Detection of Debonding Defects in Carbon Fiber-Reinforced Polymer (CFRP)-Rubber Bonded Structures Based on Active Lamb Wave Energy Analysis.

Carbon fiber-reinforced polymers (CFRPs) are widely used in the fabrication of solid rocket motor casings due to their exceptional performance. However, the bonding interface between CFRP and viscoelastic materials (rubber) is prone to debonding damage during service and storage under complex environmental conditions, which poses a significant threat to the structural integrity and reliability of the engine. Existing nondestructive testing (NDT) methods, such as X-ray imaging, infrared thermography, and ultrasonic testing, although somewhat effective, exhibit significant limitations in detecting interfacial defects in deep or multilayered composite materials, particularly under the challenging conditions of service and storage. This study proposes an innovative method based on active Lamb wave energy analysis and introduces the Damage Evolution Factor (DEF), specifically designed to detect and evaluate interfacial debonding defects in CFRP-rubber bonded structures within solid rocket motors during service and storage. Through numerical simulations and experimental validation, we selected the A0 mode Lamb wave, which is more sensitive to interfacial damage, as the incident wave and excited it on the surface of the structure. Displacement time-history response signals at observation points under different damage models were extracted and analyzed, and DEF values were calculated. The results show that DEF values increase with the size of the interfacial debonding damage. Similar trends were observed in experimental studies, further validating the effectiveness of this method and demonstrating that DEF can be used for the quantitative evaluation of interfacial debonding defects in CFRP-rubber bilayer bonded structures.

Ratiometric Imaging Detection of Amyloid-ß Fibrils by a Dual-Emissive Tris-Heteroleptic Ruthenium Complex.

Two dual fluorescent/phosphorescent tris-heteroleptic mononuclear Ru(ΙΙ) complexes (2 and 3) were designed and applied in amyloid-ß (Aß) sensing. These complexes have a general formula of [Ru(phen)(dppz)(L)](PF6)2, where L is (2-pyrazinyl)(2-pyridyl)(methyl)amine (H-L) with different substituents (-OMe for 2, -H for 3), phen is 1,10-phenanthroline, and dppz is dipyridophenazine, respectively. Compared with the previously reported ratiometric probe 1 with a di(pyrid-2-yl)(methyl)amine ligand, complex 2 can be employed for not only ratiometric emissive detection of Aß aggregation but also ratiometric imaging detection of Aß fibrils. In ratiometric emissive detection, as the incubation time of the Aß sample (Aß40 and Aß42) was prolonged, a new phosphorescence emission band appeared with gradual enhancement of the emission intensity, while the fluorescence emission was basically unchanged, which could be treated as an intrinsic internal reference signal. In comparison, a larger ratiometric photoluminescence enhancement (I640/I440) was observed for Aß40 aggregation with respect to Aß42. In ratiometric imaging detection, the imaging signals obtained from the phosphorescence emission are much brighter than the fluorescence emission in both Aß40 and Aß42 fibrils. As indicated by molecular docking results, stronger interactions were found between complex 2 with Aß40 fibrils, which included π/π, π/C-H, and π/H interactions between bidentate ligands dppz and phen with amino acid residues. Moreover, computational calculations were carried out to assist the interpretation of these experimental findings.

Natural Compound-Rhein and PROTACs Unleash Potent VEGFR-2 Degraders.

VEGFR-2 is a prominent therapeutic target in antitumor drug research to block tumor angiogenesis. This study focused on the synthesis and optimization of PROTACs based on the natural product rhein, resulting in the successful synthesis of 15 distinct molecules. In A549 cells, D9 exhibited remarkable antitumor efficacy with an IC50 of 5.88±0.50 µM, which was 15-fold higher compared to rhein (IC50=88.45±2.77 µM). An in-depth study of the effect of D9 on the degradation of VEGFR-2 revealed that D9 was able to induce the degradation of VEGFR-2 in A549 cells in a time-dependent manner. The observed effect was reversible, contingent upon the proteasome and ubiquitination system, and demonstrably linked to CRBN. Further experiments revealed that D9 induced apoptosis in A549 cells and led to cell cycle arrest in the G1 phase. Molecular docking simulations validated the binding mode of D9 to VEGFR, establishing the potential of D9 to bind to VEGFR-2 in its natural state. In summary, this study confirms the feasibility of natural product-bound PROTAC technology for the development of a new generation of VEGFR-2 degraders, offering a novel trajectory for the future development of pharmacological agents targeting VEGFR-2.

Determination of arbutin in vitro and in vivo by LC-MS/MS: Pre-clinical evaluation of natural product arbutin for its early medicinal properties.

ETHNOPHARMACOLOGICAL RELEVANCE: Arbutin is a naturally occurring glucoside extracted from plants, known for its antioxidant and tyrosinase inhibiting properties. It is widely used in cosmetic and pharmaceutical industries. With in-depth study of arbutin, its application in disease treatment is expanding, presenting promising development prospects. However, reports on the metabolic stability, plasma protein binding rate, and pharmacokinetic properties of arbutin are scarce. AIM OF THE STUDY: The aim of this study is to enrich the data of metabolic stability and pharmacokinetics of arbutin through the early pre-clinical evaluation, thereby providing some experimental basis for advancing arbutin into clinical research. MATERIALS AND METHODS: We developed an efficient and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for determining arbutin in plasma. We investigated the metabolic and pharmacokinetic properties of arbutin through in vitro metabolism assay, cytochrome enzymes P450 (CYP450) inhibition studies, plasma protein binding rate analysis, Caco-2 cell permeability tests, and rat pharmacokinetics to understand its in vivo performance. RESULTS: In vitro studies show that arbutin is stable, albeit with some species differences. It exhibits low plasma protein binding (35.35 ± 11.03% âˆ¼ 40.25 ± 2.47%), low lipophilicity, low permeability, short half-life (0.42 ± 0.30 h) and high oral bioavailability (65 ± 11.6%). Arbutin is primarily found in the liver and kidneys and is eliminated in the urine. It does not significantly inhibit CYP450 up to 10 µM, suggesting a low potential for drug interactions. Futhermore, preliminary toxicological experiments indicate arbutin's safety, supporting its potential as a therapeutic agent. CONCLUSION: This study provides a comprehensive analysis the drug metabolism and pharmacokinetics (DMPK) of arbutin, enriching our understanding of its metabolism stability and pharmacokinetics properties, It establishes a foundation for further structural optimization, pharmacological studies, and the clinical development of arbutin.

Study on Immunoregulatory Effects of Fucoidan from Sargassum graminifolium In Vivo and Immunoactivation Activity of Its Fecal Fermentation Products Using Co-Culture Model.

Fucoidan, brown seaweed-derived dietary fibers (DFs), can be considered a promising candidate for modulating immune responses. Due to its structural complexity and diversity, it is unclear whether Sargassum graminifolium fucoidans (SGFs) also show marvelous immunoregulatory effects. In the present study, two fractions, SGF-1 and SGF-2, were purified from SGFs by DEAE-Sepharose Fast Flow and Sephacryl S-400 HR column chromatography. We investigated the in vivo immune regulatory activity of SGF-2 and explored the immune activation of SGF-2 fecal fermentation products with in vitro fecal fermentation combined with a Caco-2/RAW264.7 co-culture system. In vivo results exhibited that SGF-2 could elevate the thymus/spleen indices, CD8+ splenic T lymphocyte subpopulations, and CD4+ Foxp3+ splenic Tregs. The 16S high-throughput sequencing results showed that SGF-2 administration significantly increased the relative abundance of Lactobacillus, Alloprevotella, Ruminococcus, and Akkermansia. In addition, it was found that SGF-2 fermented by feces could significantly improve the phagocytosis, NO, and cytokine (TNF-α, IL-6, and IL-10) production of macrophages in the co-culture system. These results indicated that SGFs have the potential to modulate immunity and promote health by affecting the gut microbiota.

Rapid Discovery of Substances with Anticancer Potential from Marine Fungi Based on a One Strain-Many Compounds Strategy and UPLC-QTOF-MS.

The secondary metabolites of marine fungi with rich chemical diversity and biological activity are an important and exciting target for natural product research. This study aimed to investigate the fungal community in Quanzhou Bay, Fujian, and identified 28 strains of marine fungi. A total of 28 strains of marine fungi were screened for small-scale fermentation by the OSMAC (One Strain-Many Compounds) strategy, and 77 EtOAc crude extracts were obtained and assayed for cancer cell inhibition rate. A total of six strains of marine fungi (P-WZ-2, P-WZ-3-2, P-WZ-4, P-WZ-5, P56, and P341) with significant changes in cancer cell inhibition induced by the OSMAC strategy were analysed by UPLC-QTOF-MS. The ACD/MS Structure ID Suite software was used to predict the possible structures with inhibitory effects on cancer cells. A total of 23 compounds were identified, of which 10 compounds have been reported to have potential anticancer activity or cytotoxicity. In this study, the OSMAC strategy was combined with an untargeted metabolomics approach based on UPLC-QTOF-MS to efficiently analyse the effect of changes in culture conditions on anticancer potentials and to rapidly find active substances that inhibit cancer cell growth.

Beyond traditional methods: Unveiling the skin whitening properties of Rhein-Embedded PROTACs.

Proteolysis Targeting Chimeras (PROTAC) technology has emerged as a promising approach for targeted protein degradation. In this study, we focused on tyrosinase (TYR), a key enzyme involved in melanin synthesis and pigmentation. For this target, we designed and synthesized a series of PROTACs (D3-D9), employing Rhein as the target protein-ligand. Through some experimental tests, we made a significant discovery. Preliminary experimental results show that the most promising compound (D6) demonstrated the ability to degrade MITF and inhibit the expression and TYR in B16-F10 cells, effectively suppressing melanogenesis in zebrafish. Notably, at equivalent concentrations, the whitening effect of D6 surpassed that of its precursor Rhein and was even comparable to that of the well-established whitening agent, ß-arbutin. Validating experiments further revealed that the action of D6 was reliant on the E3 ligand, indicating its capacity to degrade TYR and MITF through the ubiquitination pathway. Whether D6 acts directly on TYR or MITF needs to be further explored. These compelling results underscore the tremendous whitening potential of D6, suggesting its suitability as a valuable lead for whitening agents and its potential to expand the range of whitening cosmetic products.

Unveiling poly(rC)-binding protein 2 as the target protein for curcusone C against prostate cancer: mechanism validation through click chemistry-activity based proteomics profiling approach.

BACKGROUND: Prostate cancer is a disease that seriously troubles men. However, there are some inevitable limitations in interventional therapy for prostate cancer patients at present, most of which are caused by low selectivity and high toxic side effects due to unclear drug targets. In this study, we identified the target protein of Curcusone C with anti-prostate cancer potential activity and verified its target and mechanism of action. METHODS: Click chemistry-activity based proteomics profiling (CC-ABPP) method was used to find target protein of Curcusone C against prostate cancer. Competitive CC-ABPP, drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) methods were used to verifying the target protein. Moreover, potential mechanism was validated by western blot in vitro and by hematoxylin-eosin (HE) staining, detection of apoptosis in tumor tissue (TUNEL), and immunohistochemical (IHC) in vivo. RESULTS: We found that poly(rC)-binding protein 2 (PCBP2) was the target protein of Curcusone C. In addition, Curcusone C might disrupt the Bax/Bcl-2 balance in PC-3 cells by inhibiting the expression of the target protein PCBP2, thereby inducing mitochondrial damage and activation of the mitochondrial apoptosis pathway, and ultimately inducing apoptosis of prostate cancer cells. CONCLUSIONS: Curcusone C is a potential compound with anti-prostate cancer activity, and this effect occurs by targeting the PCBP2 protein, which in turn may affect the TGF/Smad signaling pathway and Bax/Bcl-2 balance. Our results laid a material and theoretical foundation for Curcusone C, to be widely used in anti-prostate cancer.

Design, synthesis and biological evaluation of VEGFR-2/HDAC dual inhibitors as multitargeted antitumor agents based on fruquintinib and vorinostat.

Herein, a series of 4-(benzofuran-6-yloxy)quinazoline derivatives as VEGFR-2/HDAC dual inhibitors were designed and synthesized based on fruquintinib and vorinostat. Among them, compound 13 exhibited potent inhibitory activity against VEGFR-2 and HDAC1 with IC50 values of 57.83 nM and 9.82 nM, and displayed moderate to significant antiproliferative activity against MCF-7, A549, HeLa and HUVEC. The cellular mechanism studies revealed that compound 13 arrested the cell cycle at the S and G2 phases, and induced significant apoptosis in HeLa cells. Tube formation assay in HUVECs demonstrated that 13 had a significant anti-angiogenic effect. Additionally, a molecular docking study supported the initial design strategy. These results highlighted that 13 was a valuable VEGFR-2/HDAC dual inhibitor and deserved further study for cancer therapy.

Pb2+ removal based on the confinement effect in polygonal carbon nanotubes: a molecular dynamics simulation.

Heavy metal Pb2+ pollutants have become an important environmental problem, which threatens public health and ecosystems worldwide. In this study, to explore the effective treatment of trace Pb2+ pollution in water, molecular dynamics simulation combined with DFT calculations was used to study the transportation behavior of Pb2+ using polygonal carbon nanotubes (PCNT: P = 4, 5, 6, 8)/graphene composites (PCNTs/G). It is shown that due to the confinement effect of PCNTs, both H2O and H3O+ can form a hydrogen-bonding network and transport them in the form of proton exchange through the PCNT channels. The trajectory shows that with the help of a hydrogen-bonding network, the probability of Pb2+ passing through the 8N channel is enhanced. Then, upon the fluorine modification of PCNTs, mutual effects of both the hydrogen-bonding network and electrophilic attraction make Pb2+ get through the channel of 8F. It is indicated that with respect to 4CNT/G, 5CNT/G, and 6CNT/G, 8CNT/G is not accurate for Pb2+ interception at the outlets. In addition, the RDF, and HOMO-LUMO orbitals indicate that the affinity from the hydrogen-bonding network and PCNT walls both play important roles in particle transportation. This work can not only provide a basic understanding of Pb2+ transportation in PCNTs from the perspective of diffusion but also be helpful to guide the strategy on how to deal with Pb2+ pollution in waters.

Synthesis, evaluation of anti-breast cancer activity in vitro of ICS II derivatives and summary of the structure-activity relationship.

A series of Icariside II (ICS II) derivatives were synthesized, and their structure-activity relationships (SARs) were studied in this paper. The in vitro antitumor activities towards human breast cancer cell lines (MCF-7) were evaluated by Cell Counting Kit-8 (CCK-8 kit). Preliminary results showed that, compared with ICS II, most of the derivatives displayed good micromole level activities. Among the series of derivatives, the S27, which totally acetylated hydroxyl of ICS II, possessed highest cytotoxicity, with IC50 values of 0.70 ± 0.08 µM. Furthermore, compound S27 showed better selectivity than ICS II for cancer cells over normal cells. Our findings indicate that compound S27 may be a promising anticancer lead candidate drug.

Effects of fucoidans and alginates from Sargassum graminifolium on allergic symptoms and intestinal microbiota in mice with OVA-induced food allergy.

Food allergy has been one of the main problems threatening people's health in recent years. However, there is still no way to completely cure it at present. Therefore, the development of food allergy related drugs is still necessary. Sargassum graminifolium (SG) is a kind of polysaccharide rich marine brown alga used in food and medicine. Sargassum graminifolium polysaccharides (SGP) is mainly composed of fucoidans and alginic acid. In our study, we compared the activity of fucoidans and alginates from SG against OVA-induced food allergy in a mouse model, observed the regulatory effects of fucoidans and alginates from SG on the intestinal microbiota and summarized the possible role of the intestinal microbiota in the anti-food allergy process because polysaccharides can further act on the body through the intestinal microbiota. The results showed that fucoidans and alginates from SG could relieve the symptoms of allergy, diarrhea and jejunum injury significantly in mice with food allergy (p < 0.05). Furthermore, fucoidans at 500 mg kg-1 could reduce OVA-specific IgE and TNF-α levels significantly in the serum of food allergic mice (p < 0.05), while alginates could only significantly down-regulate serum OVA-specific IgE (p < 0.05). The results also showed that fucoidans had a stronger regulatory effect on the richness and diversity of the intestinal microbiota in food allergic mice compared to alginates at the same dose. In addition, fucoidans at 500 mg kg-1 had the most significant regulatory effect on Firmicutes, Lactobacillus and Alistipes in food allergic mice. These results suggested that fucoidans and alginates might regulate food allergy in mice through different pathways. Together, this study enriched the research on the action of alga-derived polysaccharides against food allergy.

Ganoderma Lucidum Triterpenoids Improve Maternal Separation-Induced Anxiety- and Depression-like Behaviors in Mice by Mitigating Inflammation in the Periphery and Brain.

Although early life stress (ELS) can increase susceptibility to adulthood psychiatric disorders and produce a greater inflammatory response in a stressful event, targeted preventive and therapeutic drugs still remain scarce. Ganoderma lucidum triterpenoids (GLTs) can exert anti-inflammatory effects in the periphery and central nervous systems. This study employed a combined model of "childhood maternal separation + adulthood sub-stress" to explore whether GLTs may alleviate anxiety- and depression-like behaviors in male and female mice by mitigating inflammation. Male and female pups were separated from their mothers for four hours per day from postnatal day 1 (PND 1) to PND 21; starting from PND 56, GLTs were administered intraperitoneally once daily for three weeks and followed by three days of sub-stress. Results showed that maternal separation increased the anxiety- and depression-like behaviors in both male and female mice, which disappeared after the preemptive GLTs treatment (40 mg/kg) before adulthood sub-stress. Maternal separation up-regulated the pro-inflammatory markers in the periphery and brain, and activated microglia in the prefrontal cortex and hippocampus. All the abnormalities were reversed by GLTs administration, with no adverse effects on immune organ indices, liver, and renal function. Our findings suggest that GLTs can be a promising candidate in treating ELS-induced psychiatric disorders.

Discovery of quinazoline derivatives as novel small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction.

Development of small molecule PD-1/PD-L1 inhibitors as a novel immunotherapy strategy exhibits great promise. Herein, a novel series of quinazoline derivatives were designed, synthesized and their inhibitory activity against the PD-1/PD-L1 interaction was evaluated through a homogenous time-resolved fluorescence (HTRF) assay. Among them, the compound 39 exhibited the most potent inhibitory activity with an IC50 value of 1.57 nM. Furthermore, the cellular level assays revealed that 39 could inhibit the PD-1/PD-L1 interaction and restore T-cell function, and showed low toxicity on the PBMCs. In addition, the structure-activity relationships (SARs) of the novel quinazoline derivatives were explored and the binding mode of 39 with dimeric PD-L1 was analyzed by molecular docking. This work demonstrates that incorporation of pyrimidine group between the 2 and 3-positions of the biphenyl structure is an effective strategy for designing novel and more potent small molecule PD-1/PD-L1 inhibitors, and 39 can be regarded as a promising lead compound for further investigation.

Dual-Emissive Tris-Heteroleptic Ruthenium Complexes: Tuning the DNA-Triggered Ratiometric Emission Response by Ancillary Ligands.

Three tris-heteroleptic mononuclear Ru(II) complexes with dual fluorescence and phosphorescence-[Ru(dpma)(bpy)(phen)]2+ (12+), [Ru(dpma)(bpy)(dppz)]2+ (22+), and [Ru(dpma)(phen)(dppz)]2+ (32+)-have been designed and used as ratiometric light-response probes for DNA, where dpma is di(pyrid-2-yl)(methyl)-amine, bpy is 2,2'-bipyridine, phen is 1,10-phenanthroline, and dppz is dipyridophenazine, respectively. Single crystals of complex 2(PF6)2 have been obtained and studied by X-ray analysis. The interactions of these complexes with different DNAs are investigated by means of spectroscopic methods, viscosity measurements, and molecular modeling. In the presence of calf thymus DNA, complexes 2(PF6)2 and 3(PF6)2 show the emergence of a new lower-energy phosphorescence emission band; meanwhile, the higher-energy fluorescence emission band is essentially unchanged, functioning as an intrinsic internal reference. These two complexes exhibit stronger preference for calf thymus DNA over single-strand DNA (d(A)16 and d(C)16). In contrast, no binding interaction between 1(PF6)2 and calf thymus DNA is observed. The intrinsic binding constants (Kb) of 2(PF6)2 and 3(PF6)2 with calf thymus DNA are determined to be (1.4 ± 0.4) × 105 and (9.5 ± 0.15) × 104 M-1, respectively. In addition, these spectroscopic results are compared with those of the prototype complex [Ru(bpy)2(dppz)]2+ (42+), and density functional theory and time-dependent density functional theory calculations are employed to elucidate these experimental findings.

Total Synthesis and Target Identification of the Curcusone Diterpenes.

The curcusone natural products are complex diterpenes featuring a characteristic [6-7-5] tricyclic carbon skeleton similar to the daphnane and tigliane diterpenes. Among them, curcusones A-D demonstrated potent anticancer activity against a broad spectrum of human cancer cell lines. Prior to this study, no total synthesis of the curcusones was achieved and their anticancer mode of action remained unknown. Herein, we report our synthetic and chemoproteomics studies of the curcusone diterpenes which culminate in the first total synthesis of several curcusone natural products and identification of BRCA1-associated ATM activator 1 (BRAT1) as a cellular target. Our efficient synthesis is highly convergent, builds upon cheap and abundant starting materials, features a thermal [3,3]-sigmatropic rearrangement and a novel FeCl3-promoted cascade reaction to rapidly construct the critical cycloheptadienone core of the curcusones, and led us to complete the first total synthesis of curcusones A and B in only 9 steps, C and D in 10 steps, and dimericursone A in 12 steps. The chemical synthesis of dimericursone A from curcusones C and D provided direct evidence to support the proposed Diels-Alder dimerization and cheletropic elimination biosynthetic pathway. Using an alkyne-tagged probe molecule, BRAT1, an important but previously "undruggable" oncoprotein, was identified as a key cellular target via chemoproteomics. We further demonstrate for the first time that BRAT1 can be inhibited by curcusone D, resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.

The synthesis and cytotoxic activity of derivatives of 4ß-hydroxywithanolide E.

4ß-Hydroxywithanolide E, which can be obtained in large amounts from the Physalis genus, possessed anti-proliferative effects on a variety of human cancer cell lines. For discussing its anti-tumor structure-activity relationship, a series of 4ß-hydroxywithanolide E derivatives (1-17) were synthesized and evaluated for their antitumor activity in vitro towards acute promyelocytic leukemia NB4 cell line by the Alarma blue assay. Cytotoxicity data revealed that the enone structure and C-4 hydroxyl substituents of ring A, together with the side chain (C-20-C-28) play an important effect on the cytotoxicity.

New lathyrane diterpenoids with anti-inflammatory activity isolated from the roots of Jatropha curcas L.

ETHNOPHARMACOLOGICAL RELEVANCE: Jatropha curcas L. (Euphorbiaceae), as a drought resistant shrub mainly cultivated in tropical and subtropical areas worldwide, is widely used as traditional medicine to cure arthritis, dysentery, abscess and pneumonia in Asian, African and South American folklores. The methanolic extracts of the roots have been revealed the anti-inflammatory activity in vivo and vitro. AIM OF STUDY: This research aimed to provide promising anti-inflammatory candidates from the roots of J. curcas. In addition, RNA-Seq was conducted to give targeted genes involved in the anti-inflammatory action. MATERIALS AND METHODS: The diterpenoids were isolated from the CH2Cl2 fraction of the methanolic extract from the roots of J. curcas by column chromatography (CC): silica gel, Sephadex LH-20, ODS, semi-preparative reversed-phase high-performance liquid chromatography (HPLC). The structures were identified based on HR-ESI-MS and 1D, 2D-NMR spectroscopic analysis. Their anti-inflammatory effects were tested on lipopolysaccharide (LPS, 500 ng/mL)-stimulated murine RAW264.7 macrophages. Furthermore, we conducted transcriptome-wide RNA sequencing to profile gene expression alterations in LPS-induced RAW264.7 cells upon treatment with jatrocurcasenone I (4) and analyzed the underlying genes targeted by this compound. RESULTS: Six diterpenoids were obtained from J. curcas, and four of them were identified to be new lathyrane diterpenoids: jatrocurcasenones F-I (1-4). Compounds 3 and 4 exhibited potent inhibitory activities against LPS-induced nitric oxide (NO) production in RAW264.7 cells with IC50 values of 11.28 µM and 7.71 µM, respectively. Western blotting analysis showed that the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were suppressed with the supplementation of 3 and 4. The results of RNA-seq showed that 4 (20 µM) exhibited regulation on the 587 differentially expressed genes (DEGs) induced by LPS (500 ng/mL). Transcriptome-wide RNA sequencing indicated that the protective activity of 4 supplementation was most likely driven by modulating expression levels of IL-1α, IL-1ß, IL-1f6, IL-6, IL-1rn, IL-27, Ccl2, Ccl5, Ccl7, Ccl9, Ccl22, Cxcl10, Tnfsf12, Tnfsf15, Lta, Trim25, Bcl2a1a, Dusp1, Dusp2, Ptgs2, Edn1 and Nr4a1. CONCLUSIONS: This study offered four new lathyrane diterpenoids, of them, jatrocurcasenone I (4) showed significant anti-inflammatory activity. RNA-Seq suggested that jatrocurcasenone I (4) could be a candidate drug for the prevention inflammation-mediated diseases by modulating 24 candidate DEGs.

Spartinivicinus ruber gen. nov., sp. nov., a Novel Marine Gammaproteobacterium Producing Heptylprodigiosin and Cycloheptylprodigiosin as Major Red Pigments.

The red pigment prodiginines are identified as bacterial secondary metabolites and display a wide range of bioactive properties. Here, a novel rose-red pigmented bacterium, designated strain S2-4-1HT, was isolated from coastal sediment of cordgrass Spartina alterniflora. Interestingly, it simultaneously produced heptylprodigiosin (C22H29N3O) and cycloheptylprodigiosin (C22H27N3O) as major red pigments, of which their chemical structures were established by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). Bioactive assays revealed that both heptylprodigiosin and cycloheptylprodigiosin had antibacterial and antifungal activities, and notably, cycloheptylprodigiosin showed stronger bioactivity than heptylprodigiosin. The complete genome of strain S2-4-1HT was determined to be 6,687,090 bp in length with a G + C content of 40.13 mol%, including a circular chromosome with a size of 6,361,125 bp and three plasmids with a size of 141,078, 102,423, and 82,464 bp, respectively. The biosynthetic gene cluster of two red pigments was predicted on a ∼41-kb gene fragment organized on the chromosome and displayed highly conserved features compared to several gammaproteobacterial species encoding the homologous genes. Finally, based on phenotypic, genotypic, and chemotaxonomic characteristics, strain S2-4-1HT represented a novel genus-level species named Spartinivicinus ruber gen. nov., sp. nov. (type strain S2-4-1HT = MCCC 1K03745T = KCTC 72148T). Our study provided a novel bacterial source and novel prodigiosin analogs as promising pharmaceuticals in biotechnological application.

Hydroxy-octadecenoic acids instead of phorbol esters are responsible for the Jatropha curcas kernel cake's toxicity.

The toxic kernel cake of Jatropha curcas (KCakeJ) is an emerging health and environmental concern. Although phorbol esters are widely recognized as the major toxin of KCakeJ, convincing evidence is absent. Here, we show that rather than phorbol esters an isomeric mixture of 11-hydroxy-9E-octadecenoic acid, 12-hydroxy-10E-octadecenoic acid and 12-hydroxy-10Z-octadecenoic acid (hydroxy-octadecenoic acids, molecular formula C18H34O3) is the major toxic component. The toxicities of hydroxy-octadecenoic acids on experimental animals, e.g. acute lethality, causing inflammation, pulmonary hemorrhage and thrombi, allergies, diarrhea and abortion, are consistent with those on human/animals caused by Jatropha seed and/or KCakeJ. The hydroxyl group and the double bond are essential for hydroxy-octadecenoic acids' toxicity. The main pathway of the toxicity mechanism includes down-regulating UCP3 gene expression, promoting ROS production, thus activating CD62P expression (platelet activation) and mast cell degranulation. The identification of the major toxin of KCakeJ lays a foundation for establishing an environmentally friendly Jatropha biofuel industry.