The Chemical Ecology of Plant Natural Products.

Plants are excellent chemists with an impressive capability of biosynthesizing a large variety of natural products (also known as secondary or specialized metabolites) to resist various biotic and abiotic stresses. In this chapter, 989 plant natural products and their ecological functions in plant-herbivore, plant-microorganism, and plant-plant interactions are reviewed. These compounds include terpenoids, phenols, alkaloids, and other structural types. Terpenoids usually provide direct or indirect defense functions for plants, while phenolic compounds play important roles in regulating the interactions between plants and other organisms. Alkaloids are frequently toxic to herbivores and microorganisms, and can therefore also provide defense functions. The information presented should provide the basis for in-depth research of these plant natural products and their natural functions, and also for their further development and utilization.

Leucosceptrane sesterterpenoids from Tibetan Leucosceptrum canum and their immunosuppressive activity.

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 IC50 values of 13.39 and 19.34 µM, respectively.

Five anti-inflammatory compounds from the resins of Liquidambar orientalis.

Five undescribed compounds, including a triterpenoid (1), three phenylpropanoids [(±)-2 and 4], and an aromatic compound (3), as well as six known analogues (5-10), were isolated from the resins of Liquidambar orientalis Mill. Their structures, including absolute configurations, were determined by using spectroscopic and computational methods, and the five new compounds displayed anti-inflammatory activities in LPS-induced RAW264.7 cells.

Ganospirones A-G, seven undescribed spiro-meroterpenoids from Ganoderma lucidum and their biological activities.

Ganoderma lucidum, a medicinal mushroom with a long history in traditional Chinese medicine, is widely used for chronic diseases. Ganospirones A-G (1-7), seven pairs of undescribed spiro-meroterpenoids, were isolated from the fruiting bodies of G. lucidum. Their structures including absolute configurations were characterized by using NMR spectroscopic data, ECD computational and X-ray diffraction methods. The anti-inflammatory and anti-renal fibrosis activities of the meroterpenoids 1-7 were tested, and the results revealed that (-)-2 and (+)-2 could inhibit iNOS expression in lipopolysaccharide-induced RAW264.7 cells at 20 µM.

Characterization of a glycosyltransferase from Paris polyphylla for application in biosynthesis of rare ophiopogonins and ginsenosides.

Saponins are bioactive components of many medicinal plants, possessing complicated chemical structures and extensive pharmacological activities, but the production of high-value saponins remains challenging. In this study, a 6'-O-glucosyltransferase PpUGT7 (PpUGT91AH7) was functionally characterized from Paris polyphylla Smith var. yunnanensis (Franch.) Hand. -Mazz., which can transfer a glucosyl group to the C-6' position of diosgenin-3-O-rhamnosyl-(1 â†’ 2)-glucoside (1), pennogenin-3-O-rhamnosyl-(1 â†’ 2)-glucoside (2), and diosgenin-3-O-glucoside (5). The KM and Kcat values of PpUGT7 towards the substrate 2 were 8.4 µM and 2 × 10-3 s-1, respectively. Through molecular docking and site-directed mutagenesis, eight residues were identified to interact with the sugar acceptor 2 and be crucial for enzyme activity. Moreover, four rare ophiopogonins and ginsenosides were obtained by combinatorial biosynthesis, including an undescribed compound ruscogenin-3-O-glucosyl-(1 â†’ 6)-glucoside (10). Firstly, two monoglycosides 9 and 11 were generated using a known sterol 3-O-ß-glucosyltransferase PpUGT80A40 with ruscogenin (7) and 20(S)-protopanaxadiol (8) as substrates, which were further glycosylated to the corresponding diglycosides 10 and 12 under the catalysis of PpUGT7. In addition, compounds 7-11 were found to show inhibitory effects on the secretion of TNF-α and IL-6 in macrophages RAW264.7. The findings provide valuable insights into the enzymatic glycosylation processes in the biosynthesis of bioactive saponins in P. polyphylla var. yunnanensis, and also serve as a reference for utilizing UDP-glycosyltransferases to construct high-value or rare saponins for development of new therapeutic agents.

Immunosuppressive leucosesterterpane and penta-nor-leucosesterterpane sesterterpenoids from Leucosceptrum canum.

Five undescribed leucosesterterpane sesterterpenoids, leucosceptrines A-E, two undescribed penta-nor-leucosesterterpane (C20) 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.

Megastigmane glycosides from the traditional Uighur medicine Cydonia oblonga Mill.

Phytochemical investigation on the fruits of Cydonia oblonga Mill., a traditional Uighur medicine, led to the isolation of seven undescribed and nine known megastigmane glycosides. Their structures including absolute configurations were characterized by an extensive analysis of spectroscopic data including HRESIMS and NMR, combined with ECD calculations. Additionally, compounds 1, 2, 4, and 6-16 exhibited anti-inflammatory activity by inhibiting the secretion of cytokines TNF-α and IL-6 in RAW264.7 cells induced by lipopolysaccharides (LPS) with inhibitory rates of 10.79%-44.58% at 20 µM.

Naringenin modulates the NO­cGMP­PKG signaling pathway by binding to AKT to enhance osteogenic differentiation in hPDLSCs.

Naringenin (NAR) is a prominent flavanone that has been recognized for its capacity to promote the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). The present study aimed to explore how NAR promotes the osteogenic differentiation of hPDLSCs and to assess its efficacy in repairing alveolar bone defects. For this purpose, a protein­protein interaction network of NAR action was established by mRNA sequencing and network pharmacological analysis. Gene and protein expression levels were evaluated by reverse transcription­quantitative and western blotting. Alizarin red and alkaline phosphatase staining were also employed to observe the osteogenic capacity of hPDLSCs, and immunofluorescence was used to examine the co­localization of NAR molecular probes and AKT in cells. The repair of mandibular defects was assessed by micro­computed tomography (micro­CT), Masson staining and immunofluorescence. Additionally, computer simulation docking software was utilized to determine the binding affinity of NAR to the target protein, AKT. The results demonstrated that activation of the nitric oxide (NO)­cyclic guanosine monophosphate (cGMP)­protein kinase G (PKG) signaling pathway could promote the osteogenic differentiation of hPDLSCs. Inhibition of AKT, endothelial nitric oxide synthase and soluble guanylate cyclase individually attenuated the ability of NAR to promote the osteogenic differentiation of hPDLSCs. Micro­CT and Masson staining revealed that the NAR gavage group exhibited more new bone formation at the defect site. Immunofluorescence assays confirmed the upregulated expression of Runt­related transcription factor 2 and osteopontin in the NAR gavage group. In conclusion, the results of the present study suggested that NAR promotes the osteogenic differentiation of hPDLSCs by activating the NO­cGMP­PKG signaling pathway through its binding to AKT.

Antioxidant and anti-Alzheimer's disease activities of 1,8-cineole and its cyclodextrin inclusion complex.

1,8-Cineole is a bicyclic monoterpene widely distributed in the essential oils of various medicinal plants, and it exhibits significant anti-inflammatory and antioxidant activities. We aimed to investigate the therapeutic effect of 1,8-cineole on anti-Alzheimer's disease by using transgenic Caenorhabditis elegans models. Our studies demonstrated that 1,8-cineole significantly relieved Aß1-42-induced paralysis and exhibited remarkable antioxidant and anti-Aß1-42 aggregation activities in transgenic nematodes CL4176, CL2006 and CL2355. We developed a 1,8-cineole/cyclodextrin inclusion complex, displaying enhanced anti-paralysis, anti-Aß aggregation and antioxidant activities compared to 1,8-cineole. In addition, we found 1,8-cineole treatment activated the SKN-1/Nrf-2 pathway and induced autophagy in nematodes. Our results demonstrated the antioxidant and anti-Alzheimer's disease activities of 1,8-cineole, which provide a potential therapeutic approach for Alzheimer's disease.

Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans.

Twelve new alkaloids, scolopenolines A-L (1-7, 9-11, 13, 14), along with six known analogues, were isolated from Scolopendra subspinipes mutilans, identified by analysis of spectroscopic data and quantum chemical and computational methods. Scolopenoline A (1), a unique guanidyl-containing C14 quinoline alkaloid, features a 6/6/5 ring backbone. Scolopenoline B (2) is a novel sulfonyl-containing heterodimer comprising quinoline and tyramine moieties. Scolopenoline G (7) presents a rare C12 quinoline skeleton with a 6/6/5 ring system. Alkaloids 1, 8, 10, and 15-18 display anti-inflammatory activity, while 10 and 16-18 also exhibit anti-renal-fibrosis activity. Drug affinity responsive target stability and RNA-interference assays show that Lamp2 might be a potentially important target protein of 16 for anti-renal-fibrosis activity.

Nematicidal Activity of 20-Deoxyingenol-3-angelate from Euphorbia peplus Latex Through Protein Kinase C Isotype TPA-1.

The latex of Euphorbia peplus and its major component 20-deoxyingenol-3-angelate (DI3A) displayed significant nematicidal activity against Caenorhabditis elegans and Panagrellus redivivus. DI3A treatment inhibited the growth and development of nematodes and caused significantly negative effects on locomotion behavior, reproduction, and accumulation of reactive oxygen species. Transcriptome analysis indicated that differential expression genes in DI3A-treated C. elegans were mainly associated with the metabolism, growth, and development process, which were further confirmed by RT-qPCR experiments. The expression level of TPA-1 gene encoding a protein kinase C isotype was obviously upregulated by DI3A treatment, and knockdown of TPA-1 by RNAi technology in the nematode could relieve the growth-inhibitory effect of DI3A. Metabolic analysis indicated that DI3A was hardly metabolized by C. elegans, but a glycosylated indole derivative was specifically accumulated likely due to the activation of detoxification. Overall, our findings suggested that DI3A from E. peplus latex exerted a potent nematicidal effect through the gene TPA-1, which provides a potential target for the control of nematodes and also suggests the potential application value of E. peplus latex and DI3A as botanical nematicides.

Unusual immunosuppressive pyridine-containing bisnor- (c23), tetranor- (c21) and pentanor- (c20) sesterterpenoids from Tibetan Leucosceptrum canum.

An unusual pyridine-containing sesterterpenoid, leucosceptrodine (1), and five new nor-leucosceptrane sesterterpenoids, including bisnor- (C23, 2), tetranor- (C21, 3) and pentanor- (C20, 4-6) skeletons, were isolated from the leaves of Tibetan Leucosceptrum canum. Their structures including their absolute configurations were determined by extensive spectroscopic analyses and quantum chemical calculations. A single crystal of one epimer (5) was crystallized from a pair of inseparable epimers, and its structure including its absolute configuration was determined by X-ray crystallographic analysis. The immunosuppressive activities of compounds 1-4 with different potencies were evaluated by inhibiting the secretion of cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages.

Syntheses of Linear Biosynthetic C25-Precursors of Leucosceptroids.

An efficient synthetic approach was developed and applied to the syntheses of four linear biosynthetic C25-precursors of leucosceptroids. The synthesis features a Julia-Kocienski olefination and a late-stage bioinspired photo-oxidation as key steps. The immunosuppressive effects of all synthetic compounds on mouse T cells and macrophage RAW264.7 were determined.

Exploration of the profiles of steroidal saponins from Rhizoma Paridis and their metabolites in rats by UPLC-Q-TOF-MS/MS.

INTRODUCTION: Steroidal saponins characterised by intricate chemical structures are the main active components of a well-known traditional Chinese medicine (TCM) Rhizoma Paridis. The metabolic profiles of steroidal saponins in vivo remain largely unexplored, despite their renowned antitumor, immunostimulating, and haemostatic activity. OBJECTIVE: To perform a comprehensive analysis of the chemical constituents of Rhizoma Paridis total saponins (RPTS) and their metabolites in rats after oral administration. METHOD: The chemical constituents of RPTS and their metabolites were analysed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS). RESULTS: A reliable UPLC-Q-TOF-MS/MS method was established, and a total of 142 compounds were identified in RPTS. Specifically, diosgenin-type saponins showed the diagnostic ions at m/z 415.32, 397.31, 283.25, 271.21, and 253.20, whereas pennogenin-type saponins exhibited the diagnostic ions at m/z 413.31, 395.30, and 251.20. Based on the characteristic fragments and standard substances, 15 specific metabolites were further identified in the faeces, urine, plasma, and bile of rats. The metabolic pathways of RPTS, including phase I reactions (de-glycosylation and oxidation) and phase II reactions (glucuronidation), were explored and summarised, and the enrichment of metabolites was characterised by multivariate statistical analysis. CONCLUSION: The intricate RPTS could be transformed into relatively simple metabolites in rats through de-glycosylation, which provides a reference for further metabolic studies and screening of active ingredients for TCM.

Glutathione supplementation improves fat graft survival by inhibiting ferroptosis via the SLC7A11/GPX4 axis.

BACKGROUND: Autologous fat grafting is hampered by unpredictable graft survival, which is potentially regulated by ferroptosis. Glutathione (GSH), a powerful antioxidant used in tissue preservation, has ferroptosis-regulating activity; however, its effects on fat grafts are unclear. This study investigated the effects and mechanisms of GSH in fat graft survival. METHODS: Human lipoaspirates were transplanted subcutaneously into the backs of normal saline-treated (control) or GSH-treated nude mice. Graft survival was evaluated by magnetic resonance imaging and histology. RNA sequencing was performed to identify differentially expressed genes and enriched pathways. GSH activity was evaluated in vitro using an oxygen and glucose deprivation (OGD) model of adipose-derived stem cells. RESULTS: Compared with control group, GSH induced better outcomes, including superior graft retention, appearance, and histological structures. RNA sequencing suggested enhanced negative regulation of ferroptosis in the GSH-treated grafts, which showed reduced lipid peroxides, better mitochondrial ultrastructure, and SLC7A11/GPX4 axis activation. In vitro, OGD-induced ferroptosis was ameliorated by GSH, which restored cell proliferation, reduced oxidative stress, and upregulated ferroptosis defense factors. CONCLUSIONS: Our study confirms that ferroptosis participates in regulating fat graft survival and that GSH exerts a protective effect by inhibiting ferroptosis. GSH-assisted lipotransfer is a promising therapeutic strategy for future clinical application.

Highly efficient dissolution and reinforcement mechanism of robust and transparent cellulose films for smart packaging.

The packaging of fresh foods increasingly focuses on renewable and eco-friendly cellulose films, but their low dissolution efficiency and weak mechanical strength greatly limit their wide application, which also cannot be used for smart packaging. Here, a highly efficient synergistic chloride-salt dissolution method was proposed to fabricate robust, transparent, and smart cellulose films. Cellulose films with appropriate Ca2+ concentration exhibited robust mechanical strength, better thermal stability, high transparency and crystallinity. The metal chelation of Ca2+ with cellulose chains could induce cellulose chain arrangement during the cellulose regeneration process. Particularly, compared to pure cellulose films, the tensile strength and elongation at break of cellulose films with suitable Ca2+ were increased by 167 % and 200 %, respectively. Moreover, optimal cellulose films can be used to reflect the quality of the fruit by detecting changes in ethanol gas. Hence, a novel strategy is presented to fabricate robust and transparent cellulose films with great potential application for smart packaging.

New triterpenoids from the aerial parts of the Uygur medicine Salvia deserta.

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.

Self-Powered Wide-Narrow Bandgap-Laminated Perovskite Photodetector with Bipolar Photoresponse for Secure Optical Communication.

Perovskite photodetectors with bipolar photoresponse characteristics are expected to be applied in the field of secure optical communication (SOC). However, how to realize the perovskite photodetector with bipolar response remains challenging. Herein, by introducing bismuth iodide (BiI3 ) into Sn-Pb mixed perovskite precursor solution, 2D perovskite FA3 Bi2 I9 is spontaneously formed at the bottom to realize a wide-narrow bandgap-laminated perovskite film. Wavelength-dependent bipolar response is realized based on the absorption difference of the photoactive region with different bandgap combined with the carrier competition of the homotypic transport layer adopted in the as-fabricated photodetector. Under the visible/near-infrared (NIR) light irradiation, the bottom/top of the film generates a higher carrier concentration, where electrons are easier to be separated and transported by the SnO2 /PC61 BM to the bottom/top electrodes, respectively, resulting in a negative and positive bipolar response. Finally, based on positive NIR signal as the effective signal and negative visible signal as the interference signal, the SOC system is realized, where the positive NIR signal is well hidden by the negative visible signal. This work provides a simple and feasible strategy for fabrication of laminated perovskite films to achieve bipolar response.

Leucosceptrane Sesterterpenoids as a New Type of Natural Immunosuppressive Agents in Treating Sepsis.

Intragastric administration of the total sesterterpenoid extract (TSE) of medicinal plant Leucosceptrum canum at 2.5 g/kg dose protected mice from LPS-induced sepsis. Phytochemical investigation led to the isolation and identification of 47 leucosceptrane sesterterpenoids (1-47) including 30 new compounds (1-30) with complicated oxygenation patterns. Biological screening indicated their immunosuppressive activity via inhibiting IFN-γ secretion and/or proliferation of T cells with different potencies. Mechanism study of compounds 9, 25, and 32 revealed that they inhibited the activations of AKT-mTOR, JNK, p38 MAPK or ERK pathway in T cells and macrophages. In addition, compounds 9 and 25 induced G0/G1 cell arrest of T cells. The major component, leucosceptroid N (32), significantly lowered the levels of IL-6 and TNF-α in peripheral blood serum, and ameliorated the multiorgan damages of LPS-induced sepsis mice at 25 mg/kg dose. These findings suggest that leucosceptrane sesterterpenoids are a new type of potential immunosuppressive agents for sepsis treatment.

Discovery of Unusual Sesterterpenoids from Colquhounia coccinea var. mollis and Their Metabolic Implications.

Three unusual sesterterpenoids featuring unprecedented rearranged colquhounane (C25) and tetranorcolquhounane (C21) frameworks, colquhounoids E (1) and F (3) and norcolquhounoid F (2), were isolated from a Lamiaceae medicinal plant Colquhounia coccinea var. mollis. Their structures were elucidated by spectroscopic analysis and quantum chemical calculations. A biomimetic inspired regioselective cyclopropane cleavage was achieved under acidic conditions. The immunosuppressive activities of these new sesterterpenoids were also evaluated.