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Callintegers A (1) and B (2), unprecedented clerodane norditerpenoids based on a novel carbon skeleton, were isolated from Callicarpa integerrima. Compounds 1and 2possess a novel 6/6/6-fused tricyclic ring system. Their structures and absolute configurations were determined by quantum chemical calculations, spectroscopic analysis, and single-crystal X-ray diffraction methods. Biological evaluation showed that compound 2inhibited IL-1β secretion in a dose-dependent manner with an IC50value of 5.5 ± 3.2 μM. Caspase-1 maturation and IL-1β secretion were also reduced, indicating that compound 2impaired NLRP3 inflammasome activation.

To investigate the diagnostic value of casein kinase 1α (CK1α) and phosphatase and tensin homolog (PTEN) in sinonasal inverted papilloma (SNIP), 42 control subjects and 56 SNIP patients were recruited in this study. Demographic and clinical characteristics, computerized tomography scans and endoscopic examinations were analyzed according to the Krouse staging system. Real-time quantitative-polymerase chain reaction and Western blotting were performed to detect CK1α and PTEN expression levels in different subgroups. Receiver operating characteristic and correlation analyses were conducted to assess their clinical significance in SNIP diagnosis. The expression levels of CK1α and PTEN were decreased in SNIP patients. Interestingly, the declined mRNA levels were consistent with the elevated Krouse staging and closely associated with the pathophysiological characteristics. Their expression levels also negatively correlated with neutrophil counts and positively correlated with lymphocyte counts in the blood of SNIP patients. This study suggests that CK1α and PTEN might be useful biomarkers for the occurrence and recurrence diagnosis of SNIP.

Eight new aspulvinone analogues, aspulvins A–H (1–8) and aspulvinones D, M, O, and R (9–12), were isolated from cultures of the endophytic fungus Cladosporiumsp. 7951. Detailed spectroscopic analyses were conducted to determine the structures of the new compounds. All isolates displayed different degrees of inhibitory activity against the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro) at 10 μM. Notably, compounds 9, 10, and 12showed potential SARS-CoV-2 Mproinhibition with IC50values of 10.3 ± 0.6, 9.4 ± 0.6, and 7.7 ± 0.6 μM, respectively. For all compounds except 3and 4, the anti-inflammatory activity occurred by inhibiting the release of lactate dehydrogenase (LDH) with IC50values ranging from 0.7 to 7.4 μM. Compound 10showed the most potent anti-inflammatory activity by inhibiting Casp-1 cleavage, IL-1β maturation, NLRP3 inflammasome activation, and pyroptosis. The findings reveal that the aspulvinone analogues 9, 10, and 12could be promising candidates for coronavirus disease 2019 (COVID-19) treatment as they inhibit SARS-CoV-2 infection and reduce inflammatory reactions caused by SARS-CoV-2.

Background: NIMA (never in mitosis, gene A) serine/threonine kinase 7 (NEK7) is aregulator of mitosis spindle in mammals and is considered as a drug target of inflammasome relatedinflammatory diseases. However, most commercially available or reported recombinant NEK7proteins are either inactive or have low purity. These shortcomings limit the pharmacologicalstudies and development of NEK7 inhibitors. Objective: To elucidate what causes the NEK7 low purity in E. coli, and optimize a protocol to improvethe protein purity. Methods: A comparative study of expression full length NEK7 with an N-terminal His-tag or a CterminalHis-tag was performed. His-affinity resin, ion exchange and gel filtration chromatographywere used to purify NEK7. The protein was identified by mass spectrometry. The activity and foldingof 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 inincomplete translated products. The C-terminal tagged NEK7-His6 had a much higher purity thanthat of an N-terminal tag. The Ni2+ resin one-step purification led to a purity of 91.7%, meeting thecriteria of most kinase assays. With two-step and three-step procedures, the protein purities were94.7% and 100%, respectively. The NEK7 purified in this work maintained its kinase activity andcorrect conformation, and the compound-protein interaction ability. Conclusion: Our optimized protocol could produce good purity of His tagged NEK7 in E. coli, andthe kinase activity and biophysical characteristics of which are preserved.

Euphopias A–C (1–3), three rearranged jatrophane-type diterpenoids with tricyclo[8.3.0.02,7]tridecane (1and 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 1–3could significantly inhibit NLRP3 inflammasome activation and block NLRP3 inflammasome-induced pyroptosis. Additionally, a mechanistic study revealed that 2could ameliorate mitochondria damage, thereby interrupting NLRP3 inflammasome activation.

A phytochemical study on the aerial parts of Leonurus japonicusled 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 4was 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 38inhibited NO production with IC50values lower than 50 μM, with compound 30being the most active, with an IC50value of 3.9 ± 1.7 μM. Further studies show that compound 30inhibits pro-inflammatory cytokine production and IKK α/β phosphorylation and restores the IκB expression levels in the NF-κB signaling pathway.

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 Callicarpaarboreaand 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 6–8showed potent inhibitory effects against the NLRP3 inflammasome with IC50values from 1.4 to 5.3 μM, and 2significantly blocked NLRP3 inflammasome-induced pyroptosis by inhibiting Casp-1 activation and IL-1β secretion in J774A.1 cells.

Natural products (NPs) are a promising source of anti-inflammatory molecules for the development of drugs. Despite there being an abundance of reports of large numbers of NPs having bioactivity in preliminary cell-based assays of anti-inflammatory potential, their further optimization and exploration are limited by the lack of a comprehensive understanding of their effective scaffold structure or biological targets. To facilitate target-based studies of anti-inflammatory NPs, the details of 665 NPs reported to have anti-inflammatory activity were extracted from the literature and compiled into a data set we termed InflamNat. The physicochemical properties of the NPs were analyzed, and the distribution of their structures and scaffolds is presented. A compound-target network was constructed from data in the PubChem Bioassay database. The results demonstrated that, compared to natural anticancer compounds in the NPACT database, compounds from the InflamNat data set contained a comparable distribution of compound types but with a higher proportion satisfying Lipinski’s rule. The all-atom structures and scaffold of the compounds were diverse and barely convergent, with flavonoids and triterpenoids being the groups with the greatest abundance. The biological targets of the InflamNat compounds were identified as belonging to a variety of protein families that had varied function. Seventy-two percent of InflamNat compounds involved in the network were identified as having more than one biological target, highlighting the potential for multitarget anti-inflammatory drug development. In conclusion, anti-inflammatory NPs provide a good library for the screening of target-based leads or fragment-based drug design. Thus, elucidation of their biological targets is fundamental for either a specific single-target or multitarget drug development strategy. Meanwhile, a large proportion of the chemical space of anti-inflammatory NPs is still unexplored, with novel active scaffolds remaining to be discovered.

Premnafulvol A (1), a unique diterpenoid featuring a 6/5/7/3-fused tetracyclic carbon skeleton, with three biosynthetically related analogues, premnafulvols B–D (2–4), were isolated from the aerial parts of Premna fulva. Structures of 1–4were established by a combination of extensive spectroscopic analyses, quantum chemical calculations, and X-ray crystallography. Plausible biosynthetic pathways of 1–4were proposed. Interestingly, 2and 3exhibited opposite effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells by modulating the expression of aromatase.

Species belonging to the genus Callicarpaare used traditionally in Chinese medicine for the treatment of inflammation, rheumatism, and pain. Investigation of the leaves and twigs of Callicarpa bodinieriresulted in the isolation of nine new abietane diterpenoids, bodinieric acids A–I (1–9), along with six known compounds (10–15). The structures of 1–9were elucidated on the basis of the interpretation of their HRESIMS and NMR data and by ECD calculations. To explore the potential therapeutic target of this plant for immune-mediated disease, the inhibitory activities of the isolates obtained were determined against 13 kinase enzymes. Eight compounds exhibited moderate inhibitory effects on spleen tyrosine kinase (SYK), and the IC50values of compounds 2and 6were 7.2 and 10.7 μM, respectively. In addition, a preliminary structure–activity relationship of this scaffold was analyzed with both molecular docking and a 3D-QSAR pharmacophore model.

Three new highly oxygenated nortriterpenoids, wilsonianadilactones D–F (1–3), were isolated from the leaves and stems of Schisandra wilsoniana. Their structures were established by means of spectroscopic analysis. Compounds 1–3showed weak anti-HIV-1 activity with the therapeutic index (TI) values (CC50/EC50) greater than 8.16, 14.7, and 17.5, respectively.

Fourteen sesquiterpene and norsesquiterpene derivatives, comprising six different carbon skeletons, were isolated from Sanicula lamelligera. Saniculamoid A1 (1a) is an oxidation product of saniculamoid A (1), created by the transition of a formyl group to a carboxylic acid group after a period of storage in air. The known compounds 5–14were identified in Saniculaplants for the first time. The compounds were evaluated for their anti-HIV-1, cytostatic, and nitric-oxide-production-inhibiting activities using in vitro cellular assays. The results showed that 1,5-naphthalenediol inhibited nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells with an IC50value of 28.1 μM and was active toward five cancer cell lines with IC50values in the 31.1–41.6 μM range.

Investigation of whole plants of Euphorbia fischerianaafforded three new tigliane-diterpenoid glycosides, fischerosides A–C (1–3), together with 11 known diterpenoids. Fischerosides A–C (1–3) are the first tigliane-type diterpenoid glucosides. Their structures were determined by a combination of 1D and 2D NMR, MS, and acid hydrolysis. Inhibitory activity against HIV-1 was assessed for compounds 1–5. The new compound 3showed an EC50value of 0.02 μM and a therapeutic index (TI) of 17.50, while prostratin (4) and 12-deoxyphorbol-13,20-diacetate (5) showed significantly greater anti-HIV-1 activity.