. chinensis, which has been widely used in Chinese medicine (Zhang et al., 2020). It regulates immunity, improves eyesight, nourishes the kidneys and livers, and replenishes vital essence (Ye & Yan, 2000). It also showed proliferation of osteoblasts and mesenchymal stem cells and inhibition of osteoclast activity (Dai, Sun, & Zhong, 2020). Moreover, it improves endocrine function by luteinizing hormone (LH) surge in the hypothalamus-pituitary-ovarian axis (Qin & She, 1998).

2.5. Quality control of KX

Fingerprinting techniques are widely used to address the chemical composition for quality control of TCM (Maharajan et al., 2021). Recently, Xu et al. have revealed the compounds of KX such as hyperoside, epimedin A, epimedin B, epimedin C, icariin and baohuoside I based on high performance liquid chromatography (HPLC) fingerprint analysis that can be used for quality control (Xu et al., 2020). Furthermore, Zhang et al. has developed a quantitative analysis of multi-components by single marker (QAMS) method for simultaneous determination of ten flavonoids contents of KX via HPLC analysis including epimedin A, epimedin B, epimedin C, quercetin, icariin, luteolin, nobiletin, baohuoside I and kaempferol for quality control (Zhang, Peng, & He, 2018). Jing et al. (2020) has identified 51 chemical components in KX with active compounds such as celastrol, icariin, chaohuoding B, patchouli, catechol, mistletoe, luteolin, epicatechin, isorhamnetin, catechin and glycine by ultrahigh performance liquid chromatography coupled to Quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) technique. Recent chemical profiling with network pharmacology analysis by Yan et al. (2021) has reported 67 compounds from KX extract using UHPLC coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). The main active pharmaceutical ingredients were identified as terpenoids (such as triptolide and celastrol), sesquiterpene pyridines (such as wilforgine and wilforine), and flavonoids (such as icariin, epimedin A, B, and C, and 2″-O-rhamnosylicariside II). Besides, Thin layer chromatography (TLC) and HPLC method were studied for the determination triptolide, icariin and hypericin as the indicator components of KX and showed effective for quality control with strong specificity and good reproducibility (Xu et al., 2022).

3. Clinical applications of KX and their therapeutic effects

3.1. Rheumatoid arthritis (RA)

RA, a chronic autoimmune arthritis inducing synovial inflammation with a prevalence of 1% (Hansildaar et al., 2021, Huang, Zhong, Liao, Hu, & Hu, 2021, Liu et al., 2020). RA commonly affects the lining of the joints in the hands, wrists, and knees, causing damage with long-lasting or chronic pain that results in a lack of balance (unsteadiness), deformity, and loss of function (CDC, 2020). Pathologically, these chronic inflammatory processes result in the destruction of articular cartilage, subchondral bone, ligaments, and tendons. Synovial inflammation leads to juxta-articular bone erosions and systemic osteoporosis (Zhao et al., 2018). Besides, people with RA have an increased risk factor for cardiovascular disease (Li, Liu, & Zheng, 2018). Based on clinical manifestations and the disease course, RA is considered a “collateral disease” in TCM, such as “arthralgia”, “obstinate arthralgia”, “joint-running wind”, and “Wangbi”. According to TCM theory, RA is caused by insufficient internal qi; External blockage due to wind, cold, dampness, and heat; and blockage of the meridians, qi and blood due to internal phlegm and blood stasis. Therefore, RA can be managed by invigorating the liver and kidneys and dispelling wind and dampness. According to Western medicine (WM), RA is the most common inflammatory arthritis and the leading cause of disability (Xia et al., 2018). Besides, RA is also characterized by synovitis and vasculitis. Although the first-line of treatment for RA is suggested to be disease-modifying antirheumatic drugs (DMARDs), there is a search for new alternatives to overcome the drawbacks in current pharmacological therapies (Jiang et al., 2015, Liu et al., 2020). The extract of T. hypoglaucum, a component of KX, is a well-established alternative to DMARD for the RA patients (Zhang et al., 2020). Pharmacological studies have shown that KX reduces the proliferation of synovial cells, improves the symptoms of cartilage destruction, and promotes joint recovery by inhibiting the production of interleukin (IL)-8 and Interferon γ-inducible protein (γIP-10) (Lin, Wang, & Xu, 2012). Tang et al. reported that KX shows treatment effects in RA by inhibiting inflammatory responses and inducing apoptosis via the PI3K/AKT/mTOR signaling pathway (Tang, Zhang, Li, Xie, & Huang, 2020). Recently, the anti-angiogenic effect of KX extract was reported in zebrafish embryos through the intersegmental vessels and sub-intestinal vein formation via PI3K/AKT-MAPK-VEGF pathway (Ma et al., 2023).

Methotrexate (MTX) and leflunomide (LEF) are the drugs of choice for RA. MTX is a specific inhibitor of folate reductase, inhibits dihydrofolate reduction and DNA synthesis, thereby exerting immunosuppressive and anti-inflammatory effects (Lin et al., 2011, Yang, 2015). LEF exerts immunosuppressive effects by inhibiting pyrimidine synthesis, dihydroorotate dehydrogenase activity and reducing T cells. Lu (2018) showed that KX is superior to MTX for the treatment of RA, with an overall response rate of 96.67% in the KX group, which was significantly higher than that in the MTX group (80.00%, P < 0.05). A clinical observation study for the treatment of active RA found that KX was superior to LEF in terms of analgesic effects and swelling reduction, which suggests that KX could quickly relieve the clinical symptoms of RA (Jiang, Gao, & Liu, 2015). In addition, Lin et al. (2011) showed that KX and MTX had synergistic effects for the treatment of RA. Li & Shi, 2018 retrospectively analysed the clinical data of RA patients who received MTX alone (36 cases) and both KX and MTX (40 cases) between March 2015 and May 2017. They found that C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly reduced in both the groups, while the number of swollen joints and the number of painful joints were significantly lower in the KX + MTX group than in the MTX group, suggesting that KX + MTX is superior to MTX alone (P < 0.05). In RA patients, the combination of KX and MTX treatment effectively controls inflammatory responses and improves clinical outcomes.

3.2. Nephrotic syndrome (NS)

NS is a common kidney disease, affects about 12–16 per 100 000 children aged below 16 years (Esezobor, Solarin, & Gbadegesin, 2020, Lee, Kronbichler, Shin, & Oh, 2021, Trautmann et al., 2020). It causes the body to excrete a high amount of protein in urine, due to abnormal glomerular filtration of plasma proteins. It is a group of clinical glomerular disorders with similar clinical manifestations but with different aetiologies and pathologies. The clinical manifestations of NS include proteinuria, severe oedema, hyperlipidaemia, hypoproteinaemia, and other symptoms (Wörn et al., 2021). In severe cases, renal function could be damaged by bacterial infection and metabolic disorders, which in turn affect the health of patients. NS is usually managed with symptomatic care, including drugs to promote urination and reduce swelling, urinary protein, and blood lipid levels (Guo & Zhu, 2015). Yang et al. (2009) showed that KX reduced urinary protein levels, improved glomerulosclerosis and glomerular mesangial cell proliferation, reduced the thickness of the epithelial basement membrane, and repaired podocyte morphologic damage in C-BSA rats. Lu et al. investigated the effects of KX on endothelial cell function and serum transforming growth factor-β1 (TGF-β1) in patients with primary membranous nephropathy. The results showed that KX significantly reduced serum TGF-β1 and effectively improved kidney function (Lu & Ren, 2019). KX combined with Bailing Capsule has significantly enhanced kidney function by reducing serum creatinine, blood urine nitrogen, and 24-hour urinary protein (Deng, Xiong, Zhang, Wang, & Lin, 2019). Studies have reported that KX combined with glucocorticoids is effective for NS. For instance, it was found that KX combined with low-dose glucocorticoids significantly reduced total cholesterol, triglycerides, and urinary protein in NS patients (Lv, Yu, & Ren, 2018).

Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus, is the major contributor to chronic kidney disease and end-stage renal disease (Shao, Zhang, Li, Meng, & Chen, 2021). Inflammation plays a crucial role in the pathogenesis of diabetic nephropathy, with the involvement of renal and immune cells. KX treatment in diabetic nephropathy patients has improved the renal function and renal interstitial fibrosis indexes with a total effective rate of 99.20% (Zhao, Ma, & Zhang, 2021). In addition, Sun (2021) reported that KX combined with valsartan treatment in stage IV diabetic nephropathy has reduced proteinuria and improved renal function.

3.3. Systemic lupus erythematosus (SLE)

SLE is an autoimmune disease that is characterized by the impairment of connective tissues due to the recognition of accumulated DNA and nuclear components in blood by autoantibodies (Melki et al., 2021). The prevalence of SLE is about 30–50 per 100 000 people and its manifestation and severity depend on various factors such as ancestry, race, and ethnicity (Dörner & Furie, 2019). SLE displays heterogeneous clinical symptoms as a result of inflammation in multiple organs, including skin, joints, kidneys, and the nervous system (Durcan et al., 2019). Lupus nephritis (LN) is the most common manifestation (40%–70%) of SLE, which can cause irreversible kidney damage (Maria & Davidson, 2020, Mohan and Putterman, 2015). The pathogenesis of LN starts with the accumulation of nucleic acid materials in the glomeruli, which in turn activates the complement system along with the involvement of renal stromal cells and circulating pro-inflammatory cells (Maria & Davidson, 2020). LN progresses with metabolic dysfunction of the tubular epithelium, tubulointerstitial hypoxia, and accumulation of mixed lymphoid infiltrates and fibrosis. In this context, KX is effective for treating SLE and LN. For instance, Xiang et al. showed that KX significantly improved kidney function and reduced serum immunoglobulin E and immunoglobulin G in patients with LN and NS, with clear clinical benefits (Xiang, Shao, & Huang, 2019). He et al. showed that after five months of KX combined with iguratimod treatment, the urinary protein turned negative with no adverse reactions (He, Zhang, Mo, Li, & Dai, 2020). Moreover, Li et al. (2019) showed that combined treatment of glucocorticoids with KX was more effective than cyclophosphamide combined with glucocorticoids in LN patients, with fewer adverse reactions, suggesting that KX has a promising role in clinical practise.

3.4. Henoch-Schönlein purpura (HSP)

HSP is the most common autoimmune small-vessel leucocytoclastic vasculitis in children under the age of 17 and peaks between the ages of 4–6 years (Saulsbury, 2007, Oni and Sampath, 2019, Wang et al., 2020). The main clinical manifestations include nonthrombocytopenic purpura, arthritis, gastrointestinal bleeding, abdominal pain, and kidney damage (Yu et al., 2020). HSP causes damage to organs through inflammation of small blood vessels with immunoglobulin IgA-containing immune complex deposits (Gaskill et al., 2016). HSP occurs with an incidence of about 17.55 cases in southern Sweden, 18.60 in France, and 55.90 in Korea per 100 000 people a year (Wang et al., 2020). Immunoglobulin A vasculitis (IgAV) is the most common form of childhood vasculitis, with an incidence of 3–27 per 100 000 children (Oni & Sampath, 2019). In a clinical observation study of KX intervention (Ma & Song, 2018), HSP patients were randomly assigned to a control group (n = 30; routine treatment + prednisone) or an observation group (n = 30; routine treatment + prednisone + KX). In the control group, HSP was subsided in two patients after 3 d, in five patients after 7 d, and in 15 patients after one month of treatment. In the observation group, HSP was decreased in nine patients after 3 d of treatment, resolved in 21 patients after 7 d of treatment, and disappeared in 30 patients after one month of treatment. The overall response rate in treating HSP was 100% in the KX group. HSP-induced nephritis (HSPN), also known as “purpura kidney”, is more common in children and is characterized by vascular inflammation (Zeng & Zeng, 2010). Moreover, Chen et al. (2018) studied a homemade purpura formula in combination with KX and achieved an overall response rate of 96% in children with HSPN, with the advantages of a short treatment course and high efficacy.

3.5. Ankylosing spondylitis (AS)

AS, or Bechterew's disease, is a type of spondyloarthropathy and a chronic autoimmune disease (Li et al., 2016). It is characterized by inflammation and new bone formation that results in loss of flexibility due to the fusion of the spine and sacroiliac joints, resembling “bamboo” with an immobile position (Quaden, De Winter, & Somers, 2016, Zhu et al., 2019). It is suggested that there is a strong correlation exists between the inheritance of AS and the major histocompatibility complex (MHC) class I allele human leukocyte antigen (HLA)-B27 (Quaden, De Winter, & Somers, 2016, Tavasolian & Inman, 2021). Li et al. (2016) reported that KX could significantly reduce back pain and the level of morning stiffness in AS patients. Besides, they also found that KX treatment showed improvement in patients as evidenced by disease indices, ESR, CRP, and Bath Ankylosing Spondylitis Functional Index (BASFI).

3.6. Psoriatic arthritis (PsA)

PsA is a chronic, progressive, heterogenous, systemic, inflammatory and musculoskeletal disease that causes serious joint damage and disability to both peripheral and axial joints (Gottlieb & Merola, 2020, Stober, 2021). In general population, PsA occurs with a prevalence of 133 per 100,000 people (Scotti et al., 2018, Karmacharya et al., 2021). PsA is associated with psoriasis and also occurs in patients with co-morbidities such as cardiovascular disease, inflammatory bowel disease, uveitis, metabolic syndrome, obesity, diabetes, anxiety, and depression (Perez-Chada & Merola, 2020). PsA tends to recur and often causes late-stage joint stiffness, which can lead to disability (Husni, Merola, & Davin, 2017). Jia et al. reported that the response rate for KX combined with a heat-clearing and detoxifying decoction was effective for PsA (76.67%), with significant improvement in joint symptoms, suggesting that the effective improvement in the clinical symptoms and controlling the disease progression (Jia, Li, & Huang, 2014). Besides, Li et al. (2020) have investigated the efficacy and safety of KX for the treatment of progressive psoriasis vulgaris. Patients were randomly assigned to a KX group or placebo group. Clinical efficacy was evaluated via the psoriasis area and severity index (PASI) before treatment and after two and four weeks of treatment. The results showed that in the KX group, the PASI 50, PASI 75, and PASI 90 rates were 74.1%, 29.6%, and 14.8%, respectively; Whereas in the control group, the rates were 0%, which suggests that KX is effective for the treatment of progressive psoriasis vulgaris.

3.7. Eczema

Eczema, also known as atopic dermatitis, is a chronic inflammatory relapsing skin disease that affects about 200 000 people globally. It is characterized by pruritus, interrupted epidermal barrier function, and immunoglobulin E–mediated sensitization to food and environmental allergens (Sohn et al., 2011, Lusignan et al., 2021). Its long-lasting nature severely affects the quality of life (Agner & Elsner, 2020). In severe cases, the rash is widespread with erosion and exudation. In a study by Lai (2016), patients with generalized eczema received KX combined with compound glycyrrhizin (the combination therapy group; n = 42) or compound glycyrrhizin alone (the control group; n = 38). The results showed that in the combination therapy group, 20 patients responded very well and 18 responded well to the treatment; while in the control group, the responses were 12 and 16, respectively. The overall response rate was 90.48% in the combination therapy group, which was significantly higher than that in the control group (73.68%), suggesting that KX combined with compound glycyrrhizin is more effective for the treatment of generalized eczema. The clinical applications of KX in various disease conditions have been summarized in Table 2.

Table 2.

Diseases ameliorated by intervention of KX in clinical studies.

Drug details Therapeutic purpose Subjects Treatment period Response rate (%) Remarks/Description References
KX RA 30 patients Six months 96.67 After treatment, ESR, CRP and VAS score were decreased, and patients with RA symptoms was reduced. Lu, 2018
KX + Leigongteng Duogan Tablets RA 132 patients Six months 85.07 Effectively reduced the level of inflammation Sun & Chen, 2021
KX + MTX RA 40 patients 12 weeks 95.00 Serum CRP and ESR levels were decreased. Drug administrtaion decreased the joint swelling and joint pain. Li & Shi, 2018
KX NS 107 patients 12 weeks 88.79 Serum creatinine (SCr), blood urea nitrogen (BUN) and 24 h urinary protein were decreased, while total protein and albumin levels were increased. Lu & Ren, 2019
KX + Bailing Capsule NS 57 patients 12 weeks 89.47 NS symptoms were improved with reduction in SCr, BUN and 24 h urinary protein. Deng, Xiong, Zhang, Wang, & Lin, 2019
KX + glucocorticoid NS 30 patients 12 weeks 73.30 Combined treatment has decreased the urinary protein quantification (UPro), total cholesterol (TC), triglyceride (TG), BUN, and SCr levels. Lv, Yu, & Ren, 2018
KX + glucocorticoid NS 70 patients Three months 77.14 Patients showed improvements in 24-hour urinary protein, serum albumin, total cholesterol and serum inflammatory factors. (Han, Zhou, & Li, 2021)
KX + glucocorticoid and cyclophosphamide SLE 56 patients Three months 87.50 Serum IgE and IgG levels were significantly decreased. Besides, SLE activity index (SLEDAI) score, BUN, SCr, and 24 h urinary protein levels were decreased. Xiang, Shao, & Huang, 2019
KX + Iguratimod LN 1 patient Six months − After treatment, urinary protein levels turned negative. He, Zhang, Mo, Li, & Dai, 2020
KX + glucocorticoid LN 66 patients 24 weeks − Showed improvement in patients with less adverse reaction. Mei et al., 2020
KX HSP 30 patients Two months 100.00 The symptoms of the patients was completely controlled. Ma & Song, 2018
KX HSPN 50 patients Two weeks 96.00 KX administration has decreased urinary protein level. Chen & Liu, 2018
KX AS 80 patients 12 weeks 97.00 Showed better treatment effects by decreasing symptoms such as body pain and moming stiffness with reduced CRP levels. Li et al., 2016
KX + Qingrejiedu Decoction PsA 30 patients Six months 76.67 The patient's skin and joint symptoms were improved significantly. Jia, Li, & Huang, 2014
KX + glycyrrhizin Eczema 42 patients Four weeks 90.48 The skin lesions of the patients were subsided Lai, 2016
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4. KX-related adverse reactions

KX showed adverse reactions in multiple systems, such as gastrointestinal disturbances, fertility impairment, abnormal liver function, kidney damage, and skin damage (Xu et al., 2018, Liu et al., 2020, Xing et al., 2020). In this context, Li et al. (2016) has reported stomach burning sensation, gastrointestinal discomfort, elevation of transaminase, slightly decreased WBC or platelets, dry throat, dysmenorrhea, and menopause. Tang, Zhang, Li, Xie, & Huang, 2020 have found adverse reactions such as liver damage, reproductive toxicity, leukopenia, and renal dysfunction through network construction with the involvement of 136 genes. Some patients have experienced upper gastrointestinal adverse reactions after KX medication. For instance, Xu et al. (2018) have investigated the effect of intervention time on KX induced gastrointestinal adverse reactions. The results showed that the incidence of gastrointestinal adverse reactions was 3.3% when taking KX with food and 13.3% when taking KX on an empty stomach. Studies have reported that KX has significant side effects on fertility.

T. hypoglaucum, the main ingredient of KX, may cause hypomenorrhea or amenorrhea in women of childbearing age (Xu & Zhao, 2008). Recently, Le, Shi, Gong, & Yang, 2022 has reported the oligomenorrhea or menstrual irregularity, amenorrhea, abdominal pain, liver injury and skin pigmentation during the KX treatments in IgA nephropathy (IgAN) patients. Although T. hypoglaucum has various pharmacological effects, the accumulation of its phytochemicals can lead to severe renal toxicity, hepatotoxicity, and reproductive toxicity that limits its clinical application due to its toxicities associated with multiple targets and pathways (Ma et al., 2015, Zhao, Ma, & Zhang, 2021). E. brevicornu enhances the immunosuppressive effects of T. hypoglaucum (Feng et al., 2016). C. chinensis and L. barbarum can invigorate the kidneys, replenish vital essence, warm the kidneys, and nourish the Yang. Chen et al. (2014) suggests that C. chinensis in combination with L. barbarum could effectively antagonize the reproductive toxicity of T. hypoglaucum without affecting its anti-inflammatory and immunosuppressive effects. Since, KX has four different herbal components with many active compounds that might have synergistic or antagonistic effects, and hence it is difficult to compare the adverse events with the KX chemical components. Recently, Xing et al. (2020) summarized the clinical experience with KX and highlighted that the patients should be closely monitored for gastrointestinal reactions, liver damage, and fertility impairment during KX treatment. The dose should be reduced or discontinued promptly in the event of any adverse reactions, which usually resolve after intervention. Therefore, clinicians may alter the dose of KX with respect to the condition of each patient to prevent adverse reactions in clinical practice.

5. Discussion

Based on clinical studies, the KX is a TCM made of four herbal components that show therapeutic potential in curing RA, NS, SLE, HSP, AS, PsA, and eczema. Generally, medicinal plants contain many bioactive compounds that are involved in the treatment and management of various diseases. Identification of the key bioactive compounds and the underlying pharmacological mechanism of action remains a challenge in studying TCMs containing multiple herbal constituents. Although TCM consists of a combination of plant components, the polyherbal formulations act synergistically to support therapeutic effects (Sultana, Arora, Arora, & Sindhu, 2021). This review highlights the possible bioactive compounds of KX in treating various diseases along with molecular insights.

Recently, Tang, Zhang, Li, Xie, & Huang, 2020 identified 1354 targets in KX, while these targets were enriched in the calcium, cAMP, cGMP-PKG, and PI3K-AKT signaling pathways. These pathways target IL-17 and tumor necrosis factor (TNF) signaling, and Th17 cell differentiation that are related to anti-inflammatory responses. Besides, these pathways are also involved in inducing apoptosis via the PI3K/AKT/mTOR signaling pathway. Another recently study has reported the anti-angiogenic activity of KX in Zebrafish embryos through PI3K/AKT-MAPK-VEGF pathway (Ma et al., 2023). In T. hypoglaucum, more than 500 metabolites were identified, which include alkaloids, flavonoids, sesquiterpenes, lignans, diterpenes, triterpenes, and glycosides (Zhang et al., 2021). Among these compounds, triptonide, tripdiolide, triptolide, wilforlide A, and tripterine have shown good immunosuppressive and anti-inflammatory effects (Chang et al., 2021, Lin et al., 2021). Triptolide, one of the main bioactive compounds of T. hypoglaucum, has been shown to significantly relieve joint swelling. Triptolide's curative effect is mainly attributed to promoting the expression levels of IL-10 and TGF-β; inhibiting the expression of IL-17, TNF-α, vascular endothelial growth factor (VEGF), and interferon (IFN)-γ and increasing the proportion of Treg cells in type II collagen-induced RA rats (Fan et al., 2019). Recently, Zhang et al., (2022) have reported that the antiproteinuric and renoprotective effects of triptolide could exert in passive Heymann nephritis rat models by regulating PI3K/AKT/mTOR signaling pathway. Tripterine (celastrol), another important bioactive ingredient against RA, protects cartilage through immunosuppression, induction of apoptosis, inhibition of inflammation and angiogenesis (Zhao et al., 2021). Wong et al. (2019) have reported that celastrol induces autophagy-dependent cytotoxicity in synovial fibroblasts, possibly by inhibiting calcium signaling. Triptolide has been used to treat RA by promoting the expression of regulatory cytokines and enzymes and inhibiting the expression of inflammatory cytokines, thereby inducing apoptosis, inhibiting angiogenesis, and suppressing pannus formation. Although reports have evidenced the multiorgan toxicity effect of T. hypoglaucum, there are studies attempting to reduce its adverse effects. For instance, Lin et al. (2021) have developed a guideline for the clinical signs, dosage, combined medication, and safety use of T. hypoglaucum Tablets in treating RA.

The other three herbal components of KX, like E. brevicornu, C. chinensis, and L. barbarum, might play an important role in detoxication by regulating amino acid metabolism. Pharmacological studies on Epimedium have demonstrated that it possesses anti-oxidant, anti-cancer, anti-depressant, and anti-atherosclerosis activities (Guo, Wang, & Gao, 2018). It strengthens bones, protects cardio-cerebral blood vessels, and regulates immune function. Osteoblasts, chondrocytes, and osteoclasts are the three major cell types that contribute to the bone. Among these, osteoblasts are associated with the cortical structure of bone and are also involved in lamellar bone deposition to maintain stability of hard callus resorption through osteoclasts in remodeling process. Besides, osteoblasts can differentiate into chondrocyte, adipocyte, and muscle lineages, and hence, they have the potential to treat bone diseases (Zhang, Zheng, & Yuan, 2019). Icariin, the most abundant active component, is a flavonoid glycoside of Epimedium that regulates bone remodeling by stimulating osteoblastic cell proliferation and differentiation via regulation of bone morphogenetic proteins (BMP), transforming growth factor-β (TGF-β), and insulin-like growth factors (IGF) signaling (Xue et al., 2016). Icariin alleviates RA by inhibiting STAT3 activation in T cells, resulting in decreased IL-17 production (Chi, Gao, Shu, & Lu, 2014). Recently, Tang et al. (2021) discovered that icariin alleviates osteoarthritis by regulating chondrocytes autophagy mechanisms and mediating PI3K/AKT/mTOR signaling pathways.

Besides, the polysaccharides of L. barbarum, an herbal component of KX, have the capacity to proliferate and differentiate the osteoblasts. The polysaccharides are the main components of L. barbarum that are responsible for the therapeutic effects (Hao, Wang, Zhao, & Li, 2020). Liang & Yue (2019) have reported that L. barbarum polysaccharides promote the viability of osteoblasts by miR-17 mediated inhibition of PTEN and induction of the PI3K/AKT pathway. Hence, the active compounds of L. barbarum might be responsible for the therapeutic effect of KX in treating RA, AS, and PsA.

Endoplasmic reticulum (ER) is in charge of proper protein function by being involved in synthesis, post-translational modification, and folding (Liu et al., 2022). The changes in protein folding homeostasis led to the accumulation of misfolded proteins, which in turn cause ER stress. Prolonged ER stress might result in oxidative stress, inflammation, and apoptosis. The polysaccharides of L. barbarum have immunomodulatory and antioxidative properties. Goji berries contain pectic polysaccharides that could reduce ER stress and protect cells from apoptosis (Huang et al., 2018). Betaine, one of the active compounds of L. barbarum has an anti-inflammatory role in various diseases, protects the liver, and improves fertility (Zhao et al., 2018). Betaine was reported to prevent oxidative stress, inhibits nuclear factor-κB (NFκB) and the leucine-rich family, pyrin-containing 3 (NLRP3) inflammasome activation, controls energy metabolism, and alleviates ER stress and apoptosis.

Glucocorticoids possess immunosuppressive and anti-inflammatory effects and are widely used in the treatment of RA, autoimmune disease, and organ transplantation (Mo, Zhang, Li, Li, & Pu, 2019). However, the long-term use of glucocorticoids might lead to osteoporosis. Various studies have suggested that natural products with antioxidant properties could prevent glucocorticoids-triggered osteoporosis. C. chinensis contains flavonoids such as chlorogenic acid, quercetin, campherol, and many other compounds that have antioxidative, anti-inflammatory, antidepressant, and hepatoprotective properties (Zhang et al., 2020). The anti-oxidant properties of C. chinensis ameliorate osteoporosis by modulating receptor activator of nuclear factor kappa-B ligand/osteoprotegerin (RANKL/OPG) and runt-related transcription factor 2 (RunX2) signals. Recent network and pharmacology studies suggest that sesamin, an active ingredient of C. chinensis might be useful for treating osteoporosis (Dai, Sun, & Zhong, 2020).

In general, plants with medicinal value comprise numerous bioactive compounds involved in the treatment and management of diseases. The various bioactive compounds present in the herbal components of KX have contributed to the therapeutic effects through multiple targets and biological pathways. However, the adverse effects of KX might be related to the antagonistic effects of the mixtures of compounds or toxic effects of some of the herbal compounds. It is important to screen the bioactive compounds of the KX formulation for a clear understanding of the beneficial compounds. Hence, it is suggested that the key bioactive compounds of KX herbal components should be studied in detail to understand the integrative therapeutic potential with minimal adverse effects.

6. Conclusion

This review provides the latest research progress on the pharmacological effects, clinical applications, and adverse reactions to KX. Each component of KX, such as T. hypoglaucum, E. brevicornu, L. barbarum, and C. chinensis, has a significant role in treating various diseases like, autoimmune and inflammatory diseases, cancer, osteoporosis, infertility, blurred vision, etc. KX is widely used to treat RA, NS, SLE, HSP, AS, PsA, and eczema with proven efficacy. However, more research on synergistic effects of bioactive components of KX components along with its mechanism of action is required to provide a scientific basis for clinical application and to reduce the adverse effects.

Declaration of Competing Interest

Author Dong Sun is employed by Guangzhou Baiyunshan Chenliji Pharmaceutical Factory Co., Ltd., Guangzhou, China. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This study was supported by Taishan Scholars Program (tsqn202211204), National Key R&D Program of China (2018YFC1707300), Shandong Provincial Natural Science Foundation (ZR2020YQ60), Jinan Talent Project for University (2021GXRC047), Science, Education and Industry Integration Innovation Pilot Project of Qilu University of Technology (Shandong Academy of Sciences) (2022PYI016).

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