Next Article in Journal
Synthesis and Characterization of Lignin-Silver Nanoparticles
Previous Article in Journal
Environmental Dyeing and Functionalization of Silk Fabrics with Natural Dye Extracted from Lac
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 29
Issue 10
10.3390/molecules29102359
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Research Progress of Natural Active Substances with Immunosuppressive Activity

by
Fei Shao
1,
Qiying Shen
1,
Zhengfei Yang
2,
Wenqian Yang
1,
Zixiang Lu
1,
Jie Zheng
1,
Liming Zhang
1,* and
Hangying Li
1,3,*
1
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
2
School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750004, China
3
Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, Yinchuan 750004, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(10), 2359; https://doi.org/10.3390/molecules29102359
Submission received: 15 April 2024 / Revised: 14 May 2024 / Accepted: 14 May 2024 / Published: 16 May 2024
(This article belongs to the Section Natural Products Chemistry)
Browse Figures
Versions Notes

Abstract

:
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.

Graphical Abstract

1. 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.

2. The Immunosupperssive Activity of Animal and Cell Models

Seven cellular and six animal models are commonly used for screening immunosuppressive activity, as shown in Table 1 and Table 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 (CCl4), 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.

3. 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].

3.1. 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.

3.1.1. 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.
Six sesquiterpenoids (1–6) with immunosuppressive activity were isolated from Artemisia argyi, named argyinolide G (1), 8α-acetoxy-3β-chloro-1α,4α-dihydroxyguai-9,11(13)-dien-6α,12-olide (2), 8α-acetoxy-3α-chloro-1α,4β-dihydroxyguai-9,11(13)-dien-6α,12-olide (3), 8α-acetoxy-3β-chloro-1α,4α-dihydroxyguai-10(14),11(13)-dien-6α,12-olide (4), 8α-acetoxy-3α-chloro-1β,2β-epoxy-4β,10α-dihydroxy-5α,7αH-guai-11(13)-en-12,6α-olide (5), and 3β-chloro-1α,2α-epoxy-4α,10α-dihydroxy-5α,7αH-guai-11(13)-en-12,6α-olide (6). Compounds 1–6 exhibited potent inhibition of NO production in LPS-stimulated BV-2 microglia, with IC50 values of 5.3, 3.2, 6.9, 4.2, 22.2, and 6.4 μM, respectively [28].
Tremutins A and B (7 and 8) were isolated from the basidiomycetes Irpex lacteus. Compound 7 inhibited the B lymphocyte cells with an IC50 value of 22.4 μM. Meanwhile, compound 8 inhibited T-cell proliferation and B-cell proliferation with IC50 values of 16.7 and 13.6 μM, respectively [29]. Canin (9), seco-tanapartholide B (10), seco-tanapartholide A (11), arteglasin A (12), and 8-acetylarteminolide (13) were isolated from the ethyl acetate extract of A. argyi. Compounds 9–13 showed significant inhibition of T lymphocyte proliferation, with IC50 values of 2.7, 1.0, 1.2, 1.9, and 3.2 μM, respectively [28]. Maydispenoids A and B (14 and 15) were isolated from bipolaris maydis, which exhibited inhibitory effects on murine splenocyte proliferation stimulated by anti-CD3/anti-CD28 monoclonal antibodies (mAbs), with IC50 values of 5.28 and 9.38 μM [30]. A sesquiterpene named antroxazole A (16) was isolated from Epigynum griffithianum. Compound 16 was evaluated for its immunosuppressive activity on the proliferation of LPS-induced B-cells, with an IC50 value of 16.3 μM [14]. Three sesquiterpenoids, named (+)-aspersydowin A (7S) (17), (+)-aspersydowin B (7S,11S) (18), and (7S)-(+)-7-O-methylsydonol (19), were isolated from Aspergillus sydowii. Compounds 17–19 inhibited the proliferation of ConA-induced T-cells with an IC50 value greater than 40 μM. Compounds 17–19 inhibited the proliferation of LPS-induced B-cells, with IC50 values of 10.9, 17.6, and 13.4 μM, respectively [31].
Parasubolide D (20), parasubolide E (21), and parasubolide L (22) were isolated from the plant Parasenecio albus. Compounds 20–22 had immunosuppressant activity against B-cell proliferation with IC50 values of 23.1, 33.8, and 26.6 μM, respectively [32]. Four sesquiterpenoids, named steccherins A–D (23–26), were extracted from Steccherinum ochraceum. Compounds 23–26 inhibited the T and B lymphocytes with IC50 values ranging from 37.8 to over 40 μM and 6.2 to over 40 μM, respectively [33].
Soltorvum A and soltorvum B (27 and 28), obtained from the stems of Solanum torvum, could inhibit the activity of ConA-induced splenocyte proliferation and possessed IC50 values of 27 and 18 μM, respectively [34]. Craterodoratin C (29), craterodoratin J (30), craterodoratins L–O (31–34), craterodoratin Q (35), and craterodoratin S (36) were isolated from the edible mushroom Craterellus ordoratus. Compounds 29–34 and 36 exhibit potent inhibitory activity against B lymphocyte cells, with IC50 values ranging from 12.62 to 22.68 μM. Compound 35 inhibited the ConA-induced proliferation of T lymphocyte cells with an IC50 value of 31.50 μM [35].

3.1.2. Diterpenoids

The structures, sources, selected models, and immunosuppressive activities of 79 diterpenoids are summarized in Figure 2 and Figure 3 and Table S2.
Three diterpenoids, named ineleganolide (37), yonarolide (38), and scabrolide A (39), were isolated from the corals Sinularia scabra and Sinularia polydactyla. Compounds 37–39 demonstrated significant inhibitory effects on the proliferation of T and B-cells, with an IC50 value exceeding 50 μM [36]. Cinncassiol G and cinnacasol (40 and 41) were isolated from the stem bark of Cinnamomum cassia. Compounds 40 and 41 inhibited the proliferation of ConA-induced T-cells and LPS-induced B-cells. The proliferation of T-cells was significantly suppressed by both compounds at a concentration of 50 μM. Compound 40 exhibited an inhibition rate of 86.1%, while compound 41 showed a slightly lower inhibition rate of 58.8% [37].
A new diterpenoid with a five-membered ring, named 3,5,10-O-triacetyl-8- -isobutanoyl-14-O-benzoylcyclomyrsinol (42), was isolated from Euphorbia kopetdaghi Prokh. Compound 42 showed significant activity against phytohemagglutinin-activated T-cell proliferation, with an IC50 of 1.83 mg/mL [38]. Xylarilongipin A (43) was extracted from the culture broth of the fungicolous fungus Xylaria longipes HFG1018, which inhabits the medicinal fungus Fomitopsis betulinus. Compound 43 exhibited moderate inhibitory effects on the proliferation of T and B lymphocytes, with IC50 values measured at 13.6 μM and 22.4 μM, respectively [39].
Three diterpenoids, named tripterifordin (44), 16α,17-dihydroxy-ent-kaur-20-al (45), and ent-2β-hydroxymanool (46), were isolated from Ligularia fischeri. Compounds 44–46 had moderate inhibitory activity against human B lymphoblast HMy2. CIR cells with IC50 values of 56.3, 13.3, and 31.4 μM, respectively [40]. There were five diterpenoids (47–51) with immunosuppressive activity from Koilodepas hainanense, named koilodenoid D (47), koilodenoid G (48), ent-5α,2,15-dioxodolabr-3-ene-3,16-diol (49), ent-5α,3,15-dioxodolabr-1,4(18)-diene-2,16-diol (50), and ent-16-nor-5α,13α-2-oxodolabra-3-en-3-ol-15-oic acid (51). Compounds 47–51 inhibited T-cell and B-cell with IC50 values ranging from 0.86 to 30.54 μM and 0.29 to 10.2 μM, respectively [41].
Eight diterpenoids were extracted from cultures of the fungicolous fungus Xylaria longipes HFG1018: xylarinorditerpene B (52), xylarinorditerpene C (53), xylarinorditerpene D (54), xylarinorditerpene E (55), xylarinorditerpene I (56), xylarinorditerpene N (57), 14α,16-epoxy-18-norisopimar-7-en-4α-ol (58), and agatadiol (59). Compounds 52–59 inhibited T-cell and B-cell proliferation with IC50 values ranging from 1.0 to 27.2 μM and 16.1 to 51.8 μM, respectively. DXMS (dexamethasone) was selected as the positive control against T-cell and B-cell proliferation with IC50 values of 1.6 and 0.8 μM, respectively [42].
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 IC50 value of 17.42 μM. Similarly, compound 61 showed significant inhibition of the proliferation of T lymphocytes, with an IC50 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-CD3/anti-CD28 monoclonal antibodies, with IC50 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 IC50 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 IC50 value of 1.93 μM [46].
Nine diterpenoids, named xiguscabrolide H (67), 10-epi-gyrosanolide E (68), 5-epi-sinuleptolide (69), norcembrene (70), scabrolide D (71), scabrolide G (72), sinularcasbane O (73), gyrosanolide F (74), and sinuleptolide (75), were extracted from the corals Sinularia scabra and Sinularia polydactyla. Compounds 67–75 inhibited the T and B lymphocytes with IC50 values ranging from 8.5 to over 50.00 μM and 20.5 to over 50.00 μM, respectively [36].
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 IC50 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 IC50 values ranging from 11.4 to greater than 50 μM and 4.8 to greater than 50.0 μM, respectively [48].

3.1.3. 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 splenocytes, with an IC50 value of 25 μM. 14Schincarin 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 IC50 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 IC50 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 IC50 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 IC50 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 IC50 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 IC50 values ranging from 2.04 to 192.8 μM and less than 1.60 to 249.49 μM, respectively [56].

3.1.4. 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.
Peniandranoids A (137), peniandranoids B (138), peniandranoids C (139), peniandranoids D (140), peniandranoids E (141), isopenicin A (142), isopenicin B (143), and isopenicin C (142–144) were isolated from the fermentation of a soil-derived fungus, Penicillium sp. sb62. Compounds 137–144 exhibited potent immunosuppressive effects on T-cell proliferation, with EC50 values ranging from 4.3 to 27 μM. Similarly, they also demonstrated strong immunosuppressive activities against B-cell proliferation, with EC50 values ranging from 7.5 to 23 μM [56]. Three gentianellane-type sesterterpenoids named nitidasin (145), gentianelloid F (146), and alborosin (147) were isolated from whole plants of Gentianella turkestanorum, which showed moderate to significant immunosuppressive activity against anti-CD3/anti-CD28 monoclonal antibodies (mAbs), with IC50 values of 12.31, 13.68, and 14.31 μM [57].
A pair of C-14 epimeric sesterterpenoids, colquhounoid D (148) and 14-epi-colquhounoid D (149), were isolated from Colquhounia coccinea var. mollis. Compounds 148 and 149 showed significant immunosuppressive effects on the cytokine IFN-γ secretion of mouse splenocytes induced by anti-CD3/CD4, with IC50 values of 8.38 μM and 5.79 μM, respectively [58].

3.2. 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 IC50 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 IC50 values ranging from 3.9 to 100 μM and from 3.7 to 96.8 μM, respectively [61].
A pyrrole alkaloid, albifpyrrols B (158), was isolated from the endophytic fungus Albifmbria viridis collected. Compound 158 exhibits inhibition against B lymphocyte cells with an IC50 value of 16.16 μM [62]. Fumiquinazoline J and fumigaclavine C (159 and 160) were isolated from mangrove-derived Aspergillus fumigatus HQD24. Compound 159 effectively suppressed the proliferation of T lymphocytes induced by ConA and B lymphocytes induced by LPS, with IC50 values of 29.38 μM and 162.58 μM, respectively. Compound 160 remarkable inhibited proliferation of ConA-induced T with an IC50 value of 53.12 μM [63].
Four alkaloids (161–164) were isolated from Kopsia officinalis, named 12-methoxychanofruticosinic acid (161), N-(4)-methylkopsininate (162), demethoxycarbonylkopsin (163), and rhazinilam (164). Compounds 161–164 have immunosuppressive activity on human T-cell proliferation with IC50 values of 27.8, 21.6, 25.4, and 1.0 μM, respectively [64].
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 IC50 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 IC50 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 IC50 values of 16.8 μM. Additionally, they showed moderate inhibition against LPS-induced B lymphocyte proliferation, with IC50 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 IC50 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 IC50 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 IC50 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 IC50 values of 5.9 and 5.0 μM, respectively [70].

3.3. 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 Figure 7 and Figure 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), eucalyptin C (180), eucalyptin D (181), eucalyptin E (182), eucalyptin F (183), eucalyptin G (184), macrocarpal A (185), macrocarpal B (186), macrocarpal C (187), macrocarpal D (188), macrocarpal E (189), macrocarpal Q (190), eucarobustol E (191), euglobal-V (192), euglobal-III (193), 1-(2,6-dihydroxy-4-methoxy-3,5-dimethylphenyl)-2-methylbutan-1-one (194), and 1-(2,4-dihydroxy-6-methoxy-3,5-dimethylphenyl)-3-methylbutan-1-one (195). The T-cell proliferation model was utilized to evaluate the immunosuppressive effects of compounds. Compounds 178–195 displayed moderate inhibitory activity, with IC50 values ranging from 10.2 to 132.9 μM [73].
Prenyllongnol A (196), prenyllongnol B (197), prenyllongnol C (198), and prenyllongnol D (199) were extracted from Hypericum longistylum. Compounds 196–199 demonstrated significant immunosuppressive effects on the proliferation of murine splenocytes induced by ConA, with IC50 values ranging from 2.98 to 6.34 μM [74].
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 IC50 values of 0.17 μM and 2.47 μM, respectively. Additionally, they showed immunosuppressive effects on LPS-induced B-cell proliferation, with IC50 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 IC50 values of 2.0 and 1.1 μM, respectively [75].
Tyrosol (202) and 3,4-dihydroxy-ethyl ester (203) were isolated from Hydnora abyssinica ethanolic extract, which revealed immunosuppressive activity against reactive oxygen species from MNCs. Compounds 202 and 203 exhibited inhibitory effects against superoxide production at concentrations of 100 μg/mL [76]. A phenolic compound called daldiniols A (204), derived from the endophytic fungus Daldinia sp. TJ403-LS1, was isolated from the medicinally valuable plant Anoectochilus roxburghii. Compound 204 exhibited remarkable immunosuppressive activity against the proliferation of murine splenocytes activated by LPS and anti-CD3/anti-CD28 mAbs, with an identical IC50 value of 0.06 μM [77].
Two phenolic glycosides, named 2-phenylpropanoate-2-O-β-D-apiofuranosyl-(1→6)-O-β-D–glucopyranoside (205) and 3,4,5-trimethoxyphenol-β-D-apiofuranosyl-(1→6)-O-β-D-glucopyranoside (206), were isolated from the barks of Cinnamomum cassia, which had an obvious immunosuppressive activity against T-cell proliferation with IC50 values of over 200 μM and 12.5 μM, respectively [72].
Four polyprenylated acylphloroglucinols, (+)-hyperzewalsin B (207), (−)-hyperzewalsin B (208), hyperzewalsin E (209), and lupulone D (210), were isolated from the aerial parts of Hypericum przewalskii Maxim. Compounds 207–210 were tested for their immunosuppressive activities in LPS-stimulated splenocytes, with IC50 values ranging from 6.61 to 7.36 μM [78]. Ten mycophenolic acid derivatives (211–220) were obtained from the fungus Penicillium bialowiezense. The name and immunosuppressive activities are shown in Table S6. Compounds 211–220 showed significant inhibitory potency, with IC50 values ranging from 3.27 to 24.68 μM [79].
Hyperformitin A (221), hyperformitin B (222), hyperformitin C (223), hyperformitin D (224), hyperformitin E (225), hyperformitin G (226), hyperformitin H (227), hyperformitin J (228), hyperformitin K (229), hyperformitin L (230), and hyperformitin M (231) were isolated from Hypericum perforatum. Compounds 221–231 were tested for their immunosuppressive activities against LPS-induced B lymphocyte proliferation, with IC50 values ranging from 4.1 to over 10 μM [80].
Two acylphloroglucinols, przewalcyrones C and D (232 and 233), were isolated from Hypericum przewalskii Maxim. Compounds 232 and 233 exhibited remarkable immunosuppressive activity against anti-CD3/anti-CD28 mAbs, activating murine splenocyte proliferation with IC50 values of 5.01 μM and 5.26 μM, respectively [81]. A previous polycyclic polyprenylated acylphloroglucinol, cumilcinol E (234), was isolated from Hypericum wilsonii. Compound 234 demonstrated significant inhibitory activity on ConA-induced T-lymphocyte proliferation, with an IC50 value of 4.80 μM [82].

3.4. 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.
Two flavonoids named jaceosidin (235) and eupatilin (236) were isolated from Artemisia argyi. Compounds 235 and 236 showed inhibitory activity on LPS-stimulated BV-2 microglial cell proliferation with IC50 values of 1.9 and 4.0 μM [83]. Tsaokonol A (237), tsaokonol B (238), tsaokonol C (239), tsaokonol D (240), tsaokonol E (241), tsaokonol F (242), tsaokonol G (243), tsaokonol H (244), tsaokonol I (245), and tsaokonol J (246) were isolated from the fruits of Amomum tsao-ko. Compounds 237–246 were evaluated for their inhibitory effects on LPS-induced NO production, with IC50 values ranging from 10.6 to 41.5 μM [28].
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 IC50 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 IC50 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 IC50 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.
Compounds 258–262 showed excellent inhibitory effects against ConA-induced T lymphocyte proliferation, with IC50 values ranging from 19.42 to 48.05 μM [86].

3.5. 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.
Quadristerols B, quadristerols C, quadristerols D, and quadristerols F (263–266), four ergosterols, were obtained from Aspergillus quadrilineata. Compounds 263 and 264 showed excellent inhibitory effects against ConA-induced T lymphocyte proliferation, with IC50 values of 7.43 and 3.95 μM, respectively. Compounds 265 and 266 strongly inhibited LPS-induced B lymphocyte proliferation, with IC50 values of 10.96 and 7.47 μM, respectively [87].
Six new C21 steroidal glycosides, named atratcynoside A (267), atratcynoside B (268), atratcynoside C (269), and datratcynoside E (270), were isolated from the root of Cynanchum atratum. Compounds 267–270 were subjected to immunosuppressive activities by an in vitro model of ConA-induced proliferation of T-lymphocytes. Compounds 267–270 exhibited significant dose-dependent immunosuppressive activities, with IC50 values ranging from 3.3 to 7.0 μM [88].

3.6. Others

In addition, the structures, sources, selected models, and immunosuppressive activities of other compounds are shown in Figure 11 and Figure 12 and Table S9.
Six pyrone derivatives (+)-Adprepyrone B (271), (+)-Adprepyrone D (272), (−)-Adprepyrone D (273), (+)-Adprepyrone E (274), (−)-Adprepyrone E (275), 6-[(E)-3-Hydroxyprop-1-enyl]-4-methoxy-5-methyl-2-pyrone (276), were derived from the fungus Talaromyces adpressus. Compounds 271–276 demonstrated moderate inhibitory effects on 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].
Two xanthone derivatives, sydoxanthone B (279) and 13-O-acetylsydowinin B (280), were isolated from the fungus Aspergillus sydowii, occurring in the livewort Scapania ciliata S. Lac. Compound 279 inhibited T and B-cell proliferation with IC50 values of 22.53 and 12.3 μM, respectively. Meanwhile, compound 280 inhibited the LPS-induced B-cells with an IC50 value of 172.7 μM [91]. A chromone, diaporchromone A (281), was isolated from the culture of Phomopsis asparagi DHS-48. Compound 281 showed moderate to weak immunosuppressive activity against T and B lymphocyte cells with IC50 values of 34 μM and 117 μM, respectively [92].
Nine polyketides (282–290) were isolated from the leaves of Sonneratia apetala: Peniphenone (282), methyl peniphenone (283), conioxanthone A (284), methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (285), pinselin (286), sydowinin B (287), sydowinin A (288), remisporine B (289), and epiremisporine B (290). The immunosuppressive activity of compounds 282–290 was tested, which indicated these compounds had moderate activities against T-cell and B-cell proliferation with IC50 values ranging from 5.9 to 30.8 μM and 7.1 to 32.4 μM, respectively [93].
Seven undescribed side chains containing azaphilones, pestaphilone A (291), pestaphilone B (292), pestaphilone C (293), pestaphilone D (294), pestaphilone E (295), and pestaphilone F (296), were isolated from the Anoectochilus roxburghii endophytic fungus Pestalotiopsis oxyanthi. In bioassay, compounds 291–296 displayed potential immunosuppressive activity in ConA-induced T lymphocyte proliferation, with IC50 values ranging from 9.36 to 35.21 μM, respectively [94].
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 IC50 values ranging from 6.0 to 25.1 μM and LPS-induced B-cell proliferation with IC50 values ranging from 6.2 to 29.1 μM [95].
Four phenolics, named 1-naphthaleneheptanoic (308), monacolin K (309), monacolin L (310), and monacolin J (311), were isolated from the endophytic fungus Aspergillus sp. found in Tripterygium wilfordii. Compounds 308–311 showed potential immunosuppressive activity against anti-CD3/anti-CD28 mAbs-irritated murine splenocyte proliferation, with IC50 values ranging from 5.30 μM to 16.51 μM [96].
Compounds 312–322 were specifically immunosuppressive to T lymphocytes with IC50 values of 12.6 and 70.9 μM and LPS-induced B-cell proliferation with IC50 values ranging from 2.4 to 88 μM, respectively [75]. Ivorenolide B (323), a 17 membered macrolide featuring conjugated acetylenic bonds, was isolated from Khaya ivorensis. Compound 323 showed inhibitory activity on B lymphocyte proliferation with an IC50 value of 4.80 μM [97].
A new asymmetric macrodiolide immunosuppressant, named efophylin B (324), is from Streptomyces malaysiensis DSM 4137. Compound 324 demonstrated significant inhibitory activity against T lymphocyte proliferation, with an IC50 value of 24.6 μM [98].

4. 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.

5. 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 (29–36) and diterpenoids in X. longipes (52–59) have been identified as significant contributors to this field of study.
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 IC50 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 IC50 values less than 1 μM, while one hundred and nine other compounds have IC50 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].
Compounds with good immunosuppressive activity have enormous potential as immunosuppressive agents. After discovering compounds with good immunosuppressive activity from natural products, the process of transforming them into candidate drugs should be optimized. This process includes system detection of its toxicity, solubility, and target, among others. It is necessary to conduct a systematic evaluation of the pharmacology, toxicology, safety, and efficacy of candidate drugs during the development process. The reviewed products in the article are all natural products. Due to the relatively low content of compounds and the difficulty of their synthesis, most of them only undergo simple activity screening. The immunosuppressive mechanisms of several compounds have been studied.
Eucalyptin C (180) had been found to be not only an immunosuppressive agent but also a selective PI3K inhibitor. Compound 180 induces apoptosis and inhibits activation of primary splenic cells in mice with allergic contact dermatitis by inhibiting downstream expression of PI3K [73]. BC-1 (121) not only inhibited the proliferation of splenic lymphocytes and phagocytosis of macrophages but also significantly reduced Th1/Th2 cytokines (IL-2, IFN-γ) in CD4+ cells. With the production of IL-4 and IL-10, compound 121 can inhibit the activation of JNK, ERK, and PI3K/AKT signaling pathways. These results indicate that compound 121 has a potential downregulation effect on the immune system and may serve as an immunosuppressive agent for the treatment of CD4+ inflammation and adverse immune reactions [52]. Their research methods on the mechanism of action may have good reference significance for studying the mechanism of action of structurally similar compounds.
However, there are limitations in studying monomeric fractions due to their small amounts obtained through complex extraction processes [102,103,104]. Solving extraction problems is crucial if we want these monomeric components to be used clinically [105,106]. Therefore, new methods are needed to accurately determine the composition of natural active substances as well as assess their effectiveness in human and animal models [107,108,109]. This review evaluates the immunosuppressive activity of different experiments using the main criterion, IC50. This method can compare the activity of different chemical structures and estimate their future potential. The objective issue currently being studied is the need for appropriate, high-throughput synthesis methods to prepare small molecules.
In terms of food and chemistry, many plants derived from the compounds reviewed in this article may also have immunosuppressive activity. Among them, plants with the same origin in food-medicine herbs developed into a series of foods. In agriculture, the agricultural planting industry of medicinal and edible plants can be extended and expanded while promoting economic development.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29102359/s1. Tables S1–S9: Compounds 1–324 with Immunosuppressive Effects. References [28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,60,61,62,63,64,65,66,67,68,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98] are cited in the Supplementary Materials.

Author Contributions

Conceptualization and, H.L. and L.Z.; writing—original draft preparation, F.S.; writing—review and editing, Q.S., Z.Y. and W.Y.; visualization, Z.L. and F.S.; supervision, L.Z. and Q.S.; project administration, J.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Natural Science Foundation of China (22267017), the Ningxia Provincial Natural Science Foundation (2023AAC03203), the Key Laboratory of Protection, Development, and Utilization of Medicinal Resources in Liupanshan Area, the Ministry of Education (KFKT202302), and the Key Laboratory of Craniocerebral Diseases of Ningxia Medical University (LNKF202107).

Data Availability Statement

This article is a review article without any research data. All analysis results have been presented in the manuscript.

Conflicts of Interest

The authors declare no competing financial interests.

References

  1. Alexander, H.; Eirik, B.; Eystein, S.H. Autoimmune Addison’s disease—An update on pathogenesis. Ann. D’Endocrinol. 2018, 79, 157–163. [Google Scholar]
  2. Conrad, N.; Misra, S.; Verbakel, J.Y.; Verbeke, G.; Molenberghs, G.; Taylor, P.N.; Mason, J.; Sattar, N.; McMurray, J.J.V.; McInnes, I.B.; et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: A population-based cohort study of 22 million individuals in the UK. Lancet 2023, 401, 1878–1890. [Google Scholar] [CrossRef] [PubMed]
  3. Antony, R.; Satveer, K.M.; Jonathan, N.B. Psoriasis: A brief overview. Clin. Med. 2021, 21, 170–173. [Google Scholar]
  4. Lin, S.; Yan, S.; Liu, Y.; Zhang, X.; Cao, F.; He, Y.; Li, F.; Liu, J.; Wang, J.; Hu, Z.; et al. New secondary metabolites with immunosuppressive and BChE inhibitory activities from an endophytic fungus Daldinia sp. TJ403-LS1. Bioorganic Chem. 2021, 114, 105091. [Google Scholar] [CrossRef] [PubMed]
  5. Duan, Y.; Xie, S.; Bu, P.; Guo, Y.; Shi, Z.; Guo, Y.; Cao, Y.; Sun, W.; Qi, C.; Zhang, Y. Hypaluton A, an Immunosuppressive 3,4-nor-Polycyclic Polyprenylated Acylphloroglucinol from Hypericum patulum. J. Org. Chem. 2021, 86, 6478–6485. [Google Scholar] [CrossRef] [PubMed]
  6. Kawano, M.; Nagata, S. Efferocytosis and autoimmune disease. Int. Immunol. 2018, 30, 551–558. [Google Scholar] [CrossRef] [PubMed]
  7. Roberto, P.; Alessandra, F.; Alberto, F. Autoimmune Addison’s Disease as Part of the Autoimmune Polyglandular Syndrome Type 1: Historical Overview and Current Evidence. Front. Immunol. 2021, 12, 606860. [Google Scholar]
  8. Pascual, J.; Berger, S.P.; Witzke, O. Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation. J. Am. Soc. Nephrol. 2018, 29, 1979–1991. [Google Scholar] [CrossRef] [PubMed]
  9. Leroy, C.; Rigot, J.M.; Leroy, M. Immunosuppressive drugs and fertility. Orphanet J. Rare Dis. 2015, 10, 136. [Google Scholar] [CrossRef]
  10. Shin, J.S.; Chung, S.H.; Lee, W.S.; Lee, J.Y.; Kim, J.L.; Lee, K.T. Immunostimulatory effects of cordycepin-enriched WIB-801CE from Cordyceps militaris in splenocytes and cyclophosphamide induced immunosuppressed mice. Phytother. Res. 2018, 32, 132–139. [Google Scholar] [CrossRef]
  11. Ali, H.; Musharraf, S.G.; Iqbal, N.; Adhikari, A.; Abdalla, O.M.; Ahmed Mesaik, M.; Kabir, N. Immunosuppressive and hepatoprotective potential of Sarcococca saligna and its biomarker components. Int. Immunopharmacol. 2015, 28, 235–243. [Google Scholar] [CrossRef] [PubMed]
  12. Jiyan, S.; Jingjin, H.; Ziren, S.; Lian, Z.; Yao, Z.; Xiao, L.; Yu, L. T cell inhibition by pogostone from Pogostemon cablin (Blanco) Benth: In vitro and in vivo immunosuppressive analysis. Mol. Med. Rep. 2017, 16, 4511–4520. [Google Scholar]
  13. Zeynep, T.; Jing, X.; Jian, H.; Yu, L.; Hua, H.; Tao, Y. Cytotoxic lanostane triterpenoids from the fruiting bodies of Piptoporus betulinus. Phytochemistry 2017, 143, 98–103. [Google Scholar]
  14. Qun, W.; Wen, Y.L.; Yu, W. A immunosuppressive triterpenoid saponin from the stems of Epigynum griffithianum. Nat. Prod. Res. 2020, 34, 1389–1393. [Google Scholar]
  15. Renda, G.; Gökkaya, O.; Şöhretoğlu, D. Immunomodulatory properties of triterpenes. Phytochem. Rev. 2022, 21, 537–563. [Google Scholar] [CrossRef] [PubMed]
  16. Zhang, L.; Wei, W. Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony. Pharmacol. Ther. 2020, 207, 107452. [Google Scholar] [CrossRef] [PubMed]
  17. Chamani, S.; Moossavi, M.; Naghizadeh, A.; Abbasifard, M.; Majeed, M.; Johnston, T.P.; Sahebkar, A. Immunomodulatory effects of curcumin in systemic autoimmune diseases. Phytother. Res. 2022, 36, 1616–1632. [Google Scholar] [CrossRef] [PubMed]
  18. Jiang, H.; Li, J.; Wang, L.; Wang, S.; Nie, X.; Chen, Y.; He, Y. Total glucosides of paeony: A review of its phytochemistry, role in autoimmune diseases, and mechanisms of action. J. Ethnopharmacol. 2020, 258, 112913. [Google Scholar] [CrossRef] [PubMed]
  19. Yeung, C.H.C.; Yeung, S.L.A.; Schooling, C.M. Association of autoimmune diseases with Alzheimer’s disease: A mendelian randomization study. J. Psychiatr. Res. 2022, 155, 550–558. [Google Scholar] [CrossRef]
  20. Kahaly, G.J.; Frommer, L.; Schuppan, D. Celiac disease and endocrine autoimmunity-the genetic link. Autoimmun. Rev. 2018, 17, 1169–1175. [Google Scholar] [CrossRef]
  21. Craft, J.E. Follicular helper T cells in immunity and systemic autoimmunity. Nat. Rev. Rheumatol. 2012, 8, 337–347. [Google Scholar] [CrossRef]
  22. Wang, L.; Wang, F.S.; Gershwin, M.E. Human autoimmune diseases: A comprehensive update. J. Intern. Med. 2015, 278, 369–395. [Google Scholar] [CrossRef]
  23. Huang, M.; Xu, H. Genetic susceptibility to autoimmunity-Current status and challenges. Adv. Immunol. 2022, 156, 25–54. [Google Scholar]
  24. Abdel-Wahab, N.; Shah, M.; Lopez-Olivo, M.A.; Suarez-Almazor, M.E. Use of Immune Checkpoint Inhibitors in the Treatment of Patients with Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann. Intern. Med. 2018, 168, 121–130. [Google Scholar] [CrossRef]
  25. Grigore, A. Plant Phenolic Compounds as Immunomodulatory Agents; IntechOpen: London, UK, 2017. [Google Scholar]
  26. Yu, C.; Gershwin, M.E.; Chang, C. Diagnostic criteria for systemic lupus erythematosus: A critical review. J. Autoimmun. 2014, 48, 10–13. [Google Scholar] [CrossRef] [PubMed]
  27. Tetali, S.D. Terpenes and isoprenoids: A wealth of compounds for global use. Planta 2019, 249, 1–8. [Google Scholar] [CrossRef] [PubMed]
  28. Reinhardt, J.K.; Klemd, A.M.; Danton, O.; De Mieri, M.; Smieško, M.; Huber, R.; Bürgi, T.; Gründemann, C.; Hamburger, M. Sesquiterpene Lactones from Artemisia argyi: Absolute Configuration and Immunosuppressant Activity. J. Nat. Prod. 2019, 82, 1424–1433. [Google Scholar] [CrossRef]
  29. Wang, M.; Du, J.X.; Huang, Y.; Dai, Q.; Liu, Y.P.; He, J.; Liu, J.K. Irpex lacteusSesquiterpenoids from Cultures of the Basidiomycetes. J. Nat. Prod. 2020, 83, 1524–1531. [Google Scholar] [CrossRef] [PubMed]
  30. Duan, X.; Tan, X.; Gu, L.; Liu, J.; Hao, X.; Tao, L.; Zhang, Y. New secondary metabolites with immunosuppressive activity from the phytopathogenic fungus Bipolaris maydis. Bioorganic Chem. 2020, 99, 103816. [Google Scholar] [CrossRef]
  31. Jiang, Y.; Cui, C.; Chen, C.; Wang, N.; Liao, H.; Li, Q.; Zhang, Y. Two Pairs of New Bisabolane-Type Sesquiterpenoids from Aspergillus sydowii. Chem. Biodivers. 2023, 20, e202301047. [Google Scholar] [CrossRef]
  32. Zhou, M.; Duan, F.; Gao, Y.; Peng, X.; Meng, X.; Ruan, H. Eremophilane sesquiterpenoids from the whole plant of Parasenecio albus with immunosuppressive activity. Bioorganic Chem. 2021, 115, 105247. [Google Scholar] [CrossRef] [PubMed]
  33. Huang, S.S.; Yang, H.X.; He, J.; Yan, B.C.; Feng, T.; Liu, J.K. Steccherins A-D, chamigrane-type sesquiterpenes from the fungus Steccherinum ochraceum with selective inhibition on B lymphocyte proliferation. Phytochemistry 2023, 214, 113830. [Google Scholar] [CrossRef] [PubMed]
  34. Yuan, P.; Wang, X.; Jin, B.; Yang, Y.; Chen, K.; Jia, Q.; Li, Y. Sesquiterpenes with immunosuppressive effect from the stems of Solanum torvum. Phytochem. Lett. 2016, 17, 126–130. [Google Scholar] [CrossRef]
  35. Dai, Q.; Zhang, F.L.; Li, Z.H.; He, J.; Feng, T. Immunosuppressive Sesquiterpenoids from the Edible Mushroom Craterellus odoratus. J. Fungi 2021, 7, 1052. [Google Scholar] [CrossRef] [PubMed]
  36. Cui, W.X.; Yang, M.; Li, H.; Li, S.W.; Yao, L.G.; Li, G.; Tang, W.; Wang, C.H.; Liang, L.F.; Guo, Y.W. Polycyclic furanobutenolide-derived norditerpenoids from the South China Sea soft corals Sinularia scabra and Sinularia polydactyla with immunosuppressive activity. Bioorganic Chem. 2020, 94, 103350. [Google Scholar] [CrossRef]
  37. Junfen, Z.; Yongbo, X.; Penghua, S.; Huiqin, Q.; Rongjian, S.; Ming, X.; Yonghui, Z. Diterpenoids with Immunosuppressive Activities from Cinnamomum cassia. J. Nat. Prod. 2014, 77, 1948–1954. [Google Scholar]
  38. Ghanadian, S.M.; Ayatollahi, A.M.; Mesaik, M.A.; Abdalla, O.M. New immunosuppressive cyclomyrsinol diterpenes from Euphorbia kopetdaghi Prokh. Nat. Prod. Res. 2013, 27, 246–254. [Google Scholar] [CrossRef] [PubMed]
  39. Chen, H.P.; Li, J.; Zhao, Z.Z.; Li, X.; Liu, S.L.; Wang, Q.Y.; Liu, J.K. Diterpenes with bicyclo[2.2.2]octane moieties from the fungicolous fungus Xylaria longipes HFG1018. Org. Biomol. Chem. 2020, 18, 2410–2415. [Google Scholar] [CrossRef]
  40. Gobu, F.R.; Chen, J.J.; Zeng, J.; Wei, W.J.; Wang, W.F.; Lin, C.J.; Gao, K. Isolation, Structure Elucidition, and Immunosuppressive Activity of Diterpenoids from Ligularia fischeri. J. Nat. Prod. 2017, 80, 2263–2268. [Google Scholar] [CrossRef]
  41. Ren, Y.; Tong, X.; Zhao, Y.; He, S.J.; Fan, Y.Y.; Yue, J.M. Dolabrane-Type Diterpenoids with Immunosuppressive Activity from Koilodepas hainanense. J. Nat. Prod. 2022, 85, 1581–1590. [Google Scholar] [CrossRef]
  42. Chen, H.P.; Zhaso, Z.Z.; Cheng, G.G.; Zhao, K.; Han, K.Y.; Zhou, L.; Liu, J.K. Immunosuppressive Nor-isopimarane Diterpenes from Cultures of the Fungicolous Fungus HFG1018. J. Nat. Prod. 2020, 83, 401–412. [Google Scholar] [CrossRef] [PubMed]
  43. Ye, K.; Lv, X.; Zhang, X.; Wei, P.P.; Li, Z.H.; Ai, H.L.; Liu, J.K. Immunosuppressive Isopimarane Diterpenes from Cultures of the Endophytic Fungus. Front. Pharmacol. 2021, 12, 766441. [Google Scholar] [CrossRef] [PubMed]
  44. Li, X.R.; Hu, K.; Yan, B.C.; Li, X.N.; Sun, H.D.; Liu, Y.; Puno, P.T. Scopariusicides D-M, ent-clerodane-based isomeric meroditerpenoids with a cyclobutane-fused γ/δ-lactone core from Isodon scoparius. Bioorganic Chem. 2022, 127, 105973. [Google Scholar] [CrossRef] [PubMed]
  45. Zhou, M.; Zhang, H.B.; Wang, W.G.; Gong, N.B.; Zhan, R.; Li, X.N.; Sun, H.D. Scopariusic acid, a new meroditerpenoid with a unique cyclobutane ring isolated from Isodon scoparius. Org. Lett. 2013, 15, 4446–4449. [Google Scholar] [CrossRef] [PubMed]
  46. Ge, Z.P.; Xu, J.B.; Zhao, P.; Zhou, Y.; Zuo, J.P.; Zhao, J.X.; Yue, J.M. Highly Oxygenated Cephalotane-Type Diterpenoids from Cephalotaxus fortunei var. alpina and C. sinensis. ChemRxiv 2023. [Google Scholar]
  47. Yang, M.; Li, H.; Zhang, Q.; Wu, Q.H.; Li, G.; Chen, K.X.; Li, X.W. Highly diverse cembranoids from the South China Sea soft coral Sinularia scabra as a new class of potential immunosuppressive agents. Bioorg. Med. Chem. 2019, 27, 3469–3476. [Google Scholar] [CrossRef]
  48. Yang, M.; Li, X.L.; Wang, J.R.; Lei, X.; Tang, W.; Li, X.W.; Guo, Y.W. Sarcomililate A, an Unusual Diterpenoid with Tricyclo [11.3.0.0] hexadecane Carbon Skeleton, and Its Potential Biogenetic Precursors from the Hainan Soft Coral Sarcophyton mililatensis. J. Org. Chem. 2019, 84, 2568–2576. [Google Scholar] [CrossRef]
  49. Gu, W.; Huang, M.; Zhang, Y. A new limonoid with immunosuppressive activity from Munronia pinnata. Phytochem. Lett. 2023, 57, 106–109. [Google Scholar] [CrossRef]
  50. Yan, S.; Feng, H.; Sun, L.; Shi, Z.; Hu, H.; Duan, Y.; Zhang, Y. Discovery of immunosuppressive Lupane-type Triterpenoids from Hypericum longistylum. Nat. Prod. Res. 2022, 36, 4394–4400. [Google Scholar] [CrossRef]
  51. Yang, Y.; Liu, L.; Tang, Z.; Chen, M.; Jia, J.; Wang, A. Research progress on the triterpenoids from the genus Schisandra and their biological activities. Asian J. Tradit. Med. 2022, 17, 116–136. [Google Scholar]
  52. Zhao, J.Y.; Mu, L.H.; Dong, X.Z.; Hu, Y.; Liu, P. One new cycloartane triterpene glycoside from Beesia calthaefolia. Nat. Prod. Res. 2016, 30, 316–321. [Google Scholar] [CrossRef] [PubMed]
  53. Kim, N.; Cho, K.W.; Hong, S.S.; Hwang, B.Y.; Chun, T.; Lee, D. Antiproliferative glabretal-type triterpenoids from the root bark of Dictamnus dasycarpus. Bioorg. Med. Chem. Lett. 2015, 25, 621–625. [Google Scholar] [CrossRef]
  54. Song, J.; Zhou, M.; Zhou, J.; Liang, J.J.; Peng, X.G.; Liu, J.; Ruan, H.L. Schincalactones A and B, Two 5/5/6/11/3 Fused Schinortriterpenoids with a 13-Membered Carbon Ring System from Schisandra incarnata. Org. Lett. 2018, 20, 2499–2502. [Google Scholar] [CrossRef] [PubMed]
  55. Fan, Y.Y.; Zhang, H.; Zhou, Y.; Liu, H.B.; Tang, W.; Zhou, B.; Yue, J.M. Phainanoids A–F, a new class of potent immunosuppressive triterpenoids with an unprecedented carbon skeleton from Phyllanthus hainanensis. J. Am. Chem. Soc. 2015, 137, 138–141. [Google Scholar] [CrossRef] [PubMed]
  56. Chang, J.L.; Gan, Y.T.; Peng, X.G.; Ouyang, Q.X.; Pei, J.; Ruan, H.L. Peniandranoids A–E: Meroterpenoids with Antiviral and Immunosuppressive Activity from a Penicillium sp. J. Nat. Prod. 2023, 86, 66–75. [Google Scholar] [CrossRef]
  57. Guo, K.; Liu, Y.C.; Liu, Y.; Zhang, H.; Li, W.Y.; Shi, Q.M.; Li, S.H. Immunosuppressive gentianellane-type sesterterpenoids from the traditional Uighur medicine Gentianella turkestanorum. Phytochemistry 2021, 187, 112780. [Google Scholar] [CrossRef]
  58. Jing, S.; Fu, R.; Li, C.; Zhou, T.; Liu, Y.; Liu, Y.; Luo, S.; Li, X.; Zeng, F.; Li, S. Immunosuppresive Sesterterpenoids and Norsesterterpenoids from Colquhounia coccinea var. mollis. J. Org. Chem. 2021, 86, 11169–11176. [Google Scholar] [CrossRef]
  59. Szabó, T.; Volk, B.; Milen, M. Recent Advances in the Synthesis of β-Carboline Alkaloids. Molecules 2021, 26, 663. [Google Scholar] [CrossRef]
  60. Wang, Y.; Yan, J.; Zhang, Z.; Chen, M.; Wu, X.; Ma, S. Immunosuppressive Sesquiterpene Pyridine Alkaloids from Tripterygium wilfordii Hook. f. Molecules 2022, 27, 7274. [Google Scholar] [CrossRef]
  61. Wang, X.F.; Zhu, Z.; Hao, T.T.; Fang, Q.Q.; Jiang, K.; Qu, S.J.; Tan, C.H. Alopecines A–E, five chloro-containing matrine-type alkaloids with immunosuppressive activities from the seeds of Sophora alopecuroides. Bioorganic Chem. 2020, 99, 103812. [Google Scholar] [CrossRef]
  62. Wei, P.; Ji, J.; Ma, X.; Li, Z.; Ai, H.; Lei, X.; Liu, J. Three new pyrrole alkaloids from the endophytic fungus Albifimbria viridis. Nat. Prod. Bioprospecting 2022, 12, 4–5. [Google Scholar] [CrossRef]
  63. Xu, Z.; Zhang, X.; Ma, J.; Yang, Y.; Zhou, J.; Xu, J. Secondary metabolites produced by mangrove endophytic fungus Aspergillus fumigatus HQD24 with immunosuppressive activity. Biochem. Syst. Ecol. 2020, 93, 104166. [Google Scholar] [CrossRef]
  64. Zeng, T.; Wu, X.Y.; Yang, S.X.; Lai, W.C.; Shi, S.D.; Zou, Q.; Li, L.M. Monoterpenoid Indole Alkaloids from Kopsia officinalis and the Immunosuppressive Activity of Rhazinilam. J. Nat. Prod. 2017, 80, 864–871. [Google Scholar] [CrossRef]
  65. Guo, K.; Liu, X.; Zhou, T.; Liu, Y.; Liu, Y.; Shi, Q.; Li, X.; Li, S. Gentianelloids A and B: Immunosuppressive 10,11-seco-gentianellane sesterterpenoids from the traditional Uighur medicine gentianella turkestanorum. J. Org. Chem. 2020, 85, 5511–5515. [Google Scholar] [CrossRef] [PubMed]
  66. Teng, L.; Mu, R.; Liu, Y.; Xiao, C.; Li, D.; Gao, J.; Guo, K.; Li, X.; Liu, Y.; Zeng, F.; et al. Immunosuppressive and adipogenesis inhibitory sesterterpenoids with a macrocyclic ether system from Eurysolen gracilis. Org. Lett. 2021, 23, 2232–2237. [Google Scholar] [CrossRef]
  67. Liu, Y.; Yu, H.Y.; Xu, H.Z.; Liu, J.J.; Meng, X.G.; Zhou, M.; Ruan, H.L. Alkaloids with Immunosuppressive Activity from the Bark of Pausinystalia yohimbe. J. Nat. Prod. 2018, 81, 1841–1849. [Google Scholar] [CrossRef]
  68. Wang, Z.; Yang, H.X.; Li, Z.H.; Feng, T.; Liu, J.K. Indole alkaloids from Ophiorrhiza cantoniensis with immunosuppressive activity. Fitoterapia 2021, 148, 104777. [Google Scholar]
  69. Shi, B.B.; Ai, H.L.; Duan, K.T.; Feng, T.; Liu, J.K. Ophiorrhines F and G, key biogenetic intermediates of ophiorrhine alkaloids from Ophiorrhiza japonica and their immunosuppressant activities. J. Nat. Prod. 2022, 85, 453–457. [Google Scholar] [CrossRef]
  70. Im, S.H.; Wang, Z.; Lim, S.S.; Lee, O.H.; Kang, I.J. Bioactivity-Guided Isolation and Identification of New and Immunosuppressive Monoterpenoid Indole Alkaloids from Tsiang. Molecules 2019, 24, 4574. [Google Scholar]
  71. Simsek, M.; Quezada-Calvillo, R.; Nichols, B.L.; Hamaker, B.R. Phenolic compounds increase the transcription of mouse intestinal maltase-glucoamylase and sucrase-isomaltase. Food Funct. 2017, 8, 1915–1924. [Google Scholar] [CrossRef]
  72. Zeng, J.; Xue, Y.; Lai, Y.; Yao, G.; Luo, Z.; Zhang, Y.; Zhang, J. A new phenolic glycoside from the barks of Cinnamomum cassia. Molecules 2014, 19, 17727–17734. [Google Scholar] [CrossRef] [PubMed]
  73. Pham, T.A.; Hu, X.L.; Huang, X.J.; Ma, M.X.; Feng, J.H.; Li, J.Y.; Wang, H. Phloroglucinols with Immunosuppressive Activities from the Fruits of Eucalyptus globulus. J. Nat. Prod. 2019, 82, 859–869. [Google Scholar] [CrossRef] [PubMed]
  74. Shi, Z.; Zhao, X.; Song, F.; Hou, Z.; Hao, X.; Guo, J.; Sun, L.; Feng, H.; Wu, M.; Xie, P.; et al. Prenyllongnols A–D, New Prenylated Acylphloroglucinols that Fight Concanavalin A-Induced Autoimmune Hepatitis. J. Agric. Food Chem. 2023, 71, 17801–17809. [Google Scholar] [CrossRef] [PubMed]
  75. Deng, M.; Tan, X.; Qiao, Y.; Sun, W.; Xie, S.; Shi, Z.; Lu, Y.; Chen, G.; Qi, C.; Zhang, Y. New secondary metabolites from the endophytic fungus Aspergillus sp. from Tripterygium wilfordii. Nat. Prod. Res. 2022, 36, 3544–3552. [Google Scholar] [CrossRef] [PubMed]
  76. Li, J.; Zhang, X.; Li, Y.; Liu, B.; Zhan, R. Bibenzyls and lignans from Dendrobium devonianum and their immunosuppressive activities. Phytochem. Lett. 2023, 54, 137–140. [Google Scholar] [CrossRef]
  77. Koko, W.S.; Mesaik, M.A.; Ranjitt, R.; Galal, M.; Choudhary, M.I. Immunosuppressive phenolic compounds from Hydnora abyssinica A. Braun. BMC Complement. Altern. Med. 2015, 15, 400. [Google Scholar] [CrossRef]
  78. Lin, S.; Zhang, X.; Shen, L.; Mo, S.; Liu, J.; Wang, J.; Zhang, Y. A new abietane-type diterpenoid and a new long-chain alkenone from fungus sp. TJ403-LS1. Nat. Prod. Res. 2022, 36, 531–538. [Google Scholar] [CrossRef] [PubMed]
  79. Duan, Y.; Bu, P.; Xie, S.; Guo, Y.; Shi, Z.; Qi, C.; Zhang, Y. (±)-hyperzewalsins A–D, four pairs of nor-monocyclic polyprenylated acylphloroglucinols with immunosuppressive activity from hypericum przewalskii maxim. Phytochemistry 2021, 187, 112779. [Google Scholar] [CrossRef] [PubMed]
  80. Zhang, Q.; Yang, B.; Li, F.; Liu, M.; Lin, S.; Wang, J.; Xue, Y.; Zhu, H.; Sun, W.; Hu, Z.; et al. Mycophenolic Acid Derivatives with Immunosuppressive Activity from the Coral-Derived Fungus Penicillium bialowiezense. Mar. Drugs 2018, 16, 230. [Google Scholar] [CrossRef]
  81. Guo, Y.; Cao, Y.; Qi, C.; Tong, Q.; Chen, C.; Yang, J.; Zhu, H.; Zhang, Y. Polycyclic polyprenylated acylphloroglucinols with immunosuppressive activity from Hypericum perforatum and absolute configurations assignment of previously reported analogues. Bioorganic Chem. 2021, 114, 105144. [Google Scholar] [CrossRef]
  82. Duan, Y.; Xie, S.; Guo, Y.; Qiao, Y.; Shi, Z.; Tao, L.; Deng, M.; Cao, Y.; Xue, Y.; Qi, C.; et al. Przewalcyrones A–F, epoxychromene-containing polycyclic polyprenylated acylphloroglucinols with immunosuppressive activity from Hypericum przewalskii Maxim. Org. Biomol. Chem. 2019, 17, 8234–8242. [Google Scholar] [CrossRef] [PubMed]
  83. Tao, B.; Li, Y.; Shi, Z.; Duan, Y.; Guo, Y.; Huang, X.; Li, J.; Zhang, Y.; Chen, M.; Song, F.; et al. Discovery of bioactive polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons from Hypericum wilsonii. Phytochemistry 2024, 218, 113953. [Google Scholar] [CrossRef] [PubMed]
  84. Kim, J.G.; Jang, H.; Le, T.P.L.; Hong, H.R.; Lee, M.K.; Hong, J.T.; Hwang, B.Y. Pyranoflavanones and Pyranochalcones from the Fruits of Amomum tsaoko. J. Nat. Prod. 2019, 82, 1886–1892. [Google Scholar] [CrossRef] [PubMed]
  85. Li, X.; Xuan, B.; Shou, Q.; Shen, Z. New flavonoids from Campylotropis hirtella with immunosuppressive activity. Fitoterapia 2014, 95, 220–228. [Google Scholar] [CrossRef] [PubMed]
  86. Ma, Q.; Tang, Y.; Sang, Z.; Dong, J.; Wei, R. Structurally diverse biflavonoids from the fruits of Citrus medica L. var. sarcodactylis Swingle and their hypolipidemic and immunosuppressive activities. Bioorganic Chem. 2021, 117, 105450. [Google Scholar] [CrossRef] [PubMed]
  87. Ma, Q.; Wei, R.; Shang, D.; Sang, Z.; Dong, J. Structurally diverse flavonolignans with immunosuppressive and neuroprotective activities from the fruits of Hippophae rhamnoides L. J. Agric. Food Chem. 2020, 68, 6564–6575. [Google Scholar] [CrossRef] [PubMed]
  88. Wei, M.; Li, X.; Liao, H.; Liu, L.; Li, Q.; Sun, W.; Chen, C.; Zhu, H.; Zhang, Y. Quadristerols A–G: Seven undescribed ergosterols from Aspergillus quadrilineata. Phytochemistry 2023, 213, 113785. [Google Scholar] [CrossRef] [PubMed]
  89. Zhang, Z.; Ding, M.; Tao, L.; Zhang, M.; Xu, X.; Zhang, C. Immunosuppressive C21 steroidal glycosides from the root of Cynanchum atratum. Fitoterapia 2015, 105, 194–201. [Google Scholar] [CrossRef] [PubMed]
  90. Zheng, M.; Zhou, C.; Liao, H.; Li, Q.; Bao, A.; Chen, C.; He, F.; Wu, P.; Sun, W.; Zhu, H.; et al. Enantiomeric α-pyrone derivatives with immunosuppressive activity from Talaromyces adpressus. Phytochemistry 2024, 218, 113931. [Google Scholar] [CrossRef]
  91. Wan, Z.; Yao, Y.C.; Gao, F.; Cai, S.B.; Khan, A.; Zhao, T.R.; Cheng, G.G. A new immunosuppressive pregnane glycoside from aqueous fraction of Epigynum cochinchinensis. Nat. Prod. Res. 2017, 31, 2893–2899. [Google Scholar] [CrossRef]
  92. Song, X.; Zhang, X.; Han, Q.; Li, X.; Li, G.; Li, R.; Jiao, Y.; Zhou, J.; Lou, H. Xanthone derivatives from Aspergillus sydowii, an endophytic fungus from the liverwort Scapania ciliata S. Lac and their immunosuppressive activities. Phytochem. Lett. 2013, 6, 318–321. [Google Scholar] [CrossRef]
  93. Wei, C.; Sun, C.; Feng, Z.; Zhang, X.; Xu, J. Four New Chromones from the Endophytic Fungus Phomopsis asparagi DHS-48 Isolated from the Chinese Mangrove Plant Rhizophora mangle. Mar. Drugs 2021, 19, 348. [Google Scholar] [CrossRef] [PubMed]
  94. Liu, H.; Chen, S.; Liu, W.; Liu, Y.; Huang, X.; She, Z. Polyketides with Immunosuppressive Activities from Mangrove Endophytic Fungus Penicillium sp. ZJ-SY2. Mar. Drugs 2016, 14, 217. [Google Scholar] [CrossRef]
  95. Deng, M.; Chen, X.; Qiao, Y.; Shi, Z.; Wang, J.; Zhu, H.; Gu, L.; Qi, C.; Zhang, Y. Isolation, absolute configurations and bioactivities of pestaphilones A–I: Undescribed methylated side chain containing-azaphilones from Pestalotiopsis oxyanthi. Phytochemistry 2022, 194, 113045. [Google Scholar] [CrossRef] [PubMed]
  96. Gao, Y.; Duan, F.; Liu, L.; Peng, X.; Meng, X.; Ruan, H. Hypothemycin-Type Resorcylic Acid Lactones with Immunosuppressive Activities from a Podospora sp. J. Nat. Prod. 2021, 84, 483–494. [Google Scholar] [CrossRef]
  97. Wang, W.; Cheng, G.; Li, Z.; Ai, H.; He, J.; Li, J.; Feng, T.; Liu, J. Curtachalasins, immunosuppressive agents from the endophytic fungus Xylaria cf. curta. Org. Biomol. Chem. 2019, 17, 7985–7994. [Google Scholar] [CrossRef]
  98. Wang, Y.; Liu, Q.; Xue, J.; Zhou, Y.; Yu, H.; Yang, S.; Zhang, B.; Zuo, J.; Li, Y.; Yue, J. Ivorenolide B, an immunosuppressive 17-membered macrolide from khaya ivorensis: Structural Determination and Total Synthesis. Org. Lett. 2014, 16, 2062–2065. [Google Scholar] [CrossRef]
  99. Xu, J.; Zhang, X.; Huang, F.; Li, G.; Leadlay, P.F. Efophylins A and B, Two C2-Asymmetric Macrodiolide Immunosuppressants from Streptomyces malaysiensis. J. Nat. Prod. 2021, 84, 1579–1586. [Google Scholar] [CrossRef]
  100. Kanako, S.; Junnosuke, M.; Manabu, K.; Yasushi, K.; Hisashi, Y.; Yasuko, U. Genetic differences between type 1 diabetes with and without other autoimmune diseases. Diabetes/Metab. Res. Rev. 2018, 34, e3023. [Google Scholar]
  101. Bossini-Castillo, L.; López-Isac, E.; Martín, J. Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways. J. Autoimmun. 2015, 64, 53–65. [Google Scholar] [CrossRef]
  102. Zhao, C.N.; Xu, Z.; Wu, G.C.; Mao, Y.M.; Liu, L.N.; Dan, Y.L.; Pan, H.F. Emerging role of air pollution in autoimmune diseases. Autoimmun. Rev. 2019, 18, 607–614. [Google Scholar] [CrossRef] [PubMed]
  103. Lavery, A.M.; Collins, B.N.; Waldman, A.T.; Hart, C.N.; Bar-Or, A.; Marrie, R.A.; Banwell, B. The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk. Mult. Scler. 2019, 25, 515–522. [Google Scholar] [CrossRef] [PubMed]
  104. Kahaly, G.J.; Frommer, L. Autoimmune polyglandular diseases. Best Pract. Res. Clin. Endocrinol. Metab. 2019, 33, 101344. [Google Scholar] [CrossRef] [PubMed]
  105. Grant, C.R.; Liberal, R.; Mieli-Vergani, G.; Vergani, D.; Longhi, M.S. Regulatory T-cells in autoimmune diseases: Challenges, controversies and--yet--unanswered questions. Autoimmun. Rev. 2015, 14, 105–116. [Google Scholar] [CrossRef] [PubMed]
  106. Ventura, S.P.; e Silva, F.A.; Quental, M.V.; Mondal, D.; Freire, M.G.; Coutinho, J.A. Ionic-liquid-mediated extraction and separation processes for bioactive compounds: Past, present, and future trends. Chem. Rev. 2017, 117, 6984–7052. [Google Scholar] [CrossRef] [PubMed]
  107. Cools, K.; Terry, L.A. Comparative study between extraction techniques and column separation for the quantification of sinigrin and total isothiocyanates in mustard seed. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2012, 901, 115–118. [Google Scholar] [CrossRef]
  108. Ohno, H.; Miyoshi, S.; Araho, D.; Kanamoto, T.; Terakubo, S.; Nakashima, H.; Tsuda, T.; Sunaga, K.; Amano, S.; Ohkoshi, E.; et al. Efficient utilization of licorice root by alkaline extraction. In Vivo 2014, 28, 785–794. [Google Scholar]
  109. Fibigr, J.; Šatínský, D.; Solich, P. A UHPLC method for the rapid separation and quantification of anthocyanins in acai berry and dry blueberry extracts. J. Pharm. Biomed. Anal. 2017, 143, 204–213. [Google Scholar] [CrossRef]
Molecules 29 02359 g001
Figure 1. Structures of sesquiterpenoids 1–36.
Figure 1. Structures of sesquiterpenoids 1–36.
Molecules 29 02359 g001
Molecules 29 02359 g002
Figure 2. Structures of diterpenoids 37–74.
Figure 2. Structures of diterpenoids 37–74.
Molecules 29 02359 g002
Molecules 29 02359 g003
Figure 3. Structures of diterpenoids 75–115.
Figure 3. Structures of diterpenoids 75–115.
Molecules 29 02359 g003
Molecules 29 02359 g004
Figure 4. Structures of triterpenoids 116–136.
Figure 4. Structures of triterpenoids 116–136.
Molecules 29 02359 g004
Molecules 29 02359 g005
Figure 5. Structures of other terpenoids 137–149.
Figure 5. Structures of other terpenoids 137–149.
Molecules 29 02359 g005
Molecules 29 02359 g006
Figure 6. Structures of alkaloids 150–176.
Figure 6. Structures of alkaloids 150–176.
Molecules 29 02359 g006
Molecules 29 02359 g007
Figure 7. Structures of phenolic compounds 177–206.
Figure 7. Structures of phenolic compounds 177–206.
Molecules 29 02359 g007
Molecules 29 02359 g008
Figure 8. Structures of phenolic compounds 207–234.
Figure 8. Structures of phenolic compounds 207–234.
Molecules 29 02359 g008
Molecules 29 02359 g009
Figure 9. Structures of flavonoids 235–262.
Figure 9. Structures of flavonoids 235–262.
Molecules 29 02359 g009
Molecules 29 02359 g010
Figure 10. Structures of steroids 263–270.
Figure 10. Structures of steroids 263–270.
Molecules 29 02359 g010
Molecules 29 02359 g011
Figure 11. Structures of others 271–311.
Figure 11. Structures of others 271–311.
Molecules 29 02359 g011
Molecules 29 02359 g012
Figure 12. Structures of others 312–324.
Figure 12. Structures of others 312–324.
Molecules 29 02359 g012
Molecules 29 02359 g013
Figure 13. Immunosuppressive bioactive compounds sourced from natural products.
Figure 13. Immunosuppressive bioactive compounds sourced from natural products.
Molecules 29 02359 g013
Table 1. Establishment of models of the immunosuppressive efficacy in vitro.
Table 1. Establishment of models of the immunosuppressive efficacy in vitro.
NumberModelInducing Drugs
1human peripheral blood T-lymphocytesConA
2human mononuc-lear cell + stimulated RAW264.7 macrophage cellConA
3isolated peritoneal macrophagesLPS
4splenocytesConA/LPS
5RAW264.7 macrophage cellConA
6stimulated spleen cellsanti-CD3/anti-CD28
7T-cell proliferationphytohaemagglutinin
8BV-2 microgliaLPS
Table 2. Establishment of models of the immunosuppressive efficacy in vivo.
Table 2. Establishment of models of the immunosuppressive efficacy in vivo.
NumberModel Making DrugAnimalMode of Administration
1Mitogen and OVAICR miceimmunized subcutaneously in one hind limb of OVA and in saline soln
2CyclophosphamideC57BL/6 miceintraperitoneal injection
3CCl4Wistar ratsintraperitoneal injection
4XyleneBalb/c miceinjected xylene into the left ear of each mouse
5DTHBalb/c micesmearing DNCB on the shaved abdominal skin of the mice
6SRBCSwiss albino micethe mice were primed with SRBC
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Shao, F.; Shen, Q.; Yang, Z.; Yang, W.; Lu, Z.; Zheng, J.; Zhang, L.; Li, H. Research Progress of Natural Active Substances with Immunosuppressive Activity. Molecules 2024, 29, 2359. https://doi.org/10.3390/molecules29102359

AMA Style

Shao F, Shen Q, Yang Z, Yang W, Lu Z, Zheng J, Zhang L, Li H. Research Progress of Natural Active Substances with Immunosuppressive Activity. Molecules. 2024; 29(10):2359. https://doi.org/10.3390/molecules29102359

Chicago/Turabian Style

Shao, Fei, Qiying Shen, Zhengfei Yang, Wenqian Yang, Zixiang Lu, Jie Zheng, Liming Zhang, and Hangying Li. 2024. "Research Progress of Natural Active Substances with Immunosuppressive Activity" Molecules 29, no. 10: 2359. https://doi.org/10.3390/molecules29102359

APA Style

Shao, F., Shen, Q., Yang, Z., Yang, W., Lu, Z., Zheng, J., Zhang, L., & Li, H. (2024). Research Progress of Natural Active Substances with Immunosuppressive Activity. Molecules, 29(10), 2359. https://doi.org/10.3390/molecules29102359

Article Metrics

Back to TopTop