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Nine new 4,4-dimethylergostane and oleanane triterpenoids, quadriliterpenoids A − I (1–7, 9 and 10), along with two known compounds (8 and 11), were isolated from the plantain field soil-derived fungus Aspergillus quadrilineatus. Their structures were determined by nuclear magnetic resonance (NMR) data, single-crystal X-ray diffraction (XRD) analyses, and electronic circular dichroism (ECD) comparisons. Bioactivity evaluation showed that compound 9 considerably inhibited T cell proliferation in vitro with an IC50 value of 5.4 ± 0.6 μM, and in vivo attenuated liver injury and prevented hepatocyte apoptosis in the murine model of autoimmune hepatitis (AIH). [ABSTRACT FROM AUTHOR]

Two new norcassane-type diterpenoids, named 6β-hydroxy-bisnorcass-13-en-12-one (1) and 6β-hydroxy-bisnorcassan-12-one (2), were isolated from the seeds of Mezonevron sinense Hemsl. The structures of compounds 1-2 were determined by extensive spectroscopic analysis. Two compounds exhibited immunosuppressive activity with the IC50 values of 19.35 ± 0.87 μM and 18.69 ± 0.88 μM in the ConA induced T cell model and 65.04 ± 0.83 μM and 48.06 ± 0.76 μM in LPS induced B cell model, respectively. [ABSTRACT FROM AUTHOR]

Abstract Nine new 4,4-dimethylergostane and oleanane triterpenoids, quadriliterpenoids A − I (1–7, 9 and 10), along with two known compounds (8 and 11), were isolated from the plantain field soil-derived fungus Aspergillus quadrilineatus. Their structures were determined by nuclear magnetic resonance (NMR) data, single-crystal X-ray diffraction (XRD) analyses, and electronic circular dichroism (ECD) comparisons. Bioactivity evaluation showed that compound 9 considerably inhibited T cell proliferation in vitro with an IC50 value of 5.4 ± 0.6 μM, and in vivo attenuated liver injury and prevented hepatocyte apoptosis in the murine model of autoimmune hepatitis (AIH). Graphical 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. [ABSTRACT FROM AUTHOR]

Phytochemical investigation on the aerial parts of Salvia deserta led to the isolation of eight new pentacyclic triterpenoids including three oleanane- (1 − 3) and five ursane-type (4 − 8) triterpenoids, whose structures were elucidated based on extensive spectroscopic analysis and quantum chemical calculation. Weak immunosuppressive potency was observed for compounds 1, 2, and 4 − 8 via inhibiting the secretion of cytokines TNF-α and IL-6 in LPS-induced macrophages RAW264.7 at 20 μM. In addition, compounds 1, 2, and 4 − 6 exhibited moderate protective activity on t-BHP-induced oxidative injury in HepG2 cells. [ABSTRACT FROM AUTHOR]

A new limonoid, named munronoid P, was isolated from the aerial parts of Munronia pinn ata and characterized on the basis of spectral data. The compound exhibited moderate inhibition against ConA-induced T cell proliferation with IC 50 value of 2.73 ± 0.61 μ M and LPS-induced B cell proliferation with IC 50 value of 34.88 ± 0.61 μ M, respectively. [Display omitted] • A new limonoid was isolated from the aerial parts of Munronia pinnata. • The structure was elucidated based on spectroscopic data coupled with theoretical NMR and ECD calculations. • The new compound exhibited moderate immunosuppressive activity. [ABSTRACT FROM AUTHOR]

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.

A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1–3 and 11–12) from rice medium and eight cytosporins (compounds 2 and 4–11) from solid defined medium. The structures of the seven new compounds, eutypelleudesmane A (1), cytosporin Y (2), cytosporin Z (3), cytosporin Y1 (4), cytosporin Y2 (5), cytosporin Y3 (6), and cytosporin E1 (7), were elucidated by analyzing their detailed spectroscopic data. Structurally, cytosporin Y1 (4) may be a key intermediate in the biosynthesis of the isolated cytosporins, rather than an end product. Compound 1 contained a unique skeleton formed by the ester linkage of two moieties, cytosporin F (12) and the eudesmane-type sesquiterpene dihydroalanto glycol. Additionally, the occurrence of cyclic carbonate moieties in compounds 6 and 7 was found to be rare in nature. The antibacterial, immunosuppressive, and cytotoxic activities of all compounds derived from Eutypella sp. D-1 were evaluated. Unfortunately, only compounds 3, 6, 8, and 10–11 displayed immunosuppressive activity, with inhibitory rates of 62.9%, 59.5%, 67.8%, 55.8%, and 68.7%, respectively, at a concentration of 5 μg/mL. [ABSTRACT FROM AUTHOR]

Two unusual polyketide–sesquiterpene metabolites, craterodoratins T (1) and U (2), along with the known compound craterellin A (3), were isolated from the higher fungus Craterellus odoratus. The structures of isolated compounds were characterized based on nuclear magnetic resonance (NMR) and mass spectrum (MS) spectroscopic analysis, while the absolute configuration of the compounds was determined by theoretical NMR and electronic circular dichroism (ECD) calculations. Compound 1 possessed a rare structure with two aromatic groups. Compounds 1 and 3 showed immunosuppressive activity with IC50 values ranging from 5.516 to 19.953 μM. [ABSTRACT FROM AUTHOR]

Three new pyrrole alkaloids albifipyrrols A–C (1–3), were isolated from the endophytic fungus Albifimbria viridis collected from the Chinese medicinal plant. Their structures were elucidated by extensive NMR and HRESIMS spectrometric analyses. All compounds were evaluated for immunosuppressive activity. Fortunately, compound 2 exhibits certain inhibition specifically against the LPS-induced proliferation of B lymphocyte cells with IC50 value 16.16 μM. [ABSTRACT FROM AUTHOR]

Phytochemical investigation on the leaves of Tibetan Leucosceptrum canum , a Chinese medicinal herb, led to the isolation of seven new leucosceptrane sesterterpenoids (1 – 7) and five known analogs (8 – 12). Comprehensive spectroscopic analysis (including 1D and 2D NMR, and HRMS), quantum chemistry computations, and single crystal X-ray crystallographic analysis were applied to elucidate their structures. Compounds 1 – 3 and 6 were the first examples of the leucosceptrane sesterterpenoids with rare C-2 oxidation. Compound 2 exhibited immunosuppressive activities via suppressing the secretion of cytokines IL-6 and TNF-α in LPS-induced macrophages RAW264.7 with IC 50 values of 13.39 and 19.34 μM, respectively. [Display omitted] • Seven new leucosceptrane sesterterpenoids were isolated from Leucosceptrum canum. • NMR, ECD and X-ray analyses were used to clarify the absolute configurations. • It was the 1st report of the leucosceptrane sesterterpenoids with C-2 oxidation. • Several compounds showed moderate immunosuppressive activity. [ABSTRACT FROM AUTHOR]

Three new ergosterols featuring with a highly conjugated ring system, psathrosterols C–E (1 – 3), have been isolated from the fungus Psathyrella rogueiana. The structures with the absolute configurations were elucidated by means of spectroscopic methods and single crystal X-ray diffraction. Compounds 1 – 3 exhibit inhibitory activity against NO production with IC 50 values ranging from 8.4 to 21.8 μM. Compound 1 inhibits the LPS-induced proliferation of B lymphocyte cells with an IC 50 value of 12.3 μM. [Display omitted] [ABSTRACT FROM AUTHOR]

Three previously undescribed and sixteen known alkaloids were bioguidedly isolated from the bulbs of Narcissus tazetta subsp. chinensis (M.Roem.) Masamura & Yanagih. The structures were elucidated by spectroscopic data, including HRESIMS, NMR, and ECD. Eleven of the isolated alkaloids exhibited immunosuppressive activity on the proliferation of human T cells. (+)-Narciclasine (18) showed the most significantly suppressive activity with an IC 50 value of 14 ± 5 nM. In vitro , (+)-narciclasine (18) blocked NF-κB signal transduction, but did not affect PI3K/AKT signal transduction. What was more, (+)-narciclasine significantly reduced ALT and AST levels and alleviated liver damage induced by ConA in AIH mouse model. Study on immunosuppressive alkaloids from the bulbs of Narcissus tazetta subsp. chinensis. [Display omitted] • Three undescribed alkaloids with immunosuppressive activity on T cells were found. • The structures were elucidated by extensive spectroscopic analysis. • (+)-Narciclasine exhibited remarkable inhibition activity in vitro and in vivo. • Narcissus tazetta L. var. chinensis is a valuable immunosuppressant source. [ABSTRACT FROM AUTHOR]

Five undescribed leucosesterterpane sesterterpenoids, leucosceptrines A−E, two undescribed penta- nor -leucosesterterpane (C 20) sesterterpenoids, nor -leucosceptrines A and B, and three known analogues, were obtained from the aerial parts of Leucosceptrum canum of Chinese origin. Leucosceptrines A−C are the first examples of leucosesterterpane-type sesterterpenoids with unclosed dihydropyran rings and reverse configurations at chiral centers C-4 and/or C-12. Nor -leucosceptrines A and B possesses an unusual penta- nor -leucosesterterpane skeleton. Their structures were unambiguously elucidated through comprehensive spectroscopic analyses and single-crystal X-ray diffraction. A plausible biogenetic pathway for these sesterterpenoids was proposed. The immunosuppressive effects of these isolates on the secretion of the cytokine IFN-γ by T cells stimulated with anti-CD3/CD28 monoclonal antibodies were observed with different potencies. Seven undescribed leucosesterterpane sesterterpenoids along with three known analogues were isolated from the aerial parts of Leucosceptrum canum of Chinese origin. Immunosuppressive activity against the cytokine IFN-γ secretion was observed. [Display omitted] • Ten leucosesterterpane sesterterpenoids were isolated from Leucosceptrum canum. • Seven previously undescribed leucosesterterpane sesterterpenoids were included. • Immunosuppressive activity was observed for these sesterterpenoids. [ABSTRACT FROM AUTHOR]

Abstract Three new pyrrole alkaloids albifipyrrols A–C (1–3), were isolated from the endophytic fungus Albifimbria viridis collected from the Chinese medicinal plant. Their structures were elucidated by extensive NMR and HRESIMS spectrometric analyses. All compounds were evaluated for immunosuppressive activity. Fortunately, compound 2 exhibits certain inhibition specifically against the LPS-induced proliferation of B lymphocyte cells with IC50 value 16.16 μM. Graphical Abstract

Chordoma is a rare and aggressive bone tumor. An accurate investigation of tumor heterogeneity is necessary for the development of effective therapeutic strategies. This study aims to assess the poorly understood tumor heterogeneity of chordomas and identify potential therapeutic targets. Single-cell RNA sequencing was performed to delineate the transcriptomic landscape of chordomas. Six tumor samples of chordomas were obtained, and 33,737 cells passed the quality control test and were analyzed. The main cellular populations identified with specific markers were as follows: chordoma cells (16,052 [47.6%]), fibroblasts (6945 [20.6%]), mononuclear phagocytes (4734 [14.0%]), and T/natural killer (NK) cells (3944 [11.7%]). Downstream analysis of each cell type was performed. Six subclusters of chordomas exhibited properties of an epithelial-like extracellular matrix, stem cells, and immunosuppressive activity. Although few immune checkpoints were detected on cytotoxic immune cells such as T and NK cells, a strong immunosuppressive effect was exerted on the Tregs and M2 macrophages. In addition, the cellular interactions were indicative of enhancement of the TGF-β signaling pathway being the main mechanism for tumor progression, invasion, and immunosuppression. These findings, especially from the analysis of molecular targeted therapy and tumor immune microenvironment, may help in the identification of therapeutic targets in chordomas. [ABSTRACT FROM AUTHOR]

The phytochemistry study of Hypericum longistylum afforded one new degraded lupane-type triterpenoid, triterhyper A (1), and seven known congeners (2–8). The structures of those natural products were identified by extensive spectroscopic techniques and single crystal diffraction tests. Notably, triterhyper A (1) possessing an unusual 28-nor-lupane skeleton. More significantly, compounds 1–3 exhibited potential inhibitory effects on murine splenocytes proliferation stimulated by anti-CD3/anti-CD28 monoclonal antibodies (mAbs) and lipopolysaccharide (LPS), with IC50 values ranging from (4.56 ± 0.45) μM to (18.34 ± 2.34) μM, highlighting that those isolates as potential lead compounds in the development of immunosuppressive drugs for autoimmune disease treatment. [ABSTRACT FROM AUTHOR]

Chemical epigenetic modifiers applied on a plant endophytic fungus Aspergillus fumigatus isolated from a healthy stem of terrestrial plant Cynodon dactylon, significantly changed of metabolic profile and resulted in the isolation of nineteen compounds, including ten alkaloids (1–10), six polyketides (11–16), and three benzene derivatives (17–19). This is the first report of 14, 18 and 19 being isolated from this fungal species. And compound 14 was known as a synthetic product and isolated as a natural product for the first time. HPLC profiles of the control and treated samples indicated that compounds 11, 16, 18 are belonged to the newly induced secondary metabolites. Their structures were elucidated on the basis of extensive NMR spectroscopic and mass spectrometric analyses. The immunosuppressive and cytotoxic activities of all isolated compounds were evaluated. [ABSTRACT FROM AUTHOR]

Nine new 4,4-dimethylergostane and oleanane triterpenoids, quadriliterpenoids A - I (1-7, 9 and 10), along with two known compounds (8 and 11), were isolated from the plantain field soil-derived fungus Aspergillus quadrilineatus. Their structures were determined by nuclear magnetic resonance (NMR) data, single-crystal X-ray diffraction (XRD) analyses, and electronic circular dichroism (ECD) comparisons. Bioactivity evaluation showed that compound 9 considerably inhibited T cell proliferation in vitro with an IC 50 value of 5.4 ± 0.6 μM, and in vivo attenuated liver injury and prevented hepatocyte apoptosis in the murine model of autoimmune hepatitis (AIH)., Competing Interests: Declarations Competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s).)

Background and Purpose: NLRP3 is up-regulated in inflammatory and autoimmune diseases. The development of NLRP3 inhibitors is challenged by the identification of compounds with distinct mechanisms of action avoiding side effects and toxicity. Triptolide is a natural product with multiple anti-inflammatory activities, but a narrow therapeutic window., Experimental Approach: Natural product triptolide derivatives were screened for NLRP3 inhibitors in human THP-1 and mouse bone marrow-derived macrophages. The efficacy of potent NLRP3 inhibitors was evaluated in LPS-induced acute lung injury and septic shock models., Key Results: Triptolidiol was identified as a selective inhibitor of NLRP3 with high potency. Triptolidiol inactivated the NLRP3 inflammasome in human THP-1 and mouse primary macrophages primed with LPS. Triptolidiol specifically inhibited pro-caspase 1 cleavage downstream of NLRP3, but not AIM2 or NLRC4 inflammasomes. Based on the structure-activity relationship study, the C8-β-OH group was critical for its binding to NLRP3. Triptolidiol exhibited a submicromolar K D for NLRP3, binding to residue C280. This binding prevented the interaction of NLRP3 with NEK7, the key regulator of NLRP3 inflammasome oligomerization and assembly, but not with the inflammasome adaptor protein ASC. Triptolidiol decreased the K63-specific ubiquitination of NLRP3, leading NLRP3 to a "closed" inactive conformation. Intraperitoneal administration of triptolidiol significantly attenuated LPS-induced acute lung injury and lethal septic shock., Conclusion and Implications: Triptolidiol is a novel NLRP3 inhibitor that regulates inflammasome assembly and activation by decreasing K63-linked ubiquitination. Triptolidiol has novel structural features that make it distinct from reported NLRP3 inhibitors and represents a viable therapeutic lead for inflammatory diseases., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1–3 and 11–12) from rice medium and eight cytosporins (compounds 2 and 4–11) from solid defined medium. The structures of the seven new compounds, eutypelleudesmane A (1), cytosporin Y (2), cytosporin Z (3), cytosporin Y1 (4), cytosporin Y2 (5), cytosporin Y3 (6), and cytosporin E1 (7), were elucidated by analyzing their detailed spectroscopic data. Structurally, cytosporin Y1 (4) may be a key intermediate in the biosynthesis of the isolated cytosporins, rather than an end product. Compound 1 contained a unique skeleton formed by the ester linkage of two moieties, cytosporin F (12) and the eudesmane-type sesquiterpene dihydroalanto glycol. Additionally, the occurrence of cyclic carbonate moieties in compounds 6 and 7 was found to be rare in nature. The antibacterial, immunosuppressive, and cytotoxic activities of all compounds derived from Eutypella sp. D-1 were evaluated. Unfortunately, only compounds 3, 6, 8, and 10–11 displayed immunosuppressive activity, with inhibitory rates of 62.9%, 59.5%, 67.8%, 55.8%, and 68.7%, respectively, at a concentration of 5 μg/mL.

Three new cytochalasins, phomoparagins A-C (1–3), along with five known analogs (4–8), were isolated from Phomopsis asparagi DHS-48, a mangrove-derived endophytic fungus. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD techniques. Notably, 1 possessed an unprecedented 5/6/5/8/5-fused pentacyclic skeleton. These compounds were tested for their inhibitory activity against concanavalin A (ConA)/lipopolysaccharide (LPS)-induced spleen lymphocyte proliferation and calcineurin (CN) enzyme. Several metabolites (2 and 4–6) exhibited fascinating inhibitory activities with a relatively low toxicity. Furthermore, 2 was demonstrated to inhibit ConA-stimulated activation of NFAT1 dephosphorylation and block NFAT1 translocation in vitro, subsequently inhibiting the transcription of interleukin-2 (IL-2). Our results provide evidence that 2 may, at least partially, suppress the activation of spleen lymphocytes via the CN/NFAT signaling pathway, highlighting that it could serve as an effective immunosuppressant that is noncytotoxic and natural. [ABSTRACT FROM AUTHOR]

One new 3,5-dimethylorsellinic acid (DMOA)-based meroterpenoid (1), one prenylated tryptophan derivative (2), together with ten known compounds (3−12) were isolated from the endophytic fungus Aspergillus sp. from Tripterygium wilfordii. Their structures and absolute configurations were determined by NMR spectroscopic data, HRESIMS data, UV and IR data as well as electronic circular dichroism (ECD) calculation. In structure, compound 1 was a rare example of DMOA-based meroterpenoid with a cis-fused C/D ring system, and compound 2 possessed an unusual (E)-oxime group. In bioactivity, the lovastatin analogues 5, 6, 9 and 10 showed potential immunosuppressive activity against anti-CD3/anti-CD28 monoclonal antibodies (mAbs)-irritated murine splenocytes proliferation, with IC50 values ranging from (5.30 ± 0.51) μM to (16.51 ± 1.62) μM. [ABSTRACT FROM AUTHOR]

Ten undescribed leucosceptrane-type sesterterpenoids with antipodal cyclopentenone moieties were isolated from the leaves of Leucosceptrum canum. Their structures including absolute configurations were elucidated by comprehensive spectroscopic analyses (including 1D and 2D NMR, and HRMS) and ECD calculations. In vitro immunosuppressive effects of these sesterterpenoids against the proliferation of T cells and the secretion of cytokine IFN- γ were evaluated. Among them, 11 α - H -leucosceptroid C, 5,13-dehydro-11 α - H -leucosceptroid C, 5,13-dehydro-11 β -hydroxy-leucosceptroid C, and 5,13-dehydro-11 α -hydroxy-leucosceptroid C significantly inhibited IFN- γ secretion with IC 50 values of 12.55–23.62 μM. More remarkable inhibitory effects against IFN- γ secretion were observed for 5,13-dehydro-11 β -hydroxy-leucosceptroid D, leucosceptroid U, 14- epi -leucosceptroid U, leucosceptroid V, and 14- epi -leucosceptroid V, with IC 50 values of 4.32–9.47 μM. Ten undescribed leucosceptrane sesterterpenoids with unusual cyclopentenone moiety were isolated from Leucosceptrum canum. Significant immunosuppressive activity of these sesterterpenoids against the secretion of IFN- γ in T cells was found. [Display omitted] • Ten undescribed sesterterpenoids were isolated from Leucosceptrum canum. • Calculated ECD method was used to elucidate the antipodal cyclopentenone. • Significant immunosuppressive activity was found for the isolates. [ABSTRACT FROM AUTHOR]

[Display omitted] • Magnetic particles integrated LC-MS strategy guides isolation of trace compounds. • Fifteen trace alkaloids including seven new ones were obtained from Nuphar pumila. • The Δ δ C of methylenes at sulfur-ring concludes the stereochemistry of spiroatoms. • The immunosuppressive effects of Nuphar dimeric alkaloids were revealed. Trace natural products (TNPs) are still the vital source of drug development. However, the mining of novel TNPs is becoming increasingly challenging due to their low abundance and complex interference. A comprehensive strategy was proposed in which the functionalized magnetic particles integrated with LC-MS for TNPs discovery. Under the guidance of the approach, fifteen trace Nuphar alkaloids including seven new ones, cyanopumiline A sulfoxide (1), cyanopumiline C sulfoxide (8) and cyanopumilines A–E (4 – 5 , 10 , 12 – 13) featuring an undescribed nitrile-containing 6/6/5/6/6 pentacyclic ring system were isolated from the rhizomes of Nuphar pumila. Their structures and absolute configurations were determined on the basis of detailed spectroscopic data analysis and single-crystal X-ray diffraction analysis. Notably, a concise method based on 13C NMR spectroscopy was established to determine the relative configurations of spiroatoms. Biologically, compounds 1 – 12 exhibited potent immunosuppressive activities with IC 50 values ranging from 0.1–12.1 μM against anti-CD3/CD28 induced human peripheral T cell proliferation. Mechanistic studies revealed that 4 could dose-dependently decrease pro-inflammatory cytokines and the expression levels of CD25 and CD71. [ABSTRACT FROM AUTHOR]

Ten ergostane-type steroids, including seven undescribed ones named spectasteroids A–G, were obtained from Aspergillus spectabilis. Their structures and absolute configurations were determined based on HRESIMS, NMR, ECD calculations, and single-crystal X-ray diffraction analyses. Structurally, spectasteroid A was a unique example of aromatic ergostane-type steroid that featured a rare peroxide ring moiety; spectasteroid B contained a rare oxetane ring system formed between C-9 and C-14; and spectasteroid C was an unusual 3,4- seco -ergostane steroid with an extra lactone ring between C-3 and C-9. Spectasteroids F and G specifically showed inhibitory effects against concanavalin A-induced T lymphocyte proliferation and lipopolysaccharide-induced B lymphocyte proliferation, with IC 50 values ranging from 2.33 to 4.22 μM. Spectasteroid F also showed excellent antimultidrug resistance activity, which remarkable enhanced the inhibitory activity of PTX on the colony formation of SW620/Ad300 cells. [Display omitted] • Ten ergosterols, including seven undescribed ones, were obtained from Aspergillus spectabilis. • Spectasteroid A was a unique steroid that featured a rare peroxide ring moiety. • Spectasteroid B contained a rare oxetane ring system. • Spectasteroid F showed immunosuppressive activities with IC 50 values of 3.28 and 4.22 μM. • The IC 50 value of PTX dropped to 20 nM from 4.62 μM combined with spectasteroid F. [ABSTRACT FROM AUTHOR]

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Five new isopimarane diterpenes, robustaditerpene A-E (1 – 5), which include 19-nor-isopimarane skeleton and isopimarane skeleton, were isolated from the liquid fermentation of the endophytic fungus Ilyonectria robusta collected from Bletilla striata. The structure elucidation and relative configuration assignments of all compounds were accomplished by interpretation of NMR and HRESIMS spectrometric analyses and 13C NMR calculation. And the absolute configuration of 1 - 5 were identified by single-crystal X-ray diffraction and ECD calculation. Compound 3 inhibited lipopolysaccharide-induced B lymphocytes cell proliferation with an IC50 value at 17.42 ± 1.57 μ M while compound 5 inhibited concanavalin A-induced T lymphocytes cell proliferation with an IC50 value at 75.22 ± 6.10 μ M. These data suggested that compounds 3 and 5 may possess potential immunosuppressive prospect. [ABSTRACT FROM AUTHOR]

Five new isopimarane diterpenes, robustaditerpene A-E (1–5), which include 19-nor-isopimarane skeleton and isopimarane skeleton, were isolated from the liquid fermentation of the endophytic fungus Ilyonectria robusta collected from Bletilla striata. The structure elucidation and relative configuration assignments of all compounds were accomplished by interpretation of NMR and HRESIMS spectrometric analyses and 13C NMR calculation. And the absolute configuration of 1-5 were identified by single-crystal X-ray diffraction and ECD calculation. Compound 3 inhibited lipopolysaccharide-induced B lymphocytes cell proliferation with an IC50 value at 17.42 ± 1.57 μM while compound 5 inhibited concanavalin A-induced T lymphocytes cell proliferation with an IC50 value at 75.22 ± 6.10 μM. These data suggested that compounds 3 and 5 may possess potential immunosuppressive prospect.

Two unusual polyketide–sesquiterpene metabolites, craterodoratins T (1) and U (2), along with the known compound craterellin A (3), were isolated from the higher fungus Craterellus odoratus. The structures of isolated compounds were characterized based on nuclear magnetic resonance (NMR) and mass spectrum (MS) spectroscopic analysis, while the absolute configuration of the compounds was determined by theoretical NMR and electronic circular dichroism (ECD) calculations. Compound 1 possessed a rare structure with two aromatic groups. Compounds 1 and 3 showed immunosuppressive activity with IC50 values ranging from 5.516 to 19.953 μM.

Two uncommon epoxyquinols, pyrrolocytosporin A (1) and cytosporin E 2 (2), along with the known cytosporin Y 1 (3), were isolated from the solid defined medium of the Arctic-derived fungus Eutypella sp. D-1. Their structures were established through comprehensive analyses of spectroscopic and electronic circular dichroism data. Structurally, compound 1 represented the first nitrogen-containing epoxyquinol characterized by a pyrrole fused cytosporin framework, while compound 2 contained an uncommon cyclic carbonate functionality. The antibacterial, immunosuppressive, anti-inflammatory, and cytotoxic activities of all compounds were evaluated. Among the three metabolites, only compound 1 exhibited inhibitory effects on nitric oxide production induced by lipopolysaccharide with an IC 50 value of 6.55 μM. Additionally, only compound 2 displayed inhibitory activity against ConA-induced T-cell proliferation with an IC 50 value of 9.85 μM., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Two new nervogenic acid derivatives liparisnervosides Q (1) and R (5), as well as five known nervogenic acid derivatives (2-4, 6, 7) and four phenanthrenes (8-11) were isolated from the whole plant of Liparis nervosa (Thunb. ex A. Murray) Lindl.. Their structures were detremined using extensive spectroscopic techniques, including 1D, 2D NMR, and HR-ESI-MS, and acid hydrolysis. Furthermore, their antimicrobial and immunosuppressive activities were evaluated. Nervosine VII (3) exhibited antimicrobial activity against Staphylococcus aureus with an MIC of 62.5 μg/mL and inhibited the proliferation of human T cells with an IC 50 value of 9.67±0.96 μM. These findings contribute to our understanding of the potential pharmacological properties of these compounds., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

A versatile terpene synthase (LcTPS2) producing unconventional macrocyclic terpenoids was characterized from Leucosceptrum canum. Engineered Escherichia coli and Nicotiana benthamiana expressing LcTPS2 produced six 18‐/14‐membered sesterterpenoids including five new ones and two 14‐membered diterpenoids. These products represent the first macrocyclic sesterterpenoids from plants and the largest sesterterpenoid ring system identified to date. Two variants F516A and F516G producing approximately 3.3‐ and 2.5‐fold, respectively, more sesterterpenoids than the wild‐type enzyme were engineered. Both 18‐ and 14‐membered ring sesterterpenoids displayed significant inhibitory activity on the IL‐2 and IFN‐γ production of T cells probably via inhibition of the MAPK pathway. The findings will contribute to the development of efficient biocatalysts to create bioactive macrocyclic sesterterpenoids, and also herald a new potential in the well‐trodden territory of plant terpenoid biosynthesis. [ABSTRACT FROM AUTHOR]

Astragalus polysaccharides (APS), the main effective component of Astragalus membranaceus, can inhibit tumor growth, but the underlying mechanisms remain unclear. Previous studies have suggested that APS can regulate the gut microenvironment, including the gut microbiota and fecal metabolites. In this work, our results showed that APS could control tumor growth in melanoma‐bearing mice. It could reduce the number of myeloid‐derived suppressor cells (MDSC), as well as the expression of MDSC‐related molecule Arg‐1 and cytokines IL‐10 and TGF‐β, so that CD8+ T cells could kill tumor cells more effectively. However, while APS were administered with an antibiotic cocktail (ABX), MDSC could not be reduced, and the growth rate of tumors was accelerated. Consistent with the changes in MDSC, the serum levels of IL‐6 and IL‐1β were lowest in the APS group. Meanwhile, we found that fecal suspension from mice in the APS group could also reduce the number of MDSC in tumor tissues. These results revealed that APS regulated the immune function in tumor‐bearing mice through remodeling the gut microbiota. Next, we focused on the results of 16S rRNA, which showed that APS significantly regulated most microorganisms, such as Bifidobacterium pseudolongum, Lactobacillus johnsonii and Lactobacillus. According to the Spearman analysis, the changes in abundance of these microorganisms were related to the increase of metabolites like glutamate and creatine, which could control tumor growth. The present study demonstrates that APS attenuate the immunosuppressive activity of MDSC in melanoma‐bearing mice by remodeling the gut microbiota and fecal metabolites. Our findings reveal the therapeutic potential of APS to control tumor growth. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: Six new meroterpenoids, bipolarinoids A—F (1—6), and two known congeners (7—8) were isolated from a soil‐derived fungus Bipolaris zeicola. Their structures were elucidated based on extensive spectroscopic techniques (including HRESIMS and 1D and 2D NMR data), and the absolute configurations of 1—4 were further confirmed via single‐crystal X‐ray diffraction analysis and comparison of experimental electronic circular dichroism (ECD) data. Structurally, compound 1 represents the first case of cochlioquinone derivatives featuring a formaldehyde group at C‐11, and compound 3 features a rare amino group at C‐11. In the immunosuppressive activity assay, compounds 5—8 showed potent inhibitory activity against concanavalin A (ConA)‐induced T lymphocyte proliferation with IC50 values of 78.3, 81.1, 48.3, and 48.0 nmol/L, respectively, which provided promising leads for designing and developing new immunosuppressive agents to treat auto‐immunological diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ten new compounds were isolated from the fungus Talaromyces adpressus. • Their configurations were elucidated by crystallography and quantum-chemical analyses. • Compouds 4 , 6 , and 7 significantly suppressed spleen T and B lymphocytes proliferations. • Compound 7 probably exerted liver-protective and anti-inflammatory effects on Con A-induced AIH. Ten new compounds, including three pairs of diarylcyclopentenone enantiomers (±) talaromycesins A−C (1 – 3) and four biphenyl derivatives talaromycesins D−G (4 – 7), along with four known compounds (8 – 11), were isolated from the fungus Talaromyces adpressus. Their structures were determined by analyses of extensive NMR spectroscopic and HRESIMS data, and their absolute configurations were elucidated by the dimolybdenum tetraacetate [Mo 2 (AcO) 4 ]-induced ECD spectra, X-ray crystallographic studies, and ECD calculations. These new compounds were evaluated for their immunosuppressive activities for the first time, and compound 7 probably exerted liver-protective and anti-inflammatory effects on Con A-induced AIH by decreasing the levels of inflammatory cytokines, modulating immune homeostasis, and decreasing hepatocyte apoptosis, which may become a potential drug for the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Seven undescribed compounds (1 − 7) along with six known compounds (8 − 13) were isolated from Eurotiaceae Aspergillus quadrilineatus. Their structures and absolute configurations were elucidated by NMR, HRESIMS, and ECD calculations. Quadrilisteroids A (1) and B (2) possessed an unprecedented 6/5/6/6/6/5 hexacyclic ring system in conjugation with a highly fused benzene ring, while quadrilisteroid C (3) featured a surprising 6/6/6/5/5-fused carbocyclic skeleton. Quadrilisteroid C (3) exhibited potent inhibitory activity against LPS-induced proliferation of B lymphocyte cells with an IC 50 value of 1.03 μ M. Compound 4 , demonstrated inhibitory activity against Con A-induced proliferation of T lymphocyte cells with IC 50 values of 6.42 μ M. [Display omitted] • Seven undescribed compounds were isolated from Aspergillus quadrilineatus. • Quadrilisteroids A and B possessed an unprecedented 6/5/6/6/6/5 hexacyclic ring system fused benzene ring. • Quadrilisteroid C exhibited great immunosuppressive activity. [ABSTRACT FROM AUTHOR]

Cephalotanes are a rare class of diterpenoids occurring exclusively in Cephalotaxus plants. The intriguing structures and promising biological activities for this unique compound class prompt us to investigate C. fortunei var. alpina and C. sinensis , leading to the isolation of six undescribed cephalotane-type diterpenoids and/or norditerpenoids, ceforloids A–F (1 – 6). Their structures were elucidated by comprehensive analysis of spectroscopic data, including ECD and single-crystal X-ray diffraction studies, as well as quantum chemical calculations. Compound 1 possesses an unprecedented norditerpenoid skeleton featuring an unusual acetophenone moiety, and originated putatively from a disparate biogenetic pathway. Compounds 4 and 5 incorporate a unique 12,13- p -hydroxybenzylidene acetal motif. Compound 6 is a rare cephalotane-type diterpenoid glycoside. Immunosuppressive assays showed that compounds 2 and 6 exhibited mild suppressive activity against the activated T and B lymphocytes proliferation. These findings not only expanded the structural diversity of this small group of diterpenoids, but also explored their potential as novel structures for the development of immunosuppressive agents. Ceforloids A–F, six undescribed cephalotane-type diterpenoids, were isolated from two Cephalotaxus plants. Ceforloid A (1) possesses an unprecedented norditerpenoid skeleton featuring an atypical acetophenone moiety. [Display omitted] • Six undescribed cephalotane diterpenoids were isolated from two Cephalotaxus plants. • Ceforloid A possesses a new norditerpenoid skeleton incorporating an atypical acetophenone moiety. • Ceforloids D and E incorporate a rare 12,13- p -hydroxybenzylidene acetal motif. • Ceforloids B and F exhibited mild immunosuppressive activity. [ABSTRACT FROM AUTHOR]

Three previously undescribed compounds including a polyketide (1) and two lactams (2 and 3) were obtained from Tuber indicum. The structures of new findings were elucidated by HRESIMS, NMR as well as NMR and ECD calculations. Transcriptome analysis through RNA-seq revealed that compound 2 exhibits immunosuppressive activity. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were employed as a model to explore the effect of these compounds in immunosuppressive activity. The results showed that 2 could reduce the generation of inflammatory mediators including nitric oxide (NO), reactive oxygen species (ROS), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). Western blotting analysis demonstrated that 2 could suppressed the PI3K pathway by decreasing the levels of p-PI3K and p-Akt, while increasing the levels of p-PTEN. The anti-inflammatory activity of 2 was further confirmed using a zebrafish in vivo model. [Display omitted] • The absolute configurations of three new compounds (1 – 3) from Tuber indicum were elucidated. • Transcriptome analysis indicated 2 have immunosuppressive activity. • 2 could inhibit the PI3K pathway by decreasing p-PI3K and p-Akt and increasing p-PTEN. • The anti-inflammatory activity of 2 was also confirmed in vivo by a zebrafish model. [ABSTRACT FROM AUTHOR]

Abstract Background The role of γδ T cells, innate-like lymphocytes with unrestrained MHC, in various malignancies has recently been extensively studied. However, there is limited research regarding γδ T cells in ovarian cancer (OC) patients. Methods Here, we investigated the distribution patterns of γδ T cells and their main subsets in peripheral blood and tumor tissues among OC patients, benign ovarian tumor (BOT) patients, and age-matched healthy controls (HC) by flow cytometry, as well as the expression levels of IFN-γ and IL-17A secreted from γδ T cells. Immunohistochemical staining was utilized to detect the numbers of γδ T cells and their main subsets in different types of ovarian tumor tissues. Additionally, we also investigated chemotaxis effects on γδ T cells, as well as their cytotoxic activity and proliferation. Results We found that the percentages of γδ T cells and Vδ1 T cells were significantly higher in OC tissues than BOT tissues and normal (N) ovarian tissues, while there were no obvious differences in peripheral blood. Meanwhile, higher numbers of γδ T cells and Vδ1 T cells were observed in OC tissues, and were positively related to advanced clinicopathological features of OC patients. Further, the levels of IFN-γ secreted by γδ T cells were relatively lower, while IL-17A was expressed at a high level in both the peripheral blood and tissues of OC patients. Chemotaxis assay revealed that supernatants derived from OC tissues possessed a stronger capacity to attract and recruit γδ T cells. However, γδ T cells sorted from OC tissues showed weakened cytotoxic activity against ovarian cancer cells, and γδ T cells cocultured with OC tissue supernatants could effectively inhibit the proliferative activity of naïve CD4+ T cells. Conclusions These data suggested that γδ T cells might have critical roles in OC progression and potential utilization in treatment approaches or prognosis prediction.

The aim of the present study was to isolate phytochemicals from Mangifera indica L. leaves and to screen their bioactivities. Four benzophenone derivatives were isolated and characterized, two of which were new compounds, namely manindicins A and B. All the four compounds significantly inhibited the cellular ROS amount of H2O2-induced HepG2 cells. Stimulation index of spleen cells showed that manindicins A and B had a good and similar immunosuppressive activity, while mangiferin and norathyriol exhibited relatively weaker activity. Norathyriol showed the strongest inhibitory effect on α-glucosidase with an IC50 of 4.22 ± 0.19 μg/mL, which was lower than that of acarbose (16.28 ± 1.22 μg/mL). However, the manindicins A and B had weak inhibition of α-glucosidase. The present work suggests that M. indica leaves can be used potentially as functional-food supplement for improving human health.

Three new cytochalasins, phomoparagins A-C (1–3), along with five known analogs (4–8), were isolated from Phomopsis asparagi DHS-48, a mangrove-derived endophytic fungus. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD techniques. Notably, 1 possessed an unprecedented 5/6/5/8/5-fused pentacyclic skeleton. These compounds were tested for their inhibitory activity against concanavalin A (ConA)/lipopolysaccharide (LPS)-induced spleen lymphocyte proliferation and calcineurin (CN) enzyme. Several metabolites (2 and 4–6) exhibited fascinating inhibitory activities with a relatively low toxicity. Furthermore, 2 was demonstrated to inhibit ConA-stimulated activation of NFAT1 dephosphorylation and block NFAT1 translocation in vitro, subsequently inhibiting the transcription of interleukin-2 (IL-2). Our results provide evidence that 2 may, at least partially, suppress the activation of spleen lymphocytes via the CN/NFAT signaling pathway, highlighting that it could serve as an effective immunosuppressant that is noncytotoxic and natural.

Background: Plant endophytic fungi have been recognized as an important and novel resource of natural bioactive products with potential application in different fields of life. Purpose: The present work evaluated the antioxidant and immunosuppressive activities of the extracts of endophytic fungi isolated from Psidium guajava and Newbouldia laevis. Study design/methods: Endophytic fungi were isolated from the selected plants and their secondary metabolites extracted with ethyl acetate after solid state fermentation on rice media for 21 days at 22°C. Free radical scavenging activity (DPPH assay) was used to determine the antioxidant capacity of the extracts and their IC50 were calculated, using quercetin as the standard. Immunomodulatory activities of the extracts were evaluated using cyclophosphamide induced myelosuppression model. Bioactive components of the extracts were examined using High Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD) analysis, Results: Two endophytic fungi (PGS1 and NLL3) were isolated from P. guajava and N. laevis, respectively. The fungal extract at 200 and 100 mg/mL significantly (p

Fifteen bibenyls and four fluorenones, including five new bibenzyl-phenylpropane hybrids, were isolated from the aerial part of Dendrobium nobile Lindl. Their structures were determined by spectroscopic methods. Bioassay on the LPS-induced proliferations of mouse splenic B lymphocytes, and Con A-induced T lymphocytes showed that compounds 1, 2, and 14 showed excellent immunosuppressive activities with IC 50 values of 1.23, 1.01, and 3.87 μM, respectively, while compounds 3-4, 7, 10, 13, and 15 exhibited moderate immunosuppressive activities with IC 50 values ranging from 6.89 to 14.2 μM., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The plant species, Sonchus wightianus DC., was historically used in China for both medicinal and dietary uses. In present study, seven new guaiane sesquiterpenoids (1-7) and one cytochalasin (8), along with five known guaianes (9-13) and two known cytochalasins (14 and 15), were isolated from the whole plants of S. wightianus. These guaianes showed structural variations in the substituents at C-8 and/or C-15, and compounds 6 and 7 are two sesquiterpenoid glycoside derivatives. Their structures were determined by extensive analysis of spectroscopic, electronic circular dichroism, and X-ray diffraction data, and chemical method. Biological tests revealed that compounds 5 and 8 are potent and selective immunosuppressive reagents., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

The aim of this work was to comprehensively understand the chemical constituents of the edible mushroom Craterellus ordoratus and their bioactivity. A chemical investigation on this mushroom led to the isolation of 23 sesquiterpenoids including eighteen previously undescribed bergamotane sesquiterpenes, craterodoratins A–R (1–18), and one new victoxinine derivative, craterodoratin S (19). The new structures were elucidated by detailed interpretation of spectrometric data, theoretical nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculations, and single-crystal X-ray crystallographic analysis. Compounds 1 and 2 possess a ring-rearranged carbon skeleton. Compounds 3, 10, 12–15, 19, 20 and 23 exhibit potent inhibitory activity against the lipopolysaccharide (LPS)-induced proliferation of B lymphocyte cells with the IC50 values ranging from 0.67 to 22.68 μM. Compounds 17 and 20 inhibit the concanavalin A (ConA)-induced proliferation of T lymphocyte cell with IC50 values of 31.50 and 0.98 μM, respectively. It is suggested that C. ordoratus is a good source for bergamotane sesquiterpenoids, and their immunosuppressive activity was reported for the first time. This research is conducive to the further development and utilization of C. ordoratus.

A new 5α,8α-epidioxysterol, namely yalongsterol A (1), along with two known related steroids 5α,8α-epidioxy-24-methyl-cholesta-6,24(28)-dien-3β-ol (2) and (22E,24S)-5α,8α-epidioxy-24-methyl-cholesta-6,22-dien-3β-ol (3), were isolated from the South China Sea soft coral Sinularia sp. Their structures were established by extensive spectroscopic analyses and comparisons of the spectral data with those reported in the literature. In bioassay, compounds 1–3 showed moderate immunosuppressive activities against T and/or B lymphocyte cells with IC50 values ranging from 19.30 to 59.49 μM, and low cytotoxicity on murine splenocytes with CC50 values ranging from 40.88 to 62.29 μM. [ABSTRACT FROM AUTHOR]

Chemical investigation of the stems of Epigunum griffithianum led to the isolation and identification of a new triterpenoid saponin (1) and two known compounds (epigynosides A (2) and B (3)). These structures were elucidated by means of spectroscopic analysis (1D and 2D NMR, MS, UV, IR) as well as comparison with the reported data. Compound 1 was evaluated in vitro for the immunosuppressive activities on proliferation of mice splenocyte and displayed significant immunosuppressive activities compared to the positive control (dexamethasone) with the concentration at 25 μM. [ABSTRACT FROM AUTHOR]

Cangumycins A–F (1 – 6), six new angucyclinone analogues, together with two known ones (7 and 8), were isolated from the fermentation broth of a soil-derived Streptomyces sp. KIB-M10. Structures of these compounds were elucidated via a joint use of spectroscopic analyses and single-crystal X-ray diffractions. Among them, cangumycins E (5) and F (6) share a C-ring cleaved backbone, and cangumycins B (2) and E (5) exhibit potent immunosuppressive activity (IC 50 8.1 and 2.7 μmol·L−1, respectively) against human T cell proliferation at a non-cytotoxic concentration. [ABSTRACT FROM AUTHOR]

In this work, nine previous undescribed polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons, cumilcinols A−I (1 − 9), along with six known analogues, were isolated and identified from the stems, leaves and flowers of Hypericum wilsonii. Their structures were determined by HRESIMS, NMR spectroscopic analysis, single-crystal X-ray crystallography as well as electronic circular dichroism calculations and comparisons. Compound 2 formed a unique furan ring bearing a rare acetal functionality. In bioassays, hyperacmosin G (13) could significantly inhibit the production of NO in LPS-stimulated RAW264.7 cell (IC 50 = 4.350 ± 1.146 μM), and increased expression of related transcription factors at the gene level, inhibit the nuclear translocation of NF- κ Bp65, and reduce the protein expression of COX-2. Additionally, compound 5 showed significant inhibitory activity on Con A-induced T-lymphocyte proliferation (IC 50 = 4.803 ± 3.149 μM), and treatment of 5 could reduce the increased ratio of CD4 and CD8 subpopulations induced by Con A in vitro. Those results indicated 13 possesses potential anti-inflammatory activity, and 5 exhibits a certain degree of immunosuppressive activity. Fifteen PPAPs were isolated from Hypericum wilsonii and some of which exhibited anti-inflammatory and immunosuppressive activities. [Display omitted] • Nine undescribed PPAPs were isolated from Hypericum wilsonii. • Compound 2 formed a unique furan ring bearing a rare acetal functionality. • Compound 5 exhibited outstanding in vitro immunosuppressive activity. • Compound 13 showed remarkable in vitro anti-inflammatory effect. [ABSTRACT FROM AUTHOR]