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A pair of new oxindole alkaloids, named macrophyllines C (1) and D (2), together with two known oxindole alkaloids isorhynchophylline (3) and corynoxine (4) were isolated from Uncaria macrophylla. Their structures were elucidated based on detailed spectroscopic analysis and by comparison with literature data. In addition, all the isolates were tested for their anti-HIV activities and cytotoxicities in C8166 cells and compounds 2-4 showed weak anti-HIV activities with EC50 values of 11.31 ± 3.29 μM, 18.77 ± 6.14 μM and 30.02 ± 3.73 μM, respectively.

Wulfenioidins A–C (1–3) with an unusual 6/5-5 spiro tricyclic skeleton were isolated from O. wulfenioides. Compound 3 strikingly inhibited NLRP3 inflammasome activation by blocking the expression of caspase-1, GSDMD-NT, and IL-1β.

Two new compounds, including a norsesquiterpenoid, annuionone H (1), and a quassinoid, picraqualide G (2), along with eleven known compounds (3–13), were isolated from the twigs and leaves of Picrasma quassioides. Comprehensive spectroscopic analyses and NMR calculation with DP4+ analysis were used to identify their structures. Moreover, of all these compounds, compound 4 showed a week inhibition rate in the anti-inflammatory screening results against mouse macrophage J774A.1 cell.

Five unknown labdane diterpenoids Stevelin A-E (1-5), three known labdane diterpenoids (6-8) and three labdane norditerpenoids (9-11) were isolated from the Stevia rebaudiana. The structures were determined primarily via NMR spectroscopic data and HRESIMS experiments. X-ray crystallography using Cu Kα radiation was used to determine the absolute configurations of 1, and the absolute configurations of 2-5 were deduced by electronic circular dichroism (ECD) calculations. The potential anti-atherosclerosis activities of all compounds were evaluated by measuring their inhibitory effects on the macrophage foam cell formation. As a result, most isolated compounds could significantly inhibit oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation, which suggests that these compounds may be promising candidates in the treatment for atherosclerosis..

Twelve new clerodane diterpenoids named callicarpanes A-L (1-12), together with eight known compounds (13-20), were isolated from Callicarpa integerrima. Their structures were determined by comprehensive spectroscopic data. The calculated chemical shifts were used to identify relative configurations using DP4+ analysis. The absolute configurations (AC) were assigned based on quantum chemical calculations and X-ray single-crystal diffraction methods. Compounds 1, 3, 5, 9, 10, 12, 15, 16, and 19 showed significant inhibitory activity for NLRP3 inflammasome activation, with the IC50 against lactate dehydrogenase (LDH) release ranging from 0.08 to 4.78 μM. Further study revealed that compound 10 repressed IL-1β secretion and caspase-1 maturation in J774A.1 cell as well as blocked macrophage pyroptosis.

One new ionone glycoside, named centrantheroside F (1), together with 9 known compounds (2-10), were isolated from the roots of Centranthera grandiflora. Their structures were determined by spectroscopic data analyses and comparing with the literature data. The absolute configuration of 1 was confirmed via 2 D NMR and electronic circular dichroism (ECD). All isolated compounds were evaluated for their inhibitory activity on lipopolysaccharide (LPS)-induced nitric oxide (NO) production.

The phytochemical investigation on Indigofera&nbsp, heterantha root oil resulted in the identification of 121 phytochemicals using GC-MS analysis. These phytochemicals were docked against alpha-amylase, alpha-glucosidase enzymes. The docking results suggested that Hexacosyl acetate (121) possess alpha-amylase inhibitory potential with a docking score of −8.2944994 and the interaction with alpha-glucosidase enzyme was −9.73762512, followed by 9, 12, 15-Octadecatrienoic acid, 2, 3-dihydroxypropyl ester, (Z, Z, Z)-(83) with a docking score of −9.59869957, showed outstanding results in all the stages of the study and may be shown as the most auspicious phytochemical resulting from the docking studies of the new antidiabetic drug. Additionally, Pharmacokinetic and PASS studies revealed their drug-likeness, expected safety upon consumption, and likely pharmacological effects.

Two new compounds verboncin A (

Four new norceanothane-type triterpenes, cyclopalin

Our study on the roots and leaves of the never-hitherto-chemically studied S. glandulosa led to the isolation of five new diterpenes, referred to as stroglandulons A-E (1-5), alongside 18 known constituents (6-23). The structures of the new compounds were elucidated on the basis of their spectroscopic data, while the known ones were determined based on the comparison of their data with the literature values. Compounds 1-5 were evaluated for their inhibitory effects against NLRP3 inflammasome activation; compound 5 showed inhibition by an IC

Ten new prenylated flavonoids, named denticulains A-J (1-10), together with seven known prenylated flavonoids (11-17) were isolated from Macaranga denticulata. Their structures were elucidated on the basis of detailed spectroscopic analysis and by comparison with literature data. In addition, compounds 1 and 14 inhibited the proliferation of SW620 and HCT-116 cell lines with an IC

Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with ICsub50/subranging from 5.2 to 7.2 μM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bclsub2/subwere decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.

Euphopias D–F (1–3), three novel diterpenoids were isolated from Euphorbia helioscopia L. Comprehensive spectral analysis and a quantum chemical calculation strategy were employed to determine their structure. Compound 1 was defined by a unique caged tetracyclic[10.2.1.02,10.05,9]pentadecane core skeleton, compound 2 was the first example of an 8,9-norditerpenoid, possessing a tricyclic[8.3.0.02,8]tridecane core skeleton, and compound 3 had a tricyclic[10.3.0.02,8] pentadecane core skeleton. Biologically, compounds 1–3 exhibited a potential inhibitory effect on NLRP3 inflammasome. In particular, 1 could restrain the maturation of caspase-1 and regulate the secretion of cytokine interleukin-1β (IL-1β), thereby blocking GSDMD-mediated cell pyroptosis.

Covering: 2000 to 2020 Machine learning (ML) is an efficient tool for the prediction of bioactivity and the study of structure–activity relationships. Over the past decade, an emerging trend for combining these approaches with the study of natural products (NPs) has developed in order to manage the challenge of the discovery of bioactive NPs. In the present review, we will introduce the basic principles and protocols for using the ML approach to investigate the bioactivity of NPs, citing a series of practical examples regarding the study of anti-microbial, anti-cancer, and anti-inflammatory NPs, etc. ML algorithms manage a variety of classification and regression problems associated with bioactive NPs, from those that are linear to non-linear and from pure compounds to plant extracts. Inspired by cases reported in the literature and our own experience, a number of key points have been emphasized for reducing modeling errors, including dataset preparation and applicability domain analysis.

Euphopias A-C (1-3), three rearranged jatrophane-type diterpenoids with tricyclo[8.3.0.02,7]tridecane (1 and 2) and tetracyclo[11.3.0.02,10.03,7]hexadecane (3) cores, were isolated from Euphorbia helioscopia. Comprehensive spectroscopic analyses, quantum-chemical calculations, and X-ray diffractions were used to identify their structures. Compounds 1-3 could significantly inhibit NLRP3 inflammasome activation and block NLRP3 inflammasome-induced pyroptosis. Additionally, a mechanistic study revealed that 2 could ameliorate mitochondria damage, thereby interrupting NLRP3 inflammasome activation.

A phytochemical study on the aerial parts of Leonurus japonicus led to the isolation and identification of 38 labdane diterpenoids, including 18 new (1, 2, 11, 12, 16-21, 24, 30-34, 37, 38) and 20 known (3-10, 13-15, 22, 23, 25-29, 35, 36) analogues. Their structures were elucidated based on physical data analysis, including 1D and 2D NMR, HRMS, UV, IR, and X-ray diffraction. The structure of the known compound 4 was confirmed by single-crystal X-ray diffraction data. These compounds can be divided into furanolabdane (1-10), tetrahydrofuranolabdane (11-15), lactonelabdane (16-23), labdane (24-29), and seco-labdane (30-38) type diterpenoids. All compounds were screened by lipopolysaccharide (LPS)-induced nitric acid (NO) production in RAW264.7 cells to evaluate anti-inflammatory effects. Compounds 1, 5, 10-13, 16-19, 31-33, and 38 inhibited NO production with IC50 values lower than 50 μM, with compound 30 being the most active, with an IC50 value of 3.9 ± 1.7 μM. Further studies show that compound 30 inhibits pro-inflammatory cytokine production and IKK α/β phosphorylation and restores the IκB expression levels in the NF-κB signaling pathway.

Objectives Two labdane diterpenoids, leojapone B and heteronone B, were isolated from Leonurus japonicus Houtt., and their biological activity were evaluated in this study. Methods Human and mouse cancer cells, human peripheral blood mononuclear cells (PBMCs) and mouse macrophages (RAW264.7 cells) were used to evaluate the activity of leojapone B and heteronone B, while the in vivo effects of leojapone B were further examined in Lewis Lung Cancer tumour-bearing mice. Key findings In vitro studies showed that leojapone B selectively inhibited the proliferation of lung cancer cells, and both leojapone B and heteronone B inhibited the production of pro-inflammatory cytokines in activated PBMCs. In tumour-bearing mice model, lung tumours were reduced in size in mice treated with intraperitoneal injections of leojapone B at 20 and 30 mg/kg for 14 days. The population ratio of CD4+/CD8+ T cells in mouse spleens was found to be increased, while regulatory T cells were decreased after leojapone B treatment. Conclusions The inhibitory effects of leojapone B in mouse lung tumours were demonstrated for the first time in this study. The immunomodulatory activity of heteronone B were also demonstrated. Our findings indicated that both leojapone B and heteronone B may act as active components in L. japonicus.

Callicarpins A-D (1-4), possessing an unprecedented A-homoent-clerodane scaffold with a bicyclo[5.4.0]undecane ring system, and callicarpins E-G (5-7), with 5/6-fused ent-clerodane diterpenoid skeletons, were isolated from Callicarpaarborea and C. integerrim. Their structures were elucidated by comprehensive spectroscopic data, X-ray crystal diffraction, chemical derivatization, and electronic circular dichroism (ECD) data. Putative biosynthetic pathways for these callicarpins are proposed. Compounds 2, 3b, and 6-8 showed potent inhibitory effects against the NLRP3 inflammasome with IC50 values from 1.4 to 5.3 μM, and 2 significantly blocked NLRP3 inflammasome-induced pyroptosis by inhibiting Casp-1 activation and IL-1β secretion in J774A.1 cells.

A series of 2-(((5-akly/aryl-1H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones were synthesized and their anti-HIV-1 activities were evaluated. Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with EC50 values in the range of 0.0038–0.4759 μmol/L. Among those compounds, I-11 had an EC50 value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1. In vitro anti-HIV-1 activity and resistance profile studies suggested that compounds I-11 and I-12 displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 4.3 to 63.6 nmol/L and 18.9–219.3 nmol/L, respectively). On the other hand, it was observed that those two compounds were less effective with EC50 values of 2.77 and 4.87 μmol/L for HIV-1A17 (K103N + Y181C). The activity against reverse transcriptase (RT) was also evaluated for those compounds. Both I-11 and I-12 obtained sub-micromolar IC50 values showing their potential in RT inhibition. The pharmacokinetics examination in rats indicated that compound I-11 has acceptable pharmacokinetic properties and bioavailability. Preliminary structure–activity relationships and molecular modeling studies were also discussed. Key words: HIV-1, NNRTIs, S-DABOs, Antiviral activity, SAR, Molecular modeling

Callicarpa bodinieri is a Chinese traditional medicine herb with anti-inflammatory activity in clinic. Herein, we report two new 9,10-seco and etherified abietane diterpenoids bodinieric acids J and K (1 and 2) and one known compound (3) isolated from the leaves and twigs of this plant. Their chemical structures were elucidated by detailed spectrometry data analysis and DP4 + NMR calculation methods. Hypothetical biosynthetic pathways of 1−3 were preliminarily speculated. Compound 3 inhibited inflammasome activation and exhibited blockage of NLRP3 inflammasome activation at non-cytotoxic concentrations in vitro.

Six new sesquiterpenoids, named as ainslides A-F (1-6), including one carotene-type sesquiterpene (1), one eudesmane (2), four guaianolides (3-6), together with eight known sesquiterpenoids (7-14), were purified from the whole plants of Ainsliaea pertyoides. The structures of these sesquiterpenoids were characterized based on spectroscopic methods including 1D and 2D NMR, HR-ESI-MS, UV, and IR spectra, together with ECD calculations and X-ray diffraction experiments. The anti-inflammatory activity of all the isolated compounds was screened and compounds 3 and 7-13 exhibited NLRP3-inflammasome inhibitory activity with IC

A spiro

A pair of new oxindole alkaloids, named macrophyllines C (

Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent-clerodane diterpenoids from Callicarpa arborea, shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent-clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1-25) or a 6/6- (26-66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1β secretion in J771A.1 cells, revealed 28 compounds with an IC

A phytochemical investigation to obtain bioactive substances as lead compounds or agents for anti-inflammatory led to the obtainment of eleven previously undescribed clerodane diterpenoids, named caseatardies A-K (1-11), and four known clerodane diterpenoids (12-15) from the twigs and leaves of Casearia tardieuae. The structural elucidation of these clerodane diterpenoids was based on 1D and 2D-NMR spectroscopy (COSY, HSQC, HMBC and ROESY) as well as high resolution mass spectrometry (HR-ESI-MS). The relative configurations were defined by ROESY correlations. The anti-inflammatory activity of all the isolated compounds was screened and compound 15 decreased LDH level in a dose-dependent manner, showing IC

Inflammation is a biological process closely related to different kinds of diseases, such as cancer and metabolic diseases. Therefore, effective control of the occurrence and development of inflammation is of great significance for disease prevention and control. Recently, 2-substituted indoles have gradually become a research hotspot because of their stability and pharmacological activity. Here we synthesized a series of compound containing 2-substituted indoles and investigated XCR-7a's role in inflammatory response. Our data show that XCR-7a can inhibit the production of inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and inflammatory mediator cyclooxygenase-2 (COX-2) induced by lipopolysaccharide (LPS) in mouse peritoneal macrophages. Also, XCR-7a has a protective effect on LPS-induced inflammatory response in mice. Mechanically, we found that XCR-7a could inhibit the phosphorylation of c-Fos induced by LPS, which suggested that the protective effect of XCR-7a on inflammation was related to its negative regulation to phosphorylation of c-Fos. Briefly, our results demonstrated that XCR-7a could be expected to be a potential drug for controlling inflammation.

One new ionone glycoside, named centrantheroside F (

An efficiently divergent intramolecular Friedel-Crafts alkylation by unactivated alkenes with seleniranium ion-controlled Markovnikov/anti-Markovnikov specificities under mild conditions has been investigated. 2-Benzoxepin, isochroman, and isochromene can be produced in one-pot procedures from the same substrate in high yields and with high regio- and stereospecificity. The products are challenging to access via 7-endo-trig carbocyclizations and by 7-endo-trig carbocyclization/rearrangement/6-exo-trig oxycyclization and 6-exo-trig carbocyclization/deselenenylation reaction sequences, respectively. Mechanistic experiments indicated that in addition to the stereospecific anti-addition processes of the cyclization reactions, the formation of a stable carbocation after ring opening of the seleniranium ion leads to an NPSP-mediated 7-endo-trig carbocyclization; the steric hindrance of the seleniranium intermediate controls the regioselectivity when using TPSCA at 60 °C, which promotes 6-exo-trig carbocyclization. Two distinct catalytic cycles were proposed, and the structures of transition states and products were identified by ab initio calculations and X-ray analyses.

Phytochemical investigation of the leaves and twigs of Callicarpa cathayana led to the isolation of six new clerodane diterpenoids, cathayanalactones A–F (1–6), together with seven analogues (7–13). Their structures were established by extensive NMR analyses together with experimental and calculated ECD spectra analyses. Compounds 1, 2, 3, 7 and 11 showed inhibitory activities on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells.

Fungal drug resistance is a major health threat, and reports of clinical resistance worldwide are becoming increasingly common. In a research program to discover new molecules to help overcome this problem, 14 new lanostane-type triterpenoids, gibbosicolids A-G (2-8) and gibbosic acids I-O (9-15), were isolated from the fruiting bodies of Ganoderma gibbosum, along with seven known triterpenoid derivatives. These compounds featured high levels of oxidation, epimerization, and γ-lactonization. Structures were elucidated by comprehensive spectroscopic analyses and HRMS data. Absolute configurations were assigned based on quantum chemical calculations, including calculated chemical shift with DP4+ analysis, coupling constants, and electronic circular dichroism (ECD) methods. Results show that the calculated NMR with DP4+ analysis could not reliably establish the overall spatial configuration of molecules possessing independent and free-rotational stereoclusters. All these compounds significantly increased the sensitivity of fluconazole (FLC)-resistant C. albicans to FLC. Compounds 2, 5, 9, 12, 16, 17, and 21 exhibited strong antifungal activity against FLC-resistant C. albicans when combined with FLC, with MIC50 values ranging from 3.8 to 8.8 μg/mL.

Background: NIMA (never in mitosis, gene A) serine/threonine kinase 7 (NEK7) is a regulator of mitosis spindle in mammals and is considered as a drug target of inflammasome related inflammatory diseases. However, most commercially available or reported recombinant NEK7 proteins are either inactive or have low purity. These shortcomings limit the pharmacological studies and development of NEK7 inhibitors. Objective: To elucidate what causes the NEK7 low purity in E. coli, and optimize a protocol to improve the protein purity. Methods: A comparative study of expression full length NEK7 with an N-terminal His-tag or a Cterminal His-tag was performed. His-affinity resin, ion exchange and gel filtration chromatography were used to purify NEK7. The protein was identified by mass spectrometry. The activity and folding of NEK7 were evaluated by chemiluminescent assay and thermal shift assay. Results: Our results demonstrated that N-terminal tagged protein was toxic to E. coli, resulting in incomplete translated products. The C-terminal tagged NEK7-His6 had a much higher purity than that of an N-terminal tag. The Ni2+ resin one-step purification led to a purity of 91.7%, meeting the criteria of most kinase assays. With two-step and three-step procedures, the protein purities were 94.7% and ~100%, respectively. The NEK7 purified in this work maintained its kinase activity and correct conformation, and the compound-protein interaction ability. Conclusion: Our optimized protocol could produce good purity of His tagged NEK7 in E. coli, and the kinase activity and biophysical characteristics of which are preserved.

Acute lung injury (ALI) is a severe lung disease with limited therapeutic strategies. Munronoid I, a limonoid, which is extracted and purified from Munronia sinica, exhibits effective anti-neoplastic activities. In this study, we attempted to determine the anti-inflammatory effects of Munronoid I using both the lipopolysaccharide (LPS)-induced in vivo murine ALI models and in vitro assays. Our results demonstrated that Munronoid I treatment ameliorated LPS-induced ALI and inflammation in mice. Moreover, it also significantly inhibited LPS-induced pathological injuries, infiltration of inflammatory cells, and production of IL-1β and IL-6. Furthermore, the in vitro assay showed that Munronoid I could inhibit the LPS-induced expression of inflammatory mediators such as iNOS, COX2, and production of pro-inflammatory cytokines by suppressing the activation of NF-κB signaling pathway in mouse peritoneal macrophages. Munronoid I reduced the LPS-, tumor necrosis factor alpha (TNF-α)- or interleukin 1 beta (IL-1β)-induced transforming growth factor beta-activated kinase 1 (TAK1) phosphorylation and protein expression. Furthermore, the Munronoid I also promoted K48-linked ubiquitination and proteasomal degradation of TAK1. Taken together, these results demonstrated that Munronoid I exhibited anti-inflammatory activities both in vitro and in vivo, which might be a potential therapeutic candidate for the treatment of ALI and pulmonary inflammation.

Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model. Mechanistically, GM affected miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with an efficacy higher than that of enoxacin, and promoted the binding of TRBP with Dicer. Structural simplification and a preliminary structure-activity relationship study via the synthesis of 20 GM derivatives showed that compound 9 exhibited more potent inhibitory activity in HCC cell proliferation and affinity for TRBP than did GM. These results suggest that TRBP may be a novel potential therapeutic target in HCC and compound 9 may be a potential drug candidate for the treatment of HCC.

As a successful anti-tumor drug target, the family of histone deacetylases (HDACs) is also a critical player in immune response, making the research of anti-inflammatory HDAC inhibitors an attractive new focus. In this report, triterpenoids nigranoic acid (NA) and manwuweizic acid (MA) were identified as HDAC inhibitors through docking-based virtual screening and enzymatic activity assay. A series of derivatives of NA and MA were synthesized and assessed for their biological effects. As a result, hydroxamic acid derivatives of NA and MA showed moderately increased activity for HDAC1/2/4/6 inhibition (the lowest IC50 against HDAC1 is 1.14 μM), with no activity against HDAC8. In J774A.1 macrophage, compound 1–3, 13 and 17–19 demonstrated inhibitory activity against lactate dehydrogenase (LDH) and IL-1β production, without affecting cell viability. Compound 19 increased the histone acetylation level in J774A.1 cells, as well as inhibited IL-1β maturation and caspase-1 cleavage. These results indicated that compound 19 blocks the activation of NLRP3 inflammasome, probably related to HDAC inhibition. This work provided a natural scaffold for developing low-cytotoxic and anti-inflammatory HDAC inhibitors, as well as a class of tool molecules for studying the relationship between HDACs and NLRP3 activation.

Four new diterpenoids, rubellawus A-D (1-4), along with three known compounds, were isolated and identified from the flowers of Callicarpa rubella. Their structures were elucidated by various spectroscopic analysis. All the compounds were screened for their anti-inflammatory activity and 14α-hydroxyisopimaric acid and isopimaric acid showed significant NLRP3 inflammasome inhibitory activity with IC50 values of 7.02 and 3.99 μM.

Cellular inflammation is the underlying cause of several diseases and development of a safe and effective anti-inflammatory drug is need-of-the hour for treatment of diseases like lung inflammation. Callicarpa integerrima Champ. is a well-known herbal medicine with hemostatic and anti-inflammatory functions. However, the exact ingredient exhibiting anti-inflammatory activity in C. integerrima Champ. is largely unknown. Here, we first isolated, purified and characterized a novel clerodane-type diterpenoid Cintelactone A (CA) from C. integerrima Champ. We demonstrated that CA could significantly inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and mediators production both in mouse peritoneal macrophages and THP1 cells. Consistently, CA also relieved inflammation and reduced LPS-induced lung injury in mice. We systematically elucidated the mechanism of action as well. CA interacted with Arg78 of tumor necrosis factor receptor-associated factor 6 (TRAF6) by hydrogen bonding. It further promoted the K48-linked ubiquitination and proteasomal degradation of TRAF6, and suppressed the activation of NF-κB and MAPKs signaling pathways. Collectively, our study reveals that new clerodane-type diterpenoid CA suppresses LPS-induced inflammation by promoting TRAF6 degradation, suggesting that CA as the potential therapeutic candidate for the treatment of inflammation associated diseases.

Euphopias A-C (

Twenty-four new limonoids, toonaolides A−X (1–24), characterized with an α,β-unsaturated-γ-lactone A-ring were isolated from the twigs of Toona ciliata. Their structures and absolute configurations were elucidated by spectroscopic data, X-ray diffraction crystallography, and quantum chemistry calculations. Most of the isolated compounds (except 9, 18, and 24 which possessed the maleimide ring) featured the rare 21-hydroxybutenolide or 23-hydroxybutenolide moieties. In particular, compound 1 has an unprecedented limonoid architecture with 6/6 cis-fused A/B ring system and 2 has an unusual tetrahydrofuran ring B skeleton, featuring a 7/5/6/5 ring system. The biological evaluation showed that compounds 9, 11, 12, 14, and 18 exhibited significantly anti-NLRP3 inflammasome activity with IC50 values ranging from 3.2 to 9.7 μM. Analysis of IL-1β and caspase-1 expression revealed that compounds 11 and 12 are selective inhibitors of NLRP3 inflammasome, which could ameliorate cell pyroptosis by blocking NLRP3 inflammasome activation.