Research Progress of Natural Active Substances with Immunosuppressive Activity

The increasing prevalence of autoimmune diseases globally has prompted extensive research and the development of immunosuppressants. Currently, immunosuppressive drugs such as cyclosporine, rapamycin, and tacrolimus have been utilized in clinical practice. However, long-term use of these drugs may lead to a series of adverse effects. Therefore, there is an urgent need to explore novel drug candidates for treating autoimmune diseases. This review aims to find potential candidate molecules for natural immunosuppressive compounds derived from plants, animals, and fungi over the past decade. These compounds include terpenoids, alkaloids, phenolic compounds, flavonoids, and others. Among them, compounds 49, 151, 173, 200, 204, and 247 have excellent activity; their IC50 were less than 1 μM. A total of 109 compounds have good immunosuppressive activity, with IC50 ranging from 1 to 10 μM. These active compounds have high medicinal potential. The names, sources, structures, immunosuppressive activity, and the structure-activity relationship were summarized and analyzed.


Introduction
Autoimmune diseases are characterized by the immune system attacking its antigens [1], which include psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and related disorders.Currently, approximately 11-15% of the population is affected by autoimmune diseases [2].An estimated 60 million people have psoriasis worldwide [3], and the global prevalence of RA ranges from 0.23% to 0.36% [4], while the prevalence of SLE is 0.24% with a 10-year survival rate of 56.5-98.2%[5].More than 80 autoimmune diseases were identified in humans, affecting various organs and systems such as the skin, kidneys, blood vessels, brain, and joints [6,7].Therefore, effective treatment of autoimmune diseases is crucial.
The pathogenesis of autoimmune diseases may be related to factors of genetics, environment, immune tolerance damage, and abnormal regulation of immune responses [8,9].For the treatment of autoimmune diseases, the commonly used clinical treatment method is immunosuppressive drugs [10,11].Immunosuppressants can suppress aberrant immune phenomena by inhibiting the proliferation and function of immune response-related cells (mainly T-cells and B-cells) [12][13][14][15][16].It is mainly employed for the prevention and treatment of graft rejection and autoimmune diseases [17].There is the fact that immunosuppressants play a crucial role in suppressing abnormal immune responses, and the new immunosuppressants need to be explored [18][19][20].
Many immunosuppressants from natural sources have been used in clinical practice, such as mycophenolate mofetil (MMF), rapamycin (RPM), and tacrolimus.The MMF was derived from Penicillium mold fermentation [21,22].RPM is a lactone derived from the fermentation broth of Streptomyces hygroscopicus [23].Tacrolimus, a 23-membered macrolide antibiotic, was produced through fermentation by Streptomyces tsukubaensis [24].This review examines natural products with immunomodulatory properties, including terpenoids, alkaloids, phenolic compounds, flavonoids, and others, from 2013 to 2024.The names, structures, sources, and activity of natural products with immunosuppressive activity are systematically and comprehensively summarized.The structure-activity relationship of compounds with significant immunosuppressive activity is discussed.Additionally, models for screening immunosuppressive activity are also summarized.

The Immunosupperssive Activity of Animal and Cell Models
Seven cellular and six animal models are commonly used for screening immunosuppressive activity, as shown in Tables 1 and 2. Selected animals included Balb/c mice, ICR mice, C57BL/6 mice, Wistar rats, and Swiss albino mice.The drugs utilized for animal modeling include cyclophosphamide, carbon tetrachloride (CCl 4 ), pristane, delayed-type hypersensitivity (DTH), sheep red blood cells (SRBC), and xylene.For the cell models, concanavalin A (ConA) and lipopolysaccharide (LPS) are primarily employed in conjunction with human mononuclear cells, splenocytes, dendritic cells, BV-2 microglia, and RAW264.7 macrophages.In this review, the immunosuppressive activity of each compound is examined mainly using different cell models.

Natural Products with Immunosuppressive Activity
Natural products, due to their diverse activities and unique structures, offer an inexhaustible source for the discovery of small-molecule drug leads.It is expected to discover non-toxic and highly bioavailable immunosuppressants from natural products [25].Numerous studies have demonstrated the immunosuppressive activity of natural product extracts containing terpenoids, alkaloids, phenolic compounds, flavonoids, and others [26].

Terpenoids
Terpenoids are a class of naturally occurring products with diverse structures that have been used by humans in various fields such as food, pharmaceuticals, and chemical industries [27].Some sesquiterpenoids, diterpenoids, and triterpenoids exhibit immunosuppressive activity.

Sesquiterpenoids
There are 36 sesquiterpenoids with immunosuppressive activity, and their structures are shown in Figure 1.The sources, selected models, and immunosuppressive activities are shown in Table S1.

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Terpenoids
Terpenoids are a class of naturally occurring products with diverse structures that have been used by humans in various fields such as food, pharmaceuticals, and chemical industries [27].Some sesquiterpenoids, diterpenoids, and triterpenoids exhibit immunosuppressive activity.

Diterpenoids
The structures, sources, selected models, and immunosuppressive activities of 79 diterpenoids are summarized in Figures 2 and 3 and Table S2.
Robustaditerpenes C and E (60 and 61) were isolated from cultures of the endophytic fungus Ilyonectria robusta.Compound 60 effectively inhibited the proliferation of B lymphocytes, with an IC 50 value of 17.42 µM.Similarly, compound 61 showed significant inhibition of the proliferation of T lymphocytes, with an IC 50 value of 75.22 µM [43].Three diterpenoids were isolated from Isodon scoparius, named scopariusicide I (62), scopariusicide J (63), and scopariusicide L (64).Compounds 62-64 demonstrated significant suppression of murine splenocyte proliferation when stimulated with anti-CD 3 /anti-CD 28 monoclonal antibodies, with IC 50 values ranging from 9.4 to 16.3 µM [44].Scopariusic acid (66), a ent-clerodane-based meroditerpenoid with a unique cyclobutane ring, was isolated from the aerial parts of Isodon scoparius.Compound 65 showed significant activity against T-cell proliferation with an IC 50 value of 2.6 µM [45].A new diterpenoid named ceforloid F (65) was isolated from Cephalotaxus fortunei var.alpina and C. sinensis.Compound 66 exhibited noteworthy efficacy in inhibiting the proliferation of T-cells, with an IC 50 value of 1.93 µM [46].
Compounds 76-108 were extracted from the coral S. scabra, whose names are shown in Table S2.The bioassay revealed that several isolates displayed inhibitory effects on the proliferation of T lymphocytes and B lymphocytes.Compounds 76-108 inhibited T-cell and B-cell proliferation with IC 50 values ranging from 4.5 to over 50.0 µM and 4.4 to over 50.0 µM, respectively [47].
Compounds 109-115 were extracted from the Hainan Soft Coral Sarcophyton mililatensis, whose names were shown in Table S2.The immunosuppressive activity of compounds 109-115 was tested, which indicated these compounds had moderate activities against T-cell and B-cell proliferation with IC 50 values ranging from 11.4 to greater than 50 µM and 4.8 to greater than 50.0 µM, respectively [48].

Triterpenoids
There are 21 triterpenoids with promising immunosuppressive activity.Table S3 and Figure 4 summarize the sources, structures, selected models, and immunosuppressive activities of these compounds.
sis, whose names were shown in Table S2.The immunosuppressive activity of compounds 109-115 was tested, which indicated these compounds had moderate activities against Tcell and B-cell proliferation with IC50 values ranging from 11.4 to greater than 50 µM and 4.8 to greater than 50.0 µM, respectively [48].

Triterpenoids
There are 21 triterpenoids with promising immunosuppressive activity.Table S3 and Figure 4 summarize the sources, structures, selected models, and immunosuppressive activities of these compounds.A triterpene, named munronoid P (116), was discovered in the aerial parts of Munronia pinnata.Compound 116 demonstrated moderate inhibitory effects on T-cell proliferation, with an IC50 value of 2.73 µM.Additionally, it also exhibited inhibition against B-cell proliferation, with an IC50 value of 34.88 µM [49].Triterhyper A and lupeol (117 and 118) were extracted from Hypericum longistylum.These compounds showed inhibitory effects on the growth of murine splenocytes stimulated by anti-CD3/anti-CD28 monoclonal antibodies (mAbs) and LPS, with IC50 values of 4.56 µM and 18.34 µM, respectively [50].A new triterpenoid saponin (119) was isolated from Epigynum griffithianum.Compound 119 was evaluated in vitro for its immunosuppressive activity on the proliferation of mouse  A triterpene, named munronoid P (116), was discovered in the aerial parts of Munronia pinnata.Compound 116 demonstrated moderate inhibitory effects on T-cell proliferation, with an IC 50 value of 2.73 µM.Additionally, it also exhibited inhibition against B-cell proliferation, with an IC 50 value of 34.88 µM [49].Triterhyper A and lupeol (117 and 118) were extracted from Hypericum longistylum.These compounds showed inhibitory effects on the growth of murine splenocytes stimulated by anti-CD3/anti-CD28 monoclonal antibodies (mAbs) and LPS, with IC 50 values of 4.56 µM and 18.34 µM, respectively [50].A new triterpenoid saponin (119) was isolated from Epigynum griffithianum.Compound 119 was evaluated in vitro for its immunosuppressive activity on the proliferation of mouse splenocytes, with an IC 50 value of 25 µM. 14

Other Terpenoids
There are thirteen other triterpenoids with promising immunosuppressive activity.Table S4 and Figure 5 summarize the sources, structures, selected models, and immunosuppressive activities of these compounds.
splenocytes, with an IC50 value of 25 µM. 14Schincarin C (120) was isolated from the plant of the genus Schisandra, which showed immunosuppressive activities against the prolifer ation of the T and B-cells with IC50 values of 10.21 and 5.83 µM, respectively [51].BC-(121) was isolated from Beesia calthaefolia, which inhibited murine T lymphocyte prolifer ation with IC50 values of 9.8 µM [52].

Other Terpenoids
There are thirteen other triterpenoids with promising immunosuppressive activity Table S4 and Figure 5 summarize the sources, structures, selected models, and immuno suppressive activities of these compounds.

Alkaloids
Alkaloids constitute a group of nitrogen-containing organic compounds [59].Over the last ten years, several alkaloids have shown immunosuppressive activity and have been extracted from natural sources.The structures, sources, selected models, and immunosuppressive activities of 27 alkaloids are shown in Figure 6 and Table S5.Three alkaloids named wilfordatin E (150), tripfordine A (151), and wilforine (152) were isolated from the roots of Tripterygium wilfordii Hook.The inhibitory effects of compounds 150-152 on the nuclear factor-kappa B pathway were assessed in HEK293 cells induced with LPS.The IC 50 values obtained for these compounds were 8.75 µM, 0.74 µM, and 15.66 µM, respectively [60].Alopecines A-E (153-157) were isolated from the seeds of Sophora alopecuroides, which showed moderate to significant immunosuppressive activity against T-cell and B-cell proliferation, with the IC 50 values ranging from 3.9 to 100 µM and from 3.7 to 96.8 µM, respectively [61].
Two sesterterpenoids, gentianelloids A and B (165 and 166), which possess an unusual seco-gentianellane skeleton, were discovered in the traditional Uighur medicine of Gentianella turkestanorum.Compounds 165 and 166 exhibited significant immunosuppressive activity against the proliferation of murine splenocytes activated by anti-CD3/anti-CD28 monoclonal antibodies, with IC 50 values of 5.64 and 3.93 µM, respectively [65].Two novel diastereomeric sesterterpenoids, eurysoloids A (167) and B (168), were discovered in Eurysolen gracilis Prain.These compounds possess a unique pentacyclic structure with an extraordinary macrocyclic ether system.Compounds 167 and 168 exhibited immunosuppressive activity by effectively inhibiting the production of the cytokine IFN-γ in T-cells, with IC 50 values of 17.4 and 15.94 µM, respectively [66].
A monoterpenoid indole alkaloids named rhazinilam (169) was obtained from the bark of Pausinystalia yohimbe.Compounds 169 exhibited moderate inhibition against ConA-induced T lymphocyte proliferation, with IC 50 values of 16.8 µM.Additionally, they showed moderate inhibition against LPS-induced B lymphocyte proliferation, with IC 50 values of 13.5 µM [67].
Three compounds, named ophiorrhine C (170), ophiorrhine D (171), and ophiorrhine E (172), were obtained from the plant Ophiorrhiza cantoniensis Hace.Compounds 170-172 showed immunosuppressive activities against the proliferation of T and B lymphocytes, with IC 50 values from 17.9 to over 200 µM and 8.7 to 116.2 µM, respectively [68].Two alkaloids, named ophiorrhine F (173) and G (174), were obtained from the aerial parts of Ophiorrhiza japonica.Both compounds demonstrated significant inhibition of B-cell proliferation induced by LPS, with IC 50 values of 0.38 and 47.37 µM, respectively.CsA was employed as a positive control to assess its inhibitory effects on T-cell proliferation induced by ConA and B-cell proliferation induced by LPS, with IC 50 values of 0.03 and 0.32 µM, respectively [69].11-Hydroxyburnamine (175) and reserpine (176) were extracted from the total alkaloid extract of Rauvolfia yunnanensis.These compounds have shown immunosuppressive effects on human T-cell proliferation, with IC 50 values of 5.9 and 5.0 µM, respectively [70].

Phenolic Compounds
In recent years, phenolic compounds have been discovered to possess immunosuppressive activity, rendering them potential candidates for the prevention and treatment of autoimmune diseases [71].The structures, sources, selected models, and immunosuppressive activities are shown in Figures 7 and 8 and Table S6.
In recent years, phenolic compounds have been discovered to possess immunosu pressive activity, rendering them potential candidates for the prevention and treatment autoimmune diseases [71].The structures, sources, selected models, and immunosuppre sive activities are shown in Figures 7 and 8 and Table S6.Some of the resorcinols also had a significant immunosuppressive effect.Compound 177, named hypaluton A, was isolated from Hypericum patulum and had inhibitory activity against B lymphocyte proliferation with an IC50 value of 6.86 µM [72].Eighteen phloroglucinol derivatives were isolated from the fruits of Eucalyptus globulus, named eucalyptin A (178), eucalyptin B ( 179  Some of the resorcinols also had a significant immunosuppressive effect.Compound 177, named hypaluton A, was isolated from Hypericum patulum and had inhibitory activity against B lymphocyte proliferation with an IC 50 value of 6.86 µM [72].Eighteen phloroglucinol derivatives were isolated from the fruits of Eucalyptus globulus, named eucalyptin A ( 178 The cultivated Dendrobium devonianum Paxt produced two bibenzyl-phenylpropane hybrids, named dendrophenene A and dendrophenene B (200 and 201).Bioassays conducted on mouse splenic lymphocytes stimulated with ConA and LPS revealed that compounds 200 and 201 inhibited the proliferation of T lymphocytes, with IC 50 values of 0.17 µM and 2.47 µM, respectively.Additionally, they showed immunosuppressive effects on LPSinduced B-cell proliferation, with IC 50 values ranging from 28.3 µM to 52.6 µM.DXMS was selected as the positive control against ConA-induced T-cells and LPS-induced B-cell proliferation, with IC 50 values of 2.0 and 1.1 µM, respectively [75].

Flavonoids
Some flavonoid compounds have shown immunosuppressive properties in the last decade.The structures, sources, selected models, and immunosuppressive activity are shown in Figure 9 and Table S7.Compounds 247-253 were extracted from Campylotropis hirtella, whose names are Compounds 247-253 were extracted from Campylotropis hirtella, whose names are shown in Table S7.The immunosuppressive activity of compounds 247-253 was tested, which indicated these compounds had moderate activities against T-cell and B-cell proliferation with IC 50 values ranging from 0.26 to 53.16 µM and 1.55 to 29.12 µM, respectively.CsA was selected as the positive control against T and B-cell proliferation, with IC 50 values of 0.01 and 0.97 µM, respectively [84].
Four biflavonoid derivatives (254-257) were isolated from Citrus medica L. var.sarcodactylis Swingle.The names and immunosuppressive activities of other compounds are shown in Table S7.Compound 254-257 exhibited significant inhibitory activity against ConA-induced T-lymphocyte proliferation, with IC 50 values ranging from 16.83 to 50.90 µM [85].
Five dimethylallylated flavonolignans (258-262) were isolated from the fruit of Hippophae rhamnoides L. The name and immunosuppressive activity are shown in Table S7.

Steroids
Some steroid compounds have shown immunosuppressive properties in the last decade.The structures, sources, selected models, and immunosuppressive activity are shown in Figure 10 and Table S8.S7.

Steroids
Some steroid compounds have shown immunosuppressive properties in the last decade.The structures, sources, selected models, and immunosuppressive activity are shown in Figure 10 and Table S8.

Others
In addition, the structures, sources, selected models, and immunosuppressive activities of other compounds are shown in Figures 11 and 12 and Table S9.ConA-induced proliferation of T lymphocytes, with IC50 values ranging from 8.9 to 19.8 µM [89].Pinoresinol (277) and syringaresinol (278) had been isolated from the stems of Epigynum cochinchinensis.Compounds 277 and 278 inhibit ConA-stimulated proliferation of mouse splenocytes with IC50 values of 12.5 and over 50 µM, respectively [90].
Eleven hypothemycin-type resorcylic acid lactones (297-307) were obtained from the solid rice-based culture of Podospora sp.G214.The name and immunosuppressive activities are shown in Table S9.Compounds 297-307 exhibited potent immunosuppressive activities against ConA-induced T-cell proliferation with IC 50 values ranging from 6.0 to 25.1 µM and LPS-induced B-cell proliferation with IC 50 values ranging from 6.2 to 29.1 µM [95].

Structure-Activity Relationship
In this review, the structure-activity relationship of terpenoids, alkaloids, phenolic compounds, flavonoids, and others with immunosuppressive activity was analyzed.Within these categories, variations in substituents, substitution sites, and configuration result in varying degrees of immunosuppressive activity.
Sesquiterpenoids 1-9 had a similar guaiacosane skeleton.Comparing the immunosuppressive activity in pairs, compounds 1-5 with C-8-Ac had strong activity for LPS-induced proliferation of B lymphocyte cells.It seems that C-8-Ac increased immunosuppressive activity.Compounds 47-51 possessed a similar farnesanes-type diterpenoid skeleton.Compound 49 exhibited the highest activity against T-cell and B-cell proliferation, possibly attributed to the varying oxidation levels of these compounds at C-4.This suggests that increasing the oxidation levels at C-4 may enhance antibacterial activity.
Triterpenoids 117 and 118, with highly similar chemical structures, exhibited inhibitory activity on murine splenocyte proliferation, with 117 being more potent than 118.The structural disparity lies in the oxidation of the C-3 hydroxyl group in 117, which potentially impacts its activity.
In an immunosuppressive activity assay comparing alkaloids, both 173 and 174 exhibited inhibitory activity against LPS-induced B-cell proliferation, with compound 173 demonstrating greater potency than compound 174.The structural distinction lies in the presence of a methoxy group at the C-6 position in compound 173, which suggests that the methoxy group at the C-6 may increase the antibacterial activity.
The immunosuppressive activity assay of phloroglucinol derivatives was also performed.
Compounds 178 and 179, possessing isopropyl functionality at C-4 ′ , exhibited significant efficacy in promoting LPS-induced proliferation of ConA-induced murine T-cells.It seems that isopropyl functionality at C-4 ′ increases immunosuppressive activity.

Conclusions
In this review article, we have provided information on the source, structure, and immunosuppressive activity of each discussed compound.A total of 324 small-molecule compounds with immunosuppressive activity have been discovered, and their sources are counted in Figure 13.This figure showed that small-molecule compounds with immunosuppressive activity have been isolated from natural sources, including plants (62%), animal corals (6%), and fungi (32%).Among these compounds, the main plant-derived molecules identified are sesquiterpene lactones in A. argyi, specifically compounds 1-6 and 9-13.The primary coral-derived molecules identified are diterpenoids found in S. scabra and S. polydactyla.Additionally, marine coral-derived molecules such as sesquiterpenoids found in C. odorants (29)(30)(31)(32)(33)(34)(35)(36) and diterpenoids in X. longipes (52-59) have been identified as significant contributors to this field of study.
lecules 2024, 29, x FOR PEER REVIEW 20 of mal corals (6%), and fungi (32%).Among these compounds, the main plant-derived mo ecules identified are sesquiterpene lactones in A. argyi, specifically compounds 1-6 and 9 13.The primary coral-derived molecules identified are diterpenoids found in S. scabra an S. polydactyla.Additionally, marine coral-derived molecules such as sesquiterpenoid found in C. odorants (29)(30)(31)(32)(33)(34)(35)(36) and diterpenoids in X. longipes (52)(53)(54)(55)(56)(57)(58)(59) have been identifie as significant contributors to this field of study.By comparing the monomer components summarized in this review, it can be foun that phenols and terpenes have good immunosuppressive activity.In contrast, mon meric components, such as alkaloids and saponins, are less studied and deserve furth exploration.A total of 57 terpenoids have been identified, which is the most abunda type of compound.CsA is an immunosuppressive agent that inhibits the proliferation T and B lymphocytes.As a positive drug for immunosuppressive activity screening, i IC50 values in various studies ranged from 0.01 to 1 µM.By comparing positive drugs, can be found that some compounds have great potential for development.Among them compounds 49, 151, 173, 200, 204, and 247 have demonstrated good immunosuppressiv activity with IC50 values less than 1 µM, while one hundred and nine other compound have IC50 values less than 10 µM.The foundation and core of innovative drugs is activit These compounds may hold great potential to become new natural therapeutic agents fo treating autoimmune diseases [99][100][101].
Compounds with good immunosuppressive activity have enormous potential as im munosuppressive agents.After discovering compounds with good immunosuppressiv By comparing the monomer components summarized in this review, it can be found that phenols and terpenes have good immunosuppressive activity.In contrast, monomeric components, such as alkaloids and saponins, are less studied and deserve further exploration.A total of 57 terpenoids have been identified, which is the most abundant type of compound.CsA is an immunosuppressive agent that inhibits the proliferation of T and B lymphocytes.As a positive drug for immunosuppressive activity screening, its IC 50 values in various studies ranged from 0.01 to 1 µM.By comparing positive drugs, it can be found that some compounds have great potential for development.Among them, compounds 49, 151, 173, 200, 204, and 247 have demonstrated good immunosuppressive activity with IC 50 values less than 1 µM, while one hundred and nine other compounds have IC 50 values less than 10 µM.The foundation and core of innovative drugs is activity.These compounds may hold great potential to become new natural therapeutic agents for treating autoimmune diseases [99][100][101].
Schincarin C (120) was isolated from the plants of the genus Schisandra, which showed immunosuppressive activities against the proliferation of the T and B-cells with IC 50 values of 10.21 and 5.83 µM, respectively [51].BC-1 (121) was isolated from Beesia calthaefolia, which inhibited murine T lymphocyte proliferation with IC 50 values of 9.8 µM [52].Dictabretols A-D (122-125) were isolated from the root bark of Dictamnus dasycarpus using guided fractionation.An antiproliferative assay on T-cells using splenocytes was performed in vitro.Compounds 122-125 were evaluated for their immunosuppressive activity on T-cells and demonstrated inhibition of proliferation of activated T-cells, with IC 50 values of 1.5, greater than 20, 1.8, and 1.5 µM, respectively [53].Compound 126, named schincalactones A, was isolated from Schisandra.Compound 126 had certain immunosuppressive activity against LPS-induced B-cells and ConA-induced T-cells, with IC 50 values of 36.84 and over 50.91 µM, respectively [54].Four triterpenoids were isolated from Phyllanthus hainanensis, including phainanolide A (127) and phainanoid G (128); phainanoid H (129); and phainanoid I (130).The immunosuppressive activity of compounds 127-130 was tested, which indicated these compounds had moderate activities against T-cell and B-cell proliferation with IC 50 values ranging from 16.15 to 566.83 µM and 8.24 to 456.63 µM, respectively [55].Phainanoids A-F (131-136), six highly modified triterpe-noids with a new carbon skeleton, were isolated from Phylanthus hainanensis.The immunosuppressive activity of compounds 131-136 was tested, which indicated these compounds had moderate activities against T-cell and B-cell proliferation with IC 50 values ranging from 2.04 to 192.8 µM and less than 1.60 to 249.49 µM, respectively [56].
Dictabretols A-D (122-125) were isolated from th root bark of Dictamnus dasycarpus using guided fractionation.An antiproliferative assa on T-cells using splenocytes was performed in vitro.Compounds 122-125 were evaluate for their immunosuppressive activity on T-cells and demonstrated inhibition of prolifera tion of activated T-cells, with IC50 values of 1.5, greater than 20, 1.8, and 1.5 µM, respec tively [53].Compound 126, named schincalactones A, was isolated from Schisandra.Com pound 126 had certain immunosuppressive activity against LPS-induced B-cells an ConA-induced T-cells, with IC50 values of 36.84 and over 50.91 µM, respectively [54].Four triterpenoids were isolated from Phyllanthus hainanensis, including pha nanolide A (127) and phainanoid G (128); phainanoid H (129); and phainanoid I (130).Th immunosuppressive activity of compounds 127-130 was tested, which indicated thes compounds had moderate activities against T-cell and B-cell proliferation with IC50 value ranging from 16.15 to 566.83 µM and 8.24 to 456.63 µM, respectively [55].Phainanoids A F (131-136), six highly modified triterpe-noids with a new carbon skeleton, were isolate from Phylanthus hainanensis.The immunosuppressive activity of compounds 131-136 wa tested, which indicated these compounds had moderate activities against T-cell and B-ce proliferation with IC50 values ranging from 2.04 to 192.8 µM and less than 1.60 to 249.4 µM, respectively [56].

Molecules 2024 ,
29, x FOR PEER REVIEW 16 of 25 Five dimethylallylated flavonolignans (258-262) were isolated from the fruit of Hippophae rhamnoides L. The name and immunosuppressive activity are shown in Table

Table 1 .
Establishment of models of the immunosuppressive efficacy in vitro.

Table 2 .
Establishment of models of the immunosuppressive efficacy in vivo.