Jing Ma1†
Qiuyue Li2†
Ting Wang1Hanyu Lu1Jia Liu1Rangji Cai1
Yi Zhang1Jing Zhang1*Xiaolong Xie1*Jinsong Su1*- 1Ethnic Medicine Academic Heritage Innovation Research Center, Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- 2Pharmacy Intravenous Admixture Service of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
“Shengdeng”, a group of Tibetan medicines with diverse biological origins, has long been utilized in Tibet for the treatment of rheumatoid arthritis. It showcases remarkable efficacy in alleviating rheumatism, reducing swelling, and relieving pain. This study aimed to clarify the plant species used as “Shengdeng” and summarize their botanical distribution, traditional uses, phytochemistry, and pharmacology to promote its utilization and development. “Shengdeng” is derived from a remarkable collection of 14 plant species belonging to six distinct families. Extensive phytochemical investigations have led to the identification of 355 chemical constituents within “Shengdeng”. Pharmacological studies conducted on “Shengdeng” have revealed a wide range of beneficial properties, including antioxidant, anticancer, antimicrobial, antiviral, antiparasitic, anti-inflammatory, and anti-arthritic activities. Notably, flavonoids and triterpenoids emerge as the predominant groups among these constituents, contributing to the therapeutic potential and diverse applications of “Shengdeng”. The present review provides a concise summary of the recent advancements in textual research concerning the herbal and botanical distribution, traditional uses, phytochemistry, and pharmacological activities of “Shengdeng”. It is crucial to note that future research on “Shengdeng” should prioritize the analysis of its active ingredients and the establishment of rigorous quality standards. These aspects are essential for ensuring consistency, efficacy, and safety in its clinical application.
1 Introduction
Tibetan medicine stands out for its distinctive theories and treatment methods, which have been refined and perfected through extensive clinical practice by the Tibetan people over centuries. Due to the unique Tibetan medical theory, diseases such as rheumatoid arthritis are considered areas of expertise in Tibetan medicine. In particular, the Tibetan medicine “Shengdeng” has shown significant efficacy in treating rheumatoid arthritis. However, there are numerous alternative names for “Shengdeng”, and its origin is complex, leading to a significant issue of adulteration and improper usage. Therefore, it is necessary to conduct a systematic review and study on the varieties of “Shengdeng” and summarize the current research status.
“Shengdeng”, a collection of herbal medicines with diverse biological origins, holds a significant place in traditional Tibetan medicine. The records of “Shengdeng” can be found in the Crystal Beads. Renowned for its efficacy in treating rheumatoid arthritis, “Shengdeng” has attracted considerable attention. The wide distribution of “Shengdeng” in Tibetan regions, coupled with the varying descriptions found in different Tibetan materia medica texts throughout history, has led to confusion regarding its origin. Additionally, the abundance of alternative substitutes further complicates the understanding of Shengdeng’s true source (Zou et al., 2020). In this comprehensive review, we present a meticulous exploration of the herbal and botanical distribution, traditional applications, phytochemistry, and pharmacology of “Shengdeng”. By analyzing the therapeutic potential of this remarkable material in improving human health, our findings contribute valuable insights to guide future research endeavors. This review aims to facilitate a deeper understanding of “Shengdeng” and its multifaceted role in traditional Tibetan medicine, serving as a valuable resource for both researchers and practitioners in the field.
2 Textual research of the herbal
Through meticulous textual analysis of historical Tibetan botanical drug records, a fascinating revelation emerges—the authentic Tibetan botanical drug products “Shengdeng” primarily comprise leguminous plant catechins cultivated in subtropical regions encompassing India, Myanmar, Africa, Guangdong, Yunnan, Zhejiang, Guangxi, and Taiwan. Remarkably, the origin, botanical morphology, taste, nature, and therapeutic efficacy of these medicinal materials harmonize impeccably with the corresponding descriptions elucidated in the “Tara Materia Medica”. According to the descriptions, the Crystal beads can be categorized into three distinct groups based on their colors: “Tanhong Shengdeng”, “Bihuang Shengdeng” and “Songbai Shengdeng”. These categories encompass a total of 14 plant species (Li, 2020). In the present review, a series of surveys of herbal texts and research literature was conducted to explore the source of “Shengdeng” and associated plants. The results are summarized in Table 1. The original plant pictures are in Figure 1. (A is quoted from Tibetan Medicine Records. B is quoted from Chinese Tibetan medicine. C, L, and M are quoted from Chinese Materia Medica. D and F are quoted from Atlas of Chinese Higher Plants. E, H, I, J, K, and N are quoted from Flora Reipublicae Popularis Sinicae. G is quoted from Chinese Union of Botanical Gardens.) (The full botanical plant names have been checked with http://www.theplantlist.org).
TABLE 1. The herbal textual research of “Shengdeng”.
FIGURE 1. The botanical distribution of “Shengdeng”, (A) Xanthoceras sorbifolium Bunge. (B) Caesalpinia sappan L. (C) Rhamnella gilgitica Mansf. and Melch. (D) Rhamnus parvifolia Bunge. (E) Rhamnella forrestii W. W. Sm. (F) Rhamnella martinii (H. Lév.) C. K. Schneid. (G) Frangula crenata (Siebold & Zucc.) Miq. (H) Rhamnus sargentiana C. K. Schneid. (I) Rhamnus xizangensis Y.L. Chen and P.K. Chou. (J) Rhamnus dumetorum C. K. Schneid. (K) Rhamnus tangutica J. J. Vassil. (L) Cephalotaxus sinensis (Rehder and E.H.Wilson) H. L. Li. (M) Acacia catechu (L.f.) Willd. (N) Taxus yunnanensis W. C. Cheng and L. K. Fu. (C,L,M) are quoted from Chinese Materia Medica. (D,F) are quoted from Atlas of Chinese Higher Plants. (E,H,I,J,K,N) are quoted from Flora Reipublicae Popularis Sinicae. G is quoted from Chinese Union of Botanical Gardens.).
3 Botanical distribution
The “Shengdeng” species primarily inhabit the middle and lower altitude regions of the Qinghai-Tibet Plateau in China. The “Tanhong Shengdeng” variety is primarily distributed in high-altitude regions, notably Tibet, Sichuan, Yunnan, and other areas. In contrast, the “Bihuang Shengdeng” type exhibits a wide distribution and is commonly found along the hillside edges of forests. It predominantly flourishes in sub-montane to montane regions. Lastly, the “Songbai Shengdeng” variety thrives at relatively lower altitudes and can be found throughout the entirety of the country (Zou et al., 2020). This group of herbal medicines can be found in up to 12 countries and regions worldwide. In China specifically, the resources of “Shengdeng” are abundant, with presence documented in at least 20 provinces. Notably, the provinces of Sichuan and Yunnan exhibit significant concentrations of these valuable resources (Table 2).
TABLE 2. The resource distribution of “Shengdeng”.
4 Traditional uses
In accordance with traditional Tibetan medicine theory, “Shengdeng” holds significant therapeutic value in the treatment of various conditions. It is commonly employed for addressing ailments such as rheumatoid arthritis, high-altitude polycythemia, and “Huangshui disease” in Tibetan medicine (Zou et al., 2020). Some prescriptions containing “Shengdeng” have been clinically tested and modern pharmacological studies have demonstrated their significant anti-inflammatory effects. Several clinical studies have reported the effectiveness of Ershiwuwei ErCha Wan in treating rheumatoid arthritis, highlighting its high application value (Huang et al., 2001; Zha et al., 2017; Liu et al., 2023). These medicinal properties have made “Shengdeng” a prominent ingredient in traditional Tibetan healing practices. We organize the details in Tables 3, 4.
TABLE 3. The traditional uses of “Shengdeng”.
TABLE 4. Prescription preparation and functional indications of Tibetan medicine “Shengdeng”.
5 Phytochemistry
In the last few decades, extensive research has led to the isolation and identification of approximately 355 chemical constituents found in the 14 plant species used as “Shengdeng”. These constituents encompass various compound types, including flavonoids, triterpenoids, protosappanin, brazilin, and taxanes. For further details, including the names of the metabolites, their corresponding plant sources, and the references, please refer to Supplementary Table S1.
5.1 Flavonoids
Flavonoids are a ubiquitous group of naturally occurring polyphenolic metabolites characterized by the flavan nucleus (Peluso et al., 2015). A total of 69 flavonoids (1–69) have been reported. 19 flavonoids (1–19) have been isolated from Lignum X. sorbifolium Bunge (Figures 2–6) (Ni et al., 2009; Yang et al., 2020). Luteolin (20) was isolated from the husks of X. sorbifolium (Wan et al., 2015). (−)-epiafzelechin (21) was isolated from the wood of X. sorbifolium (Ma et al., 2004). Flavonoids (22–26) were isolated from Cephalotaxus sinensis (Rehder and E.H.Wilson) H.L.Li (Li et al., 2007a; Jiang et al., 2013). Flavonoids (27–68) were identified from Acacia catechu (L.f.) Willd (Li et al., 2010b; Negi et al., 2010; Li et al., 2011; Hong et al., 2015; Adhikari et al., 2021). Kaempferol-7-O-β-D-glucoside (69), Kaempferol (1), Quercetin (2), Naringenin (4), Aromadendrin (33), and Taxifolin (62) were also isolated from Rhamnella gilgitica Mansf. and Melch. (Figure 5) (Pan et al., 1998). Homoisoflavones (70–120) were identified from Caesalpinia sappan L. (Namikoshi et al., 1987; Wang et al., 2003; Nguyen et al., 2005; Wang, 2006; Shu, 2007; Chen et al., 2008; Wang et al., 2010; Zhao et al., 2010; Cai, 2012; Chen et al., 2012; Tang et al., 2012; Wang, 2013; Zhao et al., 2014; Sheng, 2016; Wang, 2016; Zhou, 2017).
FIGURE 2. The structures of flavonoids (compound 1–11).
FIGURE 3. The structures of flavonoids (compound 12–21).
FIGURE 4. The structures of flavonoids (compound 22–41).
FIGURE 5. The structures of flavonoids (compound 42–56).
FIGURE 6. The structures of flavonoids (compound 57–69).
5.2 Triterpenoids
Triterpenoids (121–185), also known as ganoderic acid, are widely distributed in nature, which are composed of several isoprene molecules linked end to end without a hydroxyl group. Most triterpenoids contain 30 carbon atoms, and a few with 27 carbon atoms (Gao et al., 2018). X. sorbifolium is known to contain triterpenoids as a frequently reported component. Among these triterpenoids, barrigenol-like triterpenoids (A, B) serve as the structural parent cores. Additionally, X. sorbifolium also contains lupane triterpenoids (C) and tirucallane triterpenoids (D). Barrigtogenol C, 16-deoxybarrigtogenol C, oleanolic acid, and protoaescigenin were also isolated from X. sorbifolium (Figures 7–9; Supplementary Tables S2–S4) (Wan et al., 2013).
FIGURE 7. Structural skeletons of triterpenoids from X. sorbifolium.
FIGURE 8. The structure of the code names in the Supplementary Table S1.
FIGURE 9. The structures of triterpenoids (compound 182–185).
5.3 Protosappanin
Nine protosappanin (186–194) were isolated from C. sappan (Wang et al., 2003; Shu, 2007; Li et al., 2012; Wang, 2016). Among them, 10-omethylprotosappanin B, isoprotosappanin B, and 10-omethylisoprotosappanin B are derivatives derived from protosappanin B. Protosappanin D, on the other hand, is a dimer formed from protosappanin C. Additionally, protosappanin E1 or protosappanin E2 is produced through the polymerization of proto hematoxylin and hematoxylin metabolites. These metabolites represent various structural modifications and polymerizations of protosappanin metabolites, expanding the chemical diversity within this group (Figure 10).
FIGURE 10. The structures of protosappanins (compound 186–194).
5.4 Brazilin
The molecular formula of brazilin is C16H14O5, which is the main active component in C. sappan. A total of 13 brazilin metabolites (195–206) have been isolated and identified (Xu et al., 1994; Shu et al., 2007; Hung et al., 2009; Cooksey, 2010; Wang and Liang, 2016; Kim and Kim, 2018). Brizilide is not a component naturally present in hematoxylin itself but rather a newly derived component that emerges during the isolation process from brazilin hematoxylin (Supplementary Figure S1).
5.5 Taxanes
The taxanes or taxoids are a closely related group of antineoplastic agents that have a unique mechanism of action as inhibitors of mitosis, which are widely used in the therapy of ovarian, breast, lung, esophageal, prostate, bladder, and head and neck cancers. Many taxanes (208–271) were isolated from Taxus yunnanensis W.C.Cheng and L.K.Fu (Supplementary Figures S2–S5) (Yue et al., 1995; Zhang et al., 1995; Zhong et al., 1996; Zhang et al., 1997; Zhou et al., 1998; Shi et al., 1999; Li et al., 2000; Li et al., 2001; Shinozaki et al., 2001; Li et al., 2002a; Li et al., 2002b; Shinozaki et al., 2002; Li et al., 2003a; Nguyen et al., 2003; Tezuka et al., 2011; Hai et al., 2014).
5.6 Other metabolites
In addition to the abovementioned chemical metabolites, several other metabolites have been identified, such as sappanols, flavonoid diglycoside, abietane diterpenoid, and norditerpenoids. Seven sappanols (272–278) were isolated from C. sappan (Supplementary Figure S6) (Xu et al., 2016; Ahmed et al., 2018; Zhao et al., 2019). A total of 20 metabolites (279–298) were isolated from C. sinensis, including flavonoid diglycoside, abietane diterpenoid, and norditerpenoids (Supplementary Figures S7, S8). Esters and fatty acid metabolites (299–313) were isolated from A. catechu (Supplementary Figures S8, S9) (Negi and Dave, 2010; Li et al., 2011; Thakur et al., 2018; Adhikari et al., 2021). Three lignans, seven steroids (314–323) and a Polyphenolic (350) were isolated from T. yunnanensis (Li et al., 2002a; Li et al., 2003b; Hafezi et al., 2020). Twenty cassane diterpenoids (324–337, 346, 351–355) and three lignans (347–349) were isolated from C. sappan (Ma et al., 2015; Tran et al., 2015; Zhu et al., 2017). Alkaloids (338–345) were isolated from C. sinensis (Supplementary Figure S10) (Ma et al., 2016).
6 Pharmacology
The pharmacological studies conducted on “Shengdeng” have consistently shown its remarkable properties, including antioxidant, anticancer, antimicrobial, antiviral, antiparasitic, anti-inflammatory, and anti-arthritic activities, alongside other beneficial characteristics (Figure 11).
FIGURE 11. Therapeutic applications of Shengdeng.
6.1 Anti-oxidant activity
Among the metabolites isolated from C. sappan, including Brazilein (203), Sappanchalcone (272), Protosappanin A (186), Protosappanin B (187), and Protosappanin C (188), Brazilin (195) displayed the highest 2,2-diphenyl-1-trinitrophenylhydrazine (DPPH) free radical scavenging activity (Wetwitayaklung et al., 2005; Sasaki et al., 2007; Batubara et al., 2009). Some findings highlight the antioxidant potential of X. sorbifolium and its potential applications in combating oxidative stress (Li et al., 2010a; Zhang et al., 2010). The in vitro scavenging activity of the ethanol extract of R. gilgitica was assessed, revealing a robust capability to scavenge free radicals and efficiently reduce Fe3+ ions (Zhang et al., 2014b; Zhou et al., 2021). The antioxidant activity of various fractions of C. sinensis was assessed using DPPH and reducing power assays. The findings demonstrated that C. sinensis exhibits significant antioxidant activity (Saeed et al., 2007). Some findings collectively emphasize the exceptional antioxidant properties of A. catechu. The regulation of reactive oxygen species and the control of oxidative stress are vital for maintaining cellular balance. Plant extracts, rich in metabolites such as polyphenols, play a significant role in mitigating oxidative stress by demonstrating potent antioxidant activity (Huang et al., 2005; Cai et al., 2006; Hiraganahalli et al., 2012; Saha et al., 2016; Patil and Modak, 2017; Kumar et al., 2018; Babita, 2021a; Adhikari et al., 2021; Babita, 2021b; Shresta et al., 2021). Similarly, the methanol, ethanol, butanol, and water metabolites of A. catechu have IC50 values ranging from 92.48 to 529.30 μg/mL for the determination of DPPH radicals, ABTS radicals, and superoxide scavengers as well as for the reduction of copper and iron ions, which is primarily due to the presence of Quercetin (2), Kaempferol (1), and Chlorogenic acid (306) (Kumar et al., 2019).
6.2 Anti-cancer activity
Natural molecules have shown promise in providing potential solutions for combating cancer (Greenwell and Rahman, 2015).
Study demonstrated that C. sappan extract can inhibit cancer cell growth by inducing apoptosis and mitochondrial dysfunction in A549 cells (Widodo et al., 2022). The effect of 3-deoxysappanchalcone (273) on colon cancer cell growth revealed its inhibitory potential on the activity of T-lymphokine-activated killer cell-originated protein kinase (TOPK). The compound inhibited colon cancer cell proliferation and anchorage-independent cell growth, and it promoted G2/M cell phase arrest and programmed cell death (Zhao et al., 2019b). The apoptotic effect of brazilin (195) was confirmed in an in vitro model of breast cancer using the MCF-7 cell line. The automated docking tool also demonstrated the therapeutic effect of the brazilin A molecule on the apoptosis inhibitor B-cell lymphoma 2 (BCL-2) protein. This calcium-dependent pathway was mediated through the upregulation of microtubule-associated protein 1A/1B-light chain 2 (LC3-II) and downregulation of P62/SQSTM1 in osteosarcoma cells (Bukke et al., 2018). Using the MG-63 cell line, Kang examined the induction of autophagy by basilicin in osteosarcoma cell cultures and found that this effect was mediated through the Ca2+ forkhead box O3A protein (FOXO3A) pathway. In addition, brazilin (195) caused autophagic cell death in MG-63 cells by activating phosphorylation at the FOXO3A Ser7 site, initiating nuclear translocation of FOXO3A, and increasing its reporter gene activity, which results in the expression of autophagy-related genes and cell death (Kang et al., 2018). The IC50 value of Phanginin R (346) from C. sappan was detected in the range of 5.3 ± 1.9 to 12.3 ± 3.1 μM, indicating that it has evident cytotoxic effects on lung cancer A549 cells and ovarian cancer cells, as well as A2780 cells. Furthermore, phaginins exhibited the expression of the tumor suppressor protein p53, arrest of the cell cycle in the G1 phase, and initiation of apoptosis in A2780 cells, reflecting their anti-cancer properties (Bao et al., 2016).
Metabolites (351–354) exhibited significant inhibition against HL-60 cells (Tran et al., 2015). Studies have shown that brazilin (195) isolated from C. sappan inhibits BAF phosphorylation in vitro and in vivo. The results show that brazilin (195) is directly related to BAF. The inhibition of BAF phosphorylation leads to abnormal nuclear envelope re-organization and cell death, indicating that the disruption of nuclear envelope re-organization may be a novel anti-cancer therapy. Brazilin (195) could be a new cancer drug (Kim et al., 2015b). In another study, various botanical metabolites obtained from ethyl acetate extracts of C. sappan showed better anti-cancer activity than the isolated metabolites, indicating that the crude extract was more effective in relieving cancer than molecular extracts (Zhang et al, 2014a).
Recent research has shed light on the potential of metabolites derived from T. yunnanensis, such as AgNPs, heteropolysaccharide, and α-conidendrin, in the development of novel anti-cancer therapies (Yan et al., 2013; Xia et al., 2016; Hafezi et al., 2020).
6.3 Anti-microbial, anti-viral, and anti-parasitic activity
Some findings suggest that C. sappan possesses diverse pharmacological properties, including antibacterial, antiviral, antimalarial, and iron-chelating activities, indicating its potential use in various therapeutic applications (Bukke et al., 2015; Bukke et al., 2015; Puttipan et al., 2018; Safitri et al., 2022).
In another study, from the heartwood of C. sappan, numerous neuraminidase inhibitory molecules were isolated, and the maximum inhibitory activity against three types of viral NAs (H1N1, H3N2, and H9N2) was exhibited by a homoisoflavonoid, namely, sappanone A (70), with IC50 values of 0.7, 1.1, and 1.0 mM, respectively. The viral neuraminidase (H1N1, H3N2, and H9N2) inhibitory activity of isolated sappanone A (70) did not significantly differ from than that of the standard drug oseltamivir with IC50 values of 5.8, 5.6, and 1.2 nM, respectively (Jeong et al., 2012). Caesalsappanin G (332) and Caesalsappanin H (333) isolated from C. sappan had a potent antimalarial activity with selectivity indices of 17.6 and 16.4, as well IC50 values of 0.78 and 0.52 mM, respectively, which are comparable to the standard compound chloroquine, with IC50 value of 0.37 ± 0.02 (Ma et al., 2015). In another study, two novel cassane diterpenes isolated from the seeds of mulberry C. sappan extracts were screened for their anti-plasmid activity against the chloroquine-resistant strain K1 of P. falciparum. The extracted metabolites Caesalsappanin R (324) and Caesalsappanin S (325) had a potent antimalarial activity with IC50 values of 3.6 and 25.1 mM, respectively, and the standard drug chloroquine has an IC50 value of 0.19 ± 0.05. However, the difference was not significant (Zhu et al., 2017).
The aqueous, 50% ethanolic, and butanol extracts of A. catechu demonstrated antimicrobial activity against various bacteria, such as Staphylococcus aureus, Pseudomonas aeruginosa, Proteus mirabilis, E. coli, B. and subtilis (Patel et al., 2009; Negi and Dave, 2010; Joshi et al., 2011; Dashtdar et al., 2013; Modi et al., 2013; Panya et al., 2019; Shresta et al., 2021). In addition, a study confirmed that drupacine (338), 11-hydroxycephalotaxine (339), cephalancetine A (340), hsocephalotaxine (341), cephalotaxine β-N-oxide (342), 4-hydroxycephalotaxine (343), wilsonine (344), and cephalotaxine (345) isolated from C. sinensis have excellent activities against tobacco mosaic virus (TMV) and cucumber mosaic virus indoors and outdoors. Its control of TMV is comparable to that of a commercialized anti-viral agent (VA, active ingredient = a mixture of moroxydine hydrochloride and copper acetate). At the same dosage, the inactivation activities against TMV were not significantly different among drupacine (338), 11-hydroxycephalotaxine (339), cephalotaxine (345), and VA (inhibition ratio = 50.76%–53.41%). The inhibited TMV replications of all tested metabolites were inferior to that of VA, but the inhibition ratios of drupacine and cephalotaxine remained greater than 50% (Ma et al., 2016).
6.4 Anti-inflammatory activity
In a study, it was demonstrated that the heat-70% EtOH and microwave-70% EtOH extracts of C. sappan exhibited significant anti-inflammatory effects. Metabolites derived from C. sappan, such as episappanol (105), brazilin (195), prosapogenin B (348), sappanol (349), and protosappanin C (347), have shown promising potential for treating inflammation (Mueller et al., 2016; Chowdhury et al., 2019). Hematoxylin A, a isoflavonoid derived from C. sappan, induces anti-inflammatory effects by inhibiting the production of IL-6, prostaglandin E2 (PGE2), and NO in mouse macrophages. Saponin A inhibits the expression of iNOS and COX-2 in LPS-treated RAW264.7 cells. Furthermore, saponin A exhibits anti-inflammatory effects in vivo and protects c57bl/6 mice from LPS-induced death by modulating nuclear factor erythroid 2-related factor 2 (Nrf2) and NF-κB signaling pathways (Lee et al., 2015). In a related study, brazilin could induce an anti-inhibitor of the active groove of NF-κB (IkB) kinase, which targets upstream signaling elements of IkB kinase, thereby promoting formation by disrupting NF-κB activation and signaling complexes at the proximal IL-1 receptor (Jeon et al., 2014). Another study found that NO produced in LPS-induced RAW264.7 cells was scavenged by brazilin and sabanchalcone with IC50 values of 10.3 and 31.0 mM, respectively. The results showed that the inhibitory effect of brazilin and saponins on NO production was better than that of indomethacin (IC50 value of 46.5). The production of TNF-α and PGE2 was also inhibited by brazilin with IC50 values of 87.2 and 12.6 mM, respectively. Hence, the downregulation of the mRNA expression level of TNF-α, iNOS, and COX-2 genes was involved in the anti-inflammatory mechanism of brazilin (Tewtrakul et al., 2015). The anti-inflammatory potential of 3-deoxysappanchalcone (273) (3-DSC) in RAW264.7 cells was confirmed. 3-DSC enhances the expression of hemooxygenase-1 (HO-1) at the translational level, thereby activating the phosphatidylinositol 3-kinase mammalian target of the rapamycin (AKT/mTOR) pathway, which contributes to its anti-inflammatory properties. Based on the concept that HO-1 has anti-inflammatory properties, 3-DSC inhibited NO and IL-6 production in LPS-stimulated RAW264.7 cells (Kim et al., 2014).
A. catechu extract demonstrates the ability to inhibit the production of important inflammatory cytokines (Burnett et al., 2007; Tseng, et al., 2010; Yimam et al., 2010; Yimam et al., 2012; Sunil et al., 2019). A recent study investigated the anti-inflammatory activities of the 70% ethanol extract of R. gilgitica in both RAW264.7 macrophages and rats with complete Freund’s adjuvant (CFA)-induced arthritis (Huang et al., 2016).
6.5 Anti-arthritic activity
Rheumatoid arthritis is a prevalent human health problem worldwide. Traditional medicines for RA worldwide have yielded some positive results. Overcoming osteoclastogenesis is considered as an active strategy for the treatment of bone-destroying diseases, RA, and osteoporosis. Brazilin could exhibit anti-inflammatory and chondroprotective effects in chondrocytes and human osteoarthritis cartilage. The antiarthritic effect of brazilin (195) was assessed using IL-1b-treated primary chondrocytes, TNF-α, and IL-1b-treated cartilage explants. The loss of glycosaminoglycan from cartilage explants stimulated with IL-1b and TNF-α reduced after Brazilin (195) treatment, and the anti-inflammatory activity was evident through the regulation of NFKB1/p50. In chondrocytes, basilicin inhibited the IL-1b-induced inhibition of osteoarthritis markers by inducing NFKB1/p50, indicating a chondroprotective effect (Weinmann et al., 2018). The acute inflammatory paw edema and arthritis index were found to be reduced by brazilin (195) in an in vivo model of arthritis using CIA mice (Jung et al., 2015a). Microstructural studies have shown that brazilin (195) treatment significantly increases bone density, prevents joint destruction and surface wear, and improves bone formation. In addition, serum concentrations of inflammatory cytokines such as IL-6, IL-1b, and TNF-α were attenuated by brazilin (195) treatment. In another study, the anti-inflammatory, bone-protective, and anti-RA activities were proven by evaluating the effect of Sappanchalcone (272) in CIA-presented male DBA/1J mice. Based on the aforementioned studies, the anti-arthritic activity of brazilin (195) (10 mg/kg) and Sappanchalcone (272) (10 mg/kg) was similar to that of standard drug methotrexate (3 mg/kg) (Jung et al., 2015a; Jung et al., 2015b). The opposite effect of brazilin (195) on osteoclast differentiation confirmed that brazilin (195) dose-dependently inhibited the receptor activator of nuclear factor Kpa-B ligand (RANKL) to promote osteoclast differentiation of RAW264.7 cells without signs of cytotoxicity. Brazilin (195) reduced RANKL-induced NF-κB p65 phosphorylation, extracellular signal-regulated kinases, and the appearance of inflammatory negotiator genes (TNF-α, INOS, IL-6, and COX-2) in RAW264.7 cells, indicating its therapeutic effect in avoiding bone loss (Kim et al., 2015a). Another study has proposed that the anti-rheumatoid arthritis effect of the ethyl acetate extract of R. gilgitica (RGEA) may be linked to its capacity to promote apoptosis and inhibit the inflammatory response, potentially by modulating the JAK-STAT pathway (Su et al., 2021). A study showed that the Tibetan medicine Qi-Sai-Er-Sang-Dang-Song Decoction inhibits TNF-α-induced rheumatoid arthritis in human fibroblast-like synoviocytes via regulating NOTCH1/NF-κB/NLRP3 pathway (Su et al., 2023).
6.6 Neuroprotective activity
Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, present a significant health challenge in industrialized countries. These diseases are characterized by microglial activation and subsequent neuroinflammatory responses (Rajput et al., 2020; Singh and Devasahayam, 2020). The ethanolic extract of C. sappan has demonstrated neuroprotective and anti-cerebral ischemic effects in an experimental model (Wan et al., 2019). Protosappanin A (186) reversed the neuroinflammatory effect of BV2 cells under the action of LPS by significantly inhibiting the production of IL-1β and TNF-α. In addition, Protosappanin A (186) dose-dependently decreased the messenger ribonucleic acid (mRNA) expression of monocyte chemoattractant protein 1 (MCP-1), IL-1β, and IL-6. Moreover, Protosappanin A (186) inhibited the inflammatory pathway of LPS treatment by downregulating JAK2 and STAT3 phosphorylation and STAT3 nuclear translocation (Wang et al., 2017a). In vitro studies using the thioflavin-T fluorescence assay and transmission electron microscopy demonstrated that hematoxylin significantly reduced the cytotoxicity induced by Aβ42 by inhibiting the formation of Aβ42 fibrils (Tu et al., 2016). Brazilein (203) has been shown to reverse the elevated expression of TNF-α and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) induced by cerebral ischemia and reperfusion in mice (Xiao et al., 2016).
6.7 Hepatoprotective activities
Study showed that ethyl acetate extract of A. catechu (250 mg/kg) can inhibit the toxicity of liver injury in tetrachloride-induced albino rat using biochemical (measurement of serum transaminases, serum alkaline phosphatase, and serum bilirubin) and histopathological assessment (Jayasekhar et al., 1997). A. catechu herbal extracts were demonstrated as hepatoprotective with IC50 of 114.8 μg/mL on HepG2 cells toxified with tert-butyl hydroperoxide (t-BH). The anti-oxidant potential of this plant is attributed to its hepatoprotective activity by reducing lipid peroxidation and cell damage (Hiraganahalli et al., 2012). Similarly, plant ethyl acetate extract showed significant hepatoprotective ability in an in vivo model (Ray et al., 2006). Moreover, in a Wistar rat model experiment, A. catechu seed and bark extracts exhibited hepatoprotective effects, which were related to the decrease of the activity of liver enzymes (alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase) by reducing lipid peroxidation, and enhanced anti-oxidant activity by increasing glutathione and increasing the activity of peptides and superoxide dismutase (Lakshmi et al., 2018).
6.8 Anti-diabetic activities
The extracts of A. catechu has shown an anti-diabetic activity with IC50 of 49.9 μg/mL toward porcine pancreatic α-amylase and 0.4977 mg/mL against α-glucosidase (Khadayat et al., 2020). Another study found that the methanol extract of A. catechu inhibited α-amylase with IC50 of 49.9 ± 0.4 μg/mL, and kinetic studies indicated that the extract exhibited mixed-type inhibition (Khadayat et al., 2020). A study showed that feeding with an ethanolic extract of catechins on streptozotocin (STZ-)-induced diabetic rats increased their glucose tolerance by 22% and 27% after 7 and 14 days, respectively, whereas those fed a low-dose STZ showed significantly increased glucose tolerance (Swayam, 2011). Catechin (27), Epicatechin (28), Gallocatechin (47), Epigallocatechin (48), and Procyanidin B1 (49)were identified from A. catechu, which exerted anti-diabetic effects by reducing the activities of α-glucosidase, α-amylase, and aldose reductase (Adhikari et al., 2021).
The hypoglycemic effect of C. sinensis leaves was studied in STZ-induced diabetic rats. The results show that C. sinensis leaf extract is a potential drug for treating diabetes, and its active ingredients include flavonoids (Li et al., 2007c) Furthermore, previous investigation suggested that C. sinensis extract has good hypoglycemic and hypolipidemic effects, which may be beneficial to hyperglycemia and may decrease HDL (Muhammad et al., 2013).
6.9 Toxicity
The historical use of “Shengdeng” as a traditional medicine for thousands of years indicates its long-standing reputation as a safe therapeutic option. Ancient texts documenting the use of “Shengdeng” do not mention any instances of toxicity associated with its usage.
6.10 Other effects
A study has found the phenols from the leaves of X. sorbifolia could be used as natural neuroinflammation inhibitors (Li et al., 2016). Another study has shown that barrigenol-like triterpenoids derived from X. sorbifolia husks exhibited s significant inhibitory activity against the proliferation of three human tumor cell lines, namely, HepG2, HCT-116, and U87-MG (Wang et al., 2017b). Furthermore, a study indicated that the husk of X. sorbifolia might prevent inflammation-related neurodegenerative disorders by controlling the expression of the nuclear NF-κB signaling pathway, which clearly inhibited LPS-induced NO production in BV-2 cells (Zhao et al., 2022).
C. sinensis extracts have the potential to be developed into herbal products with hepatoprotective and nephroprotective properties (Saeed et al., 2008). Some fundings suggest that the aqueous extract of A. catechu has immunomodulatory effects on both cell-mediated and humoral immunity (Ismail and Asad, 2009).
7 Conclusion and perspectives
According to Tibetan medical documents, a total of 14 species were used as “Shengdeng”. Extensive phytochemical investigations have resulted in the identification of 355 chemical constituents within “Shengdeng”. The pharmacological studies conducted on “Shengdeng” have unveiled a diverse array of beneficial properties, including potent antioxidant, anticancer, antimicrobial, antiviral, antiparasitic, anti-inflammatory, and anti-arthritic activities. However, it is important to acknowledge that there are still several unresolved issues that require further investigation and clarification in future research endeavors. These areas of focus will contribute to a more comprehensive understanding of the therapeutic potential and mechanisms of action of “Shengdeng”.
Firstly, as a representative multi-origin Tibetan medicine, “Shengdeng” exhibits inherent variations in chemical composition among different plant sources, leading to heterogeneity in the content of active constituents. This inherent variability may significantly impact the therapeutic efficacy and safety profiles of the medication (Kelsang et al., 2023). Secondly, although “Shengdeng” derived from different plant sources may share similar pharmacological effects, the inherent variations in botanical origin and growth conditions can give rise to nuanced pharmacodynamic profiles or even distinct therapeutic outcomes. Consequently, the evaluation of Shengdeng’s therapeutic efficacy and the design of its optimal formulations are confronted with intricate challenges. Thirdly, the research on multi-origin “Shengdeng” confronts the critical issue of establishing harmonized and comprehensive standards. The diverse array of plant species and their inherent differences necessitate the development of standardized methodologies and evaluation frameworks that can accommodate the unique characteristics of multi-origin plants. Achieving such standardization is pivotal to ensure consistent quality control and efficacy assessment. Lastly, Ancient texts documenting the use of “Shengdeng” do not mention any instances of toxicity associated with its usage. Modern pharmacological studies have not reported any side effects or toxicity at present. Therefore, further research on “Shengdeng” in this direction would be worthwhile.
Given the aforementioned challenges in the research of multi-origin Tibetan medicine “Shengdeng”, future investigations should focus on the following key areas. Firstly, it is crucial to conduct comprehensive chemical analysis and comparative studies on “Shengdeng” derived from different plant sources to identify the major bioactive metabolites and assess their quantitative variations. Innovative approaches such as multidimensional separation techniques like comprehensive two-dimensional liquid chromatography (2D-LC) should be employed to achieve improved separation and qualitative-quantitative analysis of the complex constituents in multi-origin “Shengdeng” (Bo et al., 2023). Secondly, establishing scientific quality control methods for “Shengdeng” is essential to ensure the herbal material’s quality. This involves developing standards and protocols for collection, storage, processing, and strengthening regulatory oversight and management of the entire herbal production process to ensure the stability of Shengdeng’s quality (Peng et al., 2022). Thirdly, conducting clinical research and experimental pharmacological evaluations are necessary to gain a deeper understanding of the variations and consistency in the pharmacological effects of multi-origin plants. Based on the research findings, suitable dosage forms and treatment regimens can be designed for different plant sources to enhance the consistency and controllability of therapeutic efficacy (Wang et al., 2022). Fourthly, it is imperative to establish standardized methods and evaluation systems specific to multi-origin plants like “Shengdeng” to ensure comparability and reproducibility in research and application. Developing a unified set of standards and guidelines encompassing plant collection, quality assessment, component analysis, and pharmacological evaluation is essential (Zhong et al., 2022). Lastly, Toxicity and side effects were evaluated using modern pharmacological methods in relevant animal models. These include safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism and excretion (ADME) studies, reproductive and developmental toxicity, and carcinogenic potential assessments (Cai and Suo, 2023).
This review presents a comprehensive overview of the latest advancements in the textual research of “Shengdeng”, encompassing its herbal and botanical distribution, traditional uses, phytochemistry, and pharmacological activities. As an integral component of Tibetan medicine, “Shengdeng” holds significant medicinal value and is widely employed in clinical settings. By providing a comprehensive understanding of the plant species utilized as “Shengdeng” and their applications, this review contributes to the existing knowledge in the field and serves as a valuable resource for researchers and practitioners alike.
Author contributions
JM: Writing–original draft, Writing–review and editing. QL: Writing–original draft, Writing–review and editing. TW: Writing–original draft. HL: Writing–review and editing. JL: Writing–review and editing. RC: Writing–original draft. YZ: Writing–review and editing. JZ: Writing–review and editing. XX: Writing–review and editing. JS: Writing–original draft, Writing–review and editing.
Funding
This work was funded by the National Natural Science Foundation of China (82204765), the Nature Science Foundation of Sichuan (2022NSFSC1470), Sichuan Provincial Postdoctoral Special Funding Project (TB2023020) and the Xinglin Scholars Research Promotion Program of Chengdu University of Traditional Chinese Medicine (BSH2021030).
Conflict of interest
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.
Publisher’s note
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.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1303902/full#supplementary-material
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Keywords: Tibetan medicine, Shengdeng, herbal textual research, phytochemistry, pharmacology
Citation: Ma J, Li Q, Wang T, Lu H, Liu J, Cai R, Zhang Y, Zhang J, Xie X and Su J (2023) A comprehensive review of Shengdeng in Tibetan medicine: textual research, herbal and botanical distribution, traditional uses, phytochemistry, and pharmacology. Front. Pharmacol. 14:1303902. doi: 10.3389/fphar.2023.1303902
Received: 28 September 2023; Accepted: 13 November 2023;
Published: 14 December 2023.
Edited by:
Miguel Angel Prieto Lage, University of Vigo, SpainReviewed by:
James David Adams, Independent Researcher, Benicia, CA, United StatesMd Badrul Alam, Kyungpook National University, Republic of Korea
Copyright © 2023 Ma, Li, Wang, Lu, Liu, Cai, Zhang, Zhang, Xie and Su. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 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.
*Correspondence: Jing Zhang, MzE2NDkxMjNAcXEuY29t; Xiaolong Xie, eGlleGlhb2xvbmc3OEAxNjMuY29t; Jinsong Su, c3VqaW5zb25nQGNkdXRjbS5lZHUuY24=
†These authors have contributed equally to this work