IL-6 Inhibitory Compounds from the Aerial Parts of Piper attenuatum and Their Anticancer Activities on Ovarian Cancer Cell Lines.

Piper attenuatum Buch-Ham, a perennial woody vine belonging to the Piperaceae family, is traditionally used in Southeast Asia for treating various ailments such as malaria, headache, and hepatitis. This study described the isolation and identification of three new compounds, piperamides I-III (1-3), which belong to the maleimide-type alkaloid skeletons, along with fifteen known compounds (4-18) from the methanol extract of the aerial parts of P. attnuatum. Their chemical structures were elucidated using spectroscopic methods (UV, IR, ESI-Q-TOF-MS, and 1D/2D NMR). All the isolates were evaluated for their ability to inhibit IL-6 activity in the human embryonic kidney-Blue™ IL-6 cell line and their cytotoxic activity against ovarian cancer cell lines (SKOV3/SKOV3-TR) and chemotherapy-resistant variants (cisplatin-resistant A2780/paclitaxel-resistant SKOV3). The compounds 3, 4, 11, 12, 17, and 18 exhibited IL-6 inhibition comparable to that of the positive control bazedoxifene. Notably, compound 12 displayed the most potent anticancer effect against all the tested cancer cell lines. These findings highlight the importance of researching the diverse activities of both known and newly discovered natural products to fully unlock their potential therapeutic benefits.

Discrimination of relatedness drives rice flowering and reproduction in cultivar mixtures.

The improvement of performance and yield in both cultivar and species mixtures has been well established. Despite the clear benefits of crop mixtures to agriculture, identifying the critical mechanisms behind performance increases are largely lacking. We experimentally demonstrated that the benefits of rice cultivar mixtures were linked to relatedness-mediated intraspecific neighbour recognition and discrimination under both field and controlled conditions. We then tested biochemical mechanisms of responses in incubation experiments involving the addition of root exudates and a root-secreted signal, (-)-loliolide, followed by transcriptome analysis. We found that closely related cultivar mixtures increased grain yields by modifying root behaviour and accelerating flowering over distantly related mixtures. Importantly, these responses were accompanied by altered concentration of signalling (-)-loliolide that affected rice transcriptome profiling, directly regulating root growth and flowering gene expression. These findings suggest that beneficial crop combinations may be generated a-priori by manipulating neighbour genetic relatedness in rice cultivar mixtures and that root-secreted (-)-loliolide functions as a key mediator of genetic relatedness interactions. The ability of relatedness discrimination to regulate rice flowering and yield raises an intriguing possibility to increase crop production.

Phytochemical Cue for the Fitness Costs of Herbicide-Resistant Weeds.

Despite increasing knowledge of the fitness costs of viability and fecundity involved in the herbicide-resistant weeds, relatively little is known about the linkage between herbicide resistance costs and phytochemical cues in weed species and biotypes. This study demonstrated relative fitness and phytochemical responses in six herbicide-resistant weeds and their susceptible counterparts. There were significant differences in the parameters of viability (growth and photosynthesis), fecundity fitness (flowering and seed biomass) and a ubiquitous phytochemical (-)-loliolide levels between herbicide-resistant weeds and their susceptible counterparts. Fitness costs occurred in herbicide-resistant Digitaria sanguinalis and Leptochloa chinensis but they were not observed in herbicide-resistant Alopecurus japonicas, Eleusine indica, Ammannia arenaria, and Echinochloa crus-galli. Correlation analysis indicated that the morphological characteristics of resistant and susceptible weeds were negatively correlated with (-)-loliolide concentration, but positively correlated with lipid peroxidation malondialdehyde and total phenol contents. Principal component analysis showed that the lower the (-)-loliolide concentration, the stronger the adaptability in E. crus-galli and E. indica. Therefore, not all herbicide-resistant weeds have fitness costs, but the findings showed several examples of resistance leading to improved fitness even in the absence of herbicides. In particular, (-)-loliolide may act as a phytochemical cue to explain the fitness cost of herbicide-resistant weeds by regulating vitality and fecundity.

Identification of Loliolide with Anti-Aging Properties from Scenedesmus deserticola JD052.

Herein, different extracts of Scenedesmus deserticola JD052, a green microalga, were evaluated in vitro as a potential anti-aging bioagent. Although post-treatment of microalgal culture with either UV irradiation or high light illumination did not lead to a substantial difference in the effectiveness of microalgal extracts as a potential anti-UV agent, the results indicated the presence of a highly potent compound in ethyl acetate extract with more than 20% increase in the cellular viability of normal human dermal fibroblasts (nHDFs) compared with the negative control amended with DMSO. The subsequent fractionation of the ethyl acetate extract led to two bioactive fractions with high anti-UV property; one of the fractions was further separated down to a single compound. While electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR) spectroscopy analysis identified this single compound as loliolide, its identification has been rarely reported in microalgae previously, prompting thorough systematic investigations into this novel compound for the nascent microalgal industry.

Kin Recognition in an Herbicide-Resistant Barnyardgrass (Echinochloa crus-galli L.) Biotype.

Despite increasing evidence of kin recognition in natural and crop plants, there is a lack of knowledge of kin recognition in herbicide-resistant weeds that are escalating in cropping systems. Here, we identified a penoxsulam-resistant barnyardgrass biotype with the ability for kin recognition from two biotypes of penoxsulam-susceptible barnyardgrass and normal barnyardgrass at different levels of relatedness. When grown with closely related penoxsulam-susceptible barnyardgrass, penoxsulam-resistant barnyardgrass reduced root growth and distribution, lowering belowground competition, and advanced flowering and increased seed production, enhancing reproductive effectiveness. However, such kin recognition responses were not occurred in the presence of distantly related normal barnyardgrass. Root segregation, soil activated carbon amendment, and root exudates incubation indicated chemically-mediated kin recognition among barnyardgrass biotypes. Interestingly, penoxsulam-resistant barnyardgrass significantly reduced a putative signaling (-)-loliolide production in the presence of closely related biotype but increased production when growing with distantly related biotype and more distantly related interspecific allelopathic rice cultivar. Importantly, genetically identical penoxsulam-resistant and -susceptible barnyardgrass biotypes synergistically interact to influence the action of allelopathic rice cultivar. Therefore, kin recognition in plants could also occur at the herbicide-resistant barnyardgrass biotype level, and intraspecific kin recognition may facilitate cooperation between genetically related biotypes to compete with interspecific rice, offering many potential implications and applications in paddy systems.

Penoxsulam-resistant barnyardgrass-mediated rhizosphere microbial communities affect the growth of rice.

BACKGROUND: The incidence of herbicide-resistant barnyardgrass is escalating in paddy fields, yet the interactions between resistant weeds and rice are largely unknown. The microbiota of herbicide-resistant barnyardgrass rhizosphere soil is critical for both barnyardgrass and rice fitness. RESULTS: Rice has different biomass allocation and root traits in the presence of penoxsulam-resistant versus penoxsulam-susceptible barnyardgrass or in their conditioned soil. Compared to susceptible barnyardgrass, resistant barnyardgrass led to an allelopathic increase in rice root, shoot, and whole-plant biomasses. Resistant barnyardgrass recruited distinct core and unique microbes in rhizosphere soil compared to susceptible barnyardgrass. In particular, resistant barnyardgrass assembled more Proteobacteria and Ascomycota to enhance plant stress tolerance. Furthermore, the root exudates from resistant and susceptible barnyardgrass were responsible for the assembly and establishment of the root microbial structure. Importantly, (-)-loliolide and jasmonic acid in root exudates were correlated with the core microbes in the rhizosphere soil. CONCLUSION: The interference of barnyardgrass with rice can be mediated by rhizosphere microbial communities. Biotype-specific variation in the ability to generate soil microbial communities appears to ameliorate the negative consequences for rice growth, providing an intriguing possibility for modulation of the rhizosphere microbiota to increase crop productivity and sustainability. © 2023 Society of Chemical Industry.

The Allelopathic Effects of Trewia nudiflora Leaf Extracts and Its Identified Substances.

Trewia nudiflora Linn. is a woody plant of the Euphorbiaceae family. It is well known for its use as a folk remedy, but its potential for phytotoxicity has not been explored. Therefore, this study investigated the allelopathic potential and the allelopathic substances in T. nudiflora leaves. The aqueous methanol extract of T. nudiflora was found to have a toxic effect on the plants used in the experiment. The shoot and root development of lettuce (Lactuca sativa L.) and foxtail fescue (Vulpia myuros L.) were significantly (p ≤ 0.05) reduced by the T. nudiflora extracts. The growth inhibition by the T. nudiflora extracts was proportional to the extract concentration and varied with the test plant species. The chromatographic separation of the extracts resulted in the isolation of two substances, identified as loliolide and 6,7,8-trimethoxycoumarin based on their respective spectral analyses. Both substances significantly inhibited lettuce growth at a concentration of 0.01 mM. To inhibit 50% of the growth of the lettuce, the required concentration of loliolide was 0.043 to 0.128 mM, while that of 6,7,8-trimethoxycoumarin was 0.028 to 0.032 mM. Comparing these values, the lettuce growth was more sensitive to 6,7,8-trimethoxycoumarin than loliolide, suggesting that 6,7,8-trimethoxycoumarin was more effective than loliolide. Therefore, the inhibition of the growth of the lettuce and foxtail fescue suggests that loliolide and 6,7,8-trimethoxycoumarin are responsible for the phytotoxicity of the T. nudiflora leaf extracts. Thus, the growth-inhibitory effectiveness of the T. nudiflora extracts and the identified loliolide and 6,7,8-trimethoxycoumarin may be used to develop bioherbicides that restrict the growth of weeds.

Potential function of loliolide as a novel blocker of epithelial-mesenchymal transition in colorectal and breast cancer cells.

Loliolide (LL), a naturally occurring monoterpenoid lactone isolated from Vicia tenuifolia Roth, can exhibit numerous pharmacological effects such as those related to anti-Parkinson, anti-oxidant, anti-cholinesterase, and anti-depressant. Epithelial-mesenchymal transition (EMT) plays a pivotal role in regulating tumor metastasis. CXCR4 and CXCR7 are G-protein-coupled receptors (GPRs), which can be stimulated by CXCL12. CXCL12/CXCR4/CXCXR7 axis can cause activation of multiple pathways including MAPKs, JAK/STAT pathway, and manganese superoxide dismutase (MnSOD) signaling. These events can initiate EMT process and induce cell invasion and migration. Here, we investigated whether LL can modulate the CXCR4 and CXCR7 and EMT process in colon cancer and breast cancer cells. We found that LL suppressed levels of CXCR4 and CXCR7, and exerted an inhibitory effect on these chemokines even after stimulation by CXCL12. LL suppressed expression of MnSOD and mesenchymal markers, whereas induced epithelial markers. In addition, LL significantly attenuated cellular invasion, migration, and metastasis. We noted that LL inhibited CXCR4/7 and EMT process even after stimulation of CXCL12 and MnSOD overexpression. Therefore, in this study, we provide evidences that targeting CXCR4/7 and MnSOD could inhibit the invasion, migration, and metastasis of cancer cells as well as negatively regulate the EMT process. Overall, our study suggested that LL might act as a potent suppressor of EMT process against colon and breast cancer cells.

(-)-Loliolide is a general signal of plant stress that activates jasmonate-related responses.

The production of defensive metabolites in plants can be induced by signaling chemicals released by neighboring plants. Induction is mainly known from volatile aboveground signals, with belowground signals and their underlying mechanisms largely unknown. We demonstrate that (-)-loliolide triggers defensive metabolite responses to competitors, herbivores, and pathogens in seven plant species. We further explore the transcriptional responses of defensive pathways to verify the signaling role of (-)-loliolide in wheat and rice models with well-known defensive metabolites and gene systems. In response to biotic and abiotic stressors, (-)-loliolide is produced and secreted by roots. This, in turn, induces the production of defensive compounds including phenolic acids, flavonoids, terpenoids, alkaloids, benzoxazinoids, and cyanogenic glycosides, regardless of plant species. (-)-Loliolide also triggers the expression of defense-related genes, accompanied by an increase in the concentration of jasmonic acid and hydrogen peroxide (H2 O2 ). Transcriptome profiling and inhibitor incubation indicate that (-)-loliolide-induced defense responses are regulated through pathways mediated by jasmonic acid, H2 O2 , and Ca 2+ . These findings argue that (-)-loliolide functions as a common belowground signal mediating chemical defense in plants. Such perception-dependent plant chemical defenses will yield critical insights into belowground signaling interactions.

Root placement patterns in allelopathic plant-plant interactions.

Plants actively respond to their neighbors by altering root placement patterns. Neighbor-modulated root responses involve root detection and interactions mediated by root-secreted functional metabolites. However, chemically mediated root placement patterns and their underlying mechanisms remain elusive. We used an allelopathic wheat model system challenged with 60 target species to identify root placement responses in window rhizobox experiments. We then tested root responses and their biochemical mechanisms in incubation experiments involving the addition of activated carbon and functional metabolites with amyloplast staining and auxin localization in roots. Wheat and each target species demonstrated intrusive, avoidant or unresponsive root placement, resulting in a total of nine combined patterns. Root placement patterns were mediated by wheat allelochemicals and (-)-loliolide signaling of neighbor species. In particular, (-)-loliolide triggered wheat allelochemical production that altered root growth and placement, degraded starch grains in the root cap and induced uneven distribution of auxin in target species roots. Root placement patterns in wheat-neighbor interactions were perception dependent and species dependent. Signaling (-)-loliolide induced the production and release of wheat allelochemicals that modulated root placement patterns. Therefore, root placement patterns are generated by both signaling chemicals and allelochemicals in allelopathic plant-plant interactions.

Root-secreted (-)-loliolide modulates both belowground defense and aboveground flowering in Arabidopsis and tobacco.

Plant defense, growth, and reproduction can be modulated by chemicals emitted from neighboring plants, mainly via volatile aboveground signals. However, belowground signals and their underlying control mechanisms are largely unknown. Here, we experimentally demonstrate that the root-secreted carotenoid (-)-loliolide mediates both defensive and reproductive responses in wild-type Arabidopsis, a carotenoid-deficient Arabidopsis mutant (szl1-1), and tobacco (Nicotiana benthamiana). Wild-type Arabidopsis plants flower later than szl1-1, and they secrete (-)-loliolide into the soil, whereas szl1-1 roots do not. When Arabidopsis and tobacco occur together, wild-type Arabidopsis induces nicotine production and defense-related gene expression in tobacco, whereas szl1-1 impairs this induction but accelerates tobacco flowering. Furthermore, nicotine production and the expression of the key genes involved in nicotine biosynthesis (QPT, PMT1), plant defense (CAT1, SOD1, PR-2a, PI-II, TPI), and flowering (AP1, LFY, SOC1, FT3, FLC) are differently regulated by incubation with wild-type Arabidopsis and szl1-1 root exudates or (-)-loliolide. In particular, (-)-loliolide up-regulated flowering suppressors (FT3 and FLC) and transiently down-regulated flowering stimulators (AP1 and SOC1), delaying tobacco flowering. Therefore, root-secreted (-)-loliolide modulates plant belowground defense and aboveground flowering, yielding critical insights into plant-plant signaling interactions.

(-)-Loliolide Isolated from Sargassum horneri Abate UVB-Induced Oxidative Damage in Human Dermal Fibroblasts and Subside ECM Degradation.

Ultraviolet (UV) B exposure is a prominent cause of skin aging and a contemporary subject of interest. The effects are progressing through the generation of reactive oxygen species (ROS) that alter cell signaling pathways related to inflammatory responses. The present study evaluates the protective effects of (7aR)-6-hydroxy-4,4,7a-trimethyl-6,7-dihydro-5H-1-benzofuran-2-one (HTT) isolated from the edible brown algae Sargassum horneri against UVB protective effects in human dermal fibroblasts (HDFs). HTT treatment dose-dependently suppressed intracellular ROS generation in HDFs with an IC50 of 62.43 ± 3.22 µM. HTT abated UVB-induced mitochondrial hyperpolarization and apoptotic body formation. Furthermore, UVB-induced activation of key nuclear factor (NF)-κB and mitogen-activated protein kinase signaling proteins were suppressed in HTT treated cells while downregulating pro-inflammatory cytokines (interleukin-1ß, 6, 8, 33 and tumor necrosis factor-α). Moreover, HTT treatment downregulated matrix metalloproteinase1, 2, 3, 8, 9 and 13 that was further confirmed by the inhibition of collagenase and elastase activity. The evidence implies that HTT delivers protective effects against premature skin aging caused by UVB exposure via suppressing inflammatory responses and degradation of extracellular matrix (ECM) components. Extensive research in this regard will raise perspectives for using HTT as an ingredient in UV protective ointments.

(-)-Loliolide Isolated from Sargassum horneri Suppressed Oxidative Stress and Inflammation by Activating Nrf2/HO-1 Signaling in IFN-γ/TNF-α-Stimulated HaCaT Keratinocytes.

The present study evaluated the effects of (-)-loliolide isolated from Sargassum horneri (S. horneri) against oxidative stress and inflammation, and its biological mechanism in interferon (IFN)-γ/tumor necrosis factor (TNF)-α-stimulated HaCaT keratinocytes. The results showed that (-)-loliolide improved the cell viability by reducing the production of intracellular reactive oxygen species (ROS) in IFN-γ/TNF-α-stimulated HaCaT keratinocytes. In addition, (-)-loliolide effectively decreased the expression of inflammatory cytokines (interleukin (IL)-4 IL-6, IL-13, IFN-γ and TNF-α) and chemokines (CCL11 (Eotaxin), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC)), by downregulating the expression of epidermal-derived initial cytokines (IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)). Furthermore, (-)-loliolide suppressed the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling, whereas it activated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Interestingly, the cytoprotective effects of (-)-loliolide against IFN-γ/TNF-α stimulation were significantly blocked upon inhibition of HO-1. Taken together, these results suggest that (-)-loliolide effectively suppressed the oxidative stress and inflammation by activating the Nrf2/HO-1 signaling in IFN-γ/TNF-α-stimulated HaCaT keratinocytes.

Barnyard grass [Echinochloa crus-galli (L.) Beauv] leaves extract against tomato pests.

BACKGROUND: Tomato is one of the widely cultivated crops worldwide that is affected by several pests, such as fungi (Fusarium oxysoporum, Alternaria solani), bacteria (Pectobacterium carotovorum) and weeds (Cyperus iria L., Amaranthus spinosus). A growing interest has emerged for developing plant-derived pesticidal compounds to counteract these pests. One attractive alternative is to use barnyard grass (Echinochloa crus-galli), known to be widely resistant to synthetic herbicides, as a potential biopesticide compound source. RESULTS: Phytochemical screening of the crude extract showed that phenolic compounds were the most abundant component present in barnyard grass. The crude extract was evaluated for antifungal, antibacterial and herbicidal activities. Bioassays showed inhibition against F. oxysporum (10.73 ± 1.30%) and A. solani (20.47 ± 3.51%), the causative agent of Fusarium rot and early blight disease in tomato, respectively. Antibacterial activity against P. carotovorum gave a mean zone of inhibition (paper disc diffusion assay) of 17.00 ± 1.00 mm and an IC50 (dose-response assay) of 2.26 mg mL-1 was observed. Dose-responsive herbicidal activity on the lettuce seed germination bioassay produced an IC50 of 459.30 ppm. Selectivity studies showed inhibition towards C. iria and A. spinosus with no effect on tomato. Lastly, bioassay-guided fractionation coupled with untargeted metabolomics studies using ultra-performance liquid chromatography with diode array detection-tandem mass spectrometry mass analyses revealed loliolide and tricin as the putative metabolites present in barnyard grass. CONCLUSION: To date, this is the first reported study on using barnyard grass as a potential alternative biopesticide against tomato pests such as fungi, bacteria and weeds. © 2021 Society of Chemical Industry.

Effects of (-)-Loliolide against Fine Dust Preconditioned Keratinocyte Media-Induced Dermal Fibroblast Inflammation.

At present air pollution in parts of East Asia is at an alarming level due to elevated levels of fine dust (FD). Other than pulmonary complications, FD was found to affect the pathogenesis of ROS-dependent inflammatory responses via penetrating barrier-disrupted skin, leading to degradation of extracellular matrix components through the keratinocyte-fibroblast axis. The present study discloses the evaluation of human dermal fibroblast (HDF) responses to FD preconditioned human keratinocyte media (HPM) primed without and with (-)-loliolide (HTT). HPM-FD treatment increased the ROS level in HDFs and activated mitogen-activated protein kinase-derived nuclear factor (NF)-κB inflammatory signaling pathways with a minor reduction of viability. The above events led to cell differentiation and production of matrix metalloproteinases (MMP), increasing collagenase and elastase activity despite the increase of tissue inhibitors of metalloproteinases (TIMP). Media from HTT primed keratinocytes stimulated with FD indicated ameliorated levels of MMPs, inflammatory cytokines, and chemokines in HDFs with suppressed collagenase and elastase activity. Present observations help to understand the factors that affect HDFs in the microenvironment of FD exposed keratinocytes and the therapeutic role of HTT as a suppressor of skin aging. Further studies using organotypic skin culture models could broaden the understanding of the effects of FD and the therapeutic role of HTT.

A theoretical study to the loliolide molecule and its isomers: a study by circular dichroism, QTAIM, and NMR theoretical methods.

The determination of an absolute configuration is a challenge in the structure elucidation of chiral natural products. With advancements in computational chemistry of chiroptical spectroscopy, the time-dependent density functional theory (TDDFT) calculation has emerged as a very promising tool. This paper attempts to illustrate the applicability of computational approaches in comparison with experimental data to understand the conformation, interaction, and stabilization of the loliolide's isomers. The quantum chemical calculations were used from optimized geometries of the (6R,7aS)-, (6S,7aR)-, (6R,7aR)-, and (6S,7aS)-6-hydroxy-4,4,7a-trimethyl-6,7-dihydro-5H-1-benzofuran-2-one. The spectroscopic values were obtained for 13C NMR isotropic shielding by GIAO method in mPW1PW91/cc-pVTZ level, in TDDFT at the ωB97X-D/cc-pVTZ level to the circular dichroism, and in theoretical analyses of non-covalent interaction to study the isomer's stability. The TDDFT calculation of circular dichroism can be used to quantify the individual isomers and the nature of excitation in the molecule. The (6R,7aS) and (6R,7aR) isomers present a higher stability due to electronegativity associated at the hydroxyl group.

Lipid Inhibitory Effect of (-)-loliolide Isolated from Sargassum horneri in 3T3-L1 Adipocytes: Inhibitory Mechanism of Adipose-Specific Proteins.

Sargassum horneri (S. horneri) is a well-known brown seaweed widely distributed worldwide. Several biological activities of S. horneri have been reported. However, its effects on lipid metabolism and the underlying mechanisms remain elusive. In the present study, we examined the inhibitory effect of the active compound "(-)-loliolide ((6S,7aR)-6-hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydro-1-benzofuran-2(4H)-one (HTT))" from S. horneri extract on lipid accumulation in differentiated adipocytes. MTT assays demonstrated that (-)-loliolide is not toxic to 3T3-L1 adipocytes in a range of concentrations. (-)-loliolide significantly reduced intracellular lipid accumulation in the differentiated phase of 3T3-L1 adipocytes as shown by Oil Red O staining. Western blot analysis revealed that (-)-loliolide increased the expression of lipolytic protein phospho-hormone-sensitive lipase (p-HSL) and thermogenic protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1). Additionally, (-)-loliolide decreased expression of adipogenic and lipogenic proteins, including sterol regulatory element-binding protein-1 (SREBP-1), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding protein-α (C/EBP-α), and fatty acid-binding protein 4 (FABP4) in 3T3-L1 adipocytes. These results indicate that (-)-loliolide from S. horneri could suppress lipid accumulation via regulation of antiadipogenic and prolipolytic mechanisms in 3T3-L1 cells. Considering the multifunctional effect of (-)-loliolide, it can be useful as a lipid-lowering agent in the management of patients who suffer from obesity.

Anti-Hepatocellular Carcinoma (HepG2) Activities of Monoterpene Hydroxy Lactones Isolated from the Marine Microalga Tisochrysis Lutea.

Tisochrysis lutea is a marine haptophyte rich in omega-3 polyunsaturated fatty acids (e.g., docosahexaenoic acid (DHA)) and carotenoids (e.g., fucoxanthin). Because of the nutraceutical applications of these compounds, this microalga is being used in aquaculture to feed oyster and shrimp larvae. In our earlier report, T. lutea organic crude extracts exhibited in vitro cytotoxic activity against human hepatocarcinoma (HepG2) cells. However, so far, the compound(s) accountable for the observed bioactivity have not been identified. Therefore, the aim of this study was to isolate and identify the chemical component(s) responsible for the bioactivity observed. Bioassay-guided fractionation through a combination of silica-gel column chromatography, followed by preparative thin layer chromatography (PTLC), led to the isolation of two diastereomers of a monoterpenoid lactone, namely, loliolide (1) and epi-loliolide (2), isolated for the first time in this species. The structural elucidation of both compounds was carried out by GC-MS and 1D (1H and 13C APT) and 2D (COSY, HMBC, HSQC-ed, and NOESY) NMR analysis. Both compounds significantly reduced the viability of HepG2 cells and were considerably less toxic towards a non-tumoral murine stromal (S17) cell line, although epi-loliolide was found to be more active than loliolide.

(-)-Loliolide Isolated from Sargassum horneri Protects against Fine Dust-Induced Oxidative Stress in Human Keratinocytes.

The emergence of fine dust (FD) among air pollutants has taken a toll during the past few decades, and it has provided both controversy and a platform for open conversation amongst world powers for finding sustainable solutions and effective treatments for health issues. The present study emphasizes the protective effects of (-)-loliolide (HTT) isolated from Sargassum horneri against FD-induced oxidative stress in human HaCaT keratinocytes. The purification of (-)-loliolide was carried out by centrifugal partition chromatography. HTT did not show any cytotoxicity, and it further illustrated the potential to increase cell viability by reducing the reactive oxygen species (ROS) production in FD-stimulated keratinocytes. Furthermore, HTT suppressed FD-stimulated DNA damage and the formation of apoptotic bodies, and it reduced the population of cells in the sub-G1 apoptosis phase. FD-induced apoptosis was advancing through the mitochondria-mediated apoptosis pathway. The cytoprotective effects of the HTT against FD-stimulated oxidative damage is mediated through squaring the nuclear factor E2-related factor 2 (Nrf2)-mediated heme oxygenase-1 (HO-1) pathway, dose-dependently increasing HO-1 and NAD(P)H dehydrogenase (quinone) 1 (NQO1) levels in the cytosol while concomitantly improving the nuclear translocation of Nrf2. Future studies could implement the protective functionality of HTT in producing pharmaceuticals that utilize natural products and benefit the diseased.