Synergy of synthesis, computation and NMR reveals correct baulamycin structures.

Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines. Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule-including assigning its relative and absolute configurations-is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging. The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J-based configurational analysis, but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory-combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared-enabled us rapidly to pinpoint and synthesize the correct structures.

Total Synthesis of the Proposed Structure of (-)-Novofumigatamide, Isomers Thereof, and Analogues. Part I.

The total synthesis of the suggested structure of (-)-novofumigatamide, a natural product containing a C3-reverse prenylated N-acetyl-exo-hexahydropyrrolo[2,3-b]indole motif fused to a 10-membered ring lactam, was achieved using the macrolactam formation in advance of a diastereoselective bromocyclization and reverse prenylation steps. Since the NMR data of the synthetic sample did not match those of the natural product, the endo-bromo precursor of a N-Boc analogue and additional diastereomers derived from l-Trp were also synthesized. Five alternative synthetic routes, which differed in the order of final key steps used for the construction of the 10-membered ring lactam and the hexahydropyrrolo[2,3-b]indole framework within the polycyclic skeleton and also in the amide bond selected for the ring-closing of the macrolactam, were thoroughly explored. Much to our dismay, the lack of spectroscopic correlations between the proposed structure of natural (-)-novofumigatamide and the synthetic products suggested a different connectivity between the atoms. Additional synthetic efforts to assemble alternative structures of the natural product and isomers thereof (see accompanying paper; DOI: 10.1021/acs.joc.2c01228) further highlighted the frustrating endeavors toward the identification of a natural product.

Effect of plant origin and phenological stage on the allelopathic activity of the invasive species Oxalis pes-caprae.

PREMISE: Invasion processes involve several mechanisms, some of which have received little attention. Allelopathy has been invoked as an invasion driver according to the novel weapon hypothesis (NWH), and polyploidization can also be an important factor for invasion success. However, very few studies have addressed both topics together. We analyzed the allelopathic effect of the polyploid Oxalis pes-caprae, an invader in mediterranean-climate areas worldwide, from different origins and ploidy levels (native: South Africa; invaded: Chile, Australia, California, and the Mediterranean Basin) on Lactuca sativa as a model species. METHODS: We measured seed germination, initial plant height, and aboveground and belowground biomass of Lactuca grown in field soil mixed with Oxalis material and with or without activated carbon in a common garden experiment. We performed the experiment twice, when Oxalis was vigorous and when senescent. RESULTS: Vigorous plants of Oxalis tended to reduce Lactuca germination, but both vigorous and senescent Oxalis plants increased Lactuca biomass, probably due to an increase in nutrients provided by plant material. The highest increase in Lactuca traits occurred with Oxalis plants from the Iberian Peninsula. Allelopathy only happened when Oxalis was senescent and was especially strong with plants from Chile. CONCLUSIONS: Although we did not find broad evidence for the NWH considering all areas together, we reported differences in the allelopathic potential of Oxalis plants depending on their origin. These results highlight the independent evolution of invasiveness traits in distant introduced ranges and the importance of the invaders' origin when testing hypotheses about invasion drivers.

Influence of Acacia dealbata Link bark extracts on the growth of Allium cepa L. plants under high salinity conditions.

BACKGROUND: Acacia dealbata Link is an invasive plant worldwide. Finding potential uses for its waste that contribute to controling its spread and result in benefits for agriculture has recently become a new topic of research. This study aimed to evaluate the potential biostimulant effect of bark extract derived from the management of A. dealbata (0, 450 or 900 ppm) on onion plants growing under stressful conditions, such as in soils treated with saline solutions (0, 60 or 120 mmol L-1 NaCl) and with reduced irrigation (100%, 50% or 25%). RESULTS: A. dealbata Link bark extract significantly increased height as well as leaf, root and total biomass of plants in soils irrigated with NaCl solution (120 mmol L-1 ). These plants also had a higher content of Cl in roots, but a lower content of P in leaves and of K in bulbs. The 450 ppm bark treatment additionally increased the protein content in leaves and decreased the Na and Mg content in bulbs and bulbs and roots, respectively. The bark extract also increased the sugar content in plants under saline conditions. However, the effect of bark extract was negligible on plants that grew under drought stress. CONCLUSION: Results revealed that the bark extract might attenuate stress effects in plants growing at high salinity levels, probably by increasing their sugar and protein content and via the accumulation of ions in the roots. Although additional experiments are required, we suggest that the bark extract of A. dealbata has potential applications in agriculture concerned with biostimulant formulations. © 2019 Society of Chemical Industry.

Stereospecific Allylic Functionalization: The Reactions of Allylboronate Complexes with Electrophiles.

Allylboronic esters react readily with carbonyls and imines (π-electrophiles), but are unreactive toward a range of other electrophiles. By addition of an aryllithium, the corresponding allylboronate complexes display enhanced nucleophilicity, enabling addition to a range of electrophiles (tropylium, benzodithiolylium, activated pyridines, Eschenmoser's salt, Togni's reagent, Selectfluor, diisopropyl azodicarboxylate (DIAD), MeSX) in high regio- and stereocontrol. This protocol provides access to key new functionalities, including quaternary stereogenic centers bearing moieties such as fluorine and the trifluoromethyl group. The allylboronate complexes were determined to be 7 to 10 orders of magnitude more reactive than the parent boronic ester.

Total synthesis and structural revision of (+)-cristatumin C.

Naturally occurring (+)-cristatumin C, a bis-pyrrolidinoindoline diketopiperazine alkaloid isolated from Eurotium cristatum EN-220, is the 2R,3R,11S,15R,2'R,3'R,11'S,15'S enantiomer, as confirmed by total synthesis.

Repurposing Waste from Aggressive Acacia Invaders to Promote Its Management in Large Invaded Areas in Southwestern Europe.

Several Acacia species are aggressive invaders outside their native range, often occupying extensive areas. Traditional management approaches have proven to be ineffective and economically unfeasible, especially when dealing with large infestations. Here, we explain a different approach to complement traditional management by using the waste from Acacia management activities. This approach can provide stakeholders with tools to potentially reduce management costs and encourage proactive management actions. It also prioritizes potential applications of Acacia waste biomass for agriculture and forestry as a way of sequestering the carbon released during control actions. We advocate the use of compost/vermicompost, green manure and charcoal produced from Acacia waste, as several studies have shown their effectiveness in improving soil fertility and supporting crop growth. The use of waste and derivatives as bioherbicides or biostimulants is pending validation under field conditions. Although invasive Acacia spp. are banned from commercialization and cultivation, the use of their waste remains permissible. In this respect, we recommend the collection of Acacia waste during the vegetative stage and its subsequent use after being dried or when dead, to prevent further propagation. Moreover, it is crucial to establish a legal framework to mitigate potential risks associated with the handling and disposal of Acacia waste.

Olive Tree Belowground Microbiota: Plant Growth-Promoting Bacteria and Fungi.

The olive tree is one of the most significant crops in the Mediterranean region. Its remarkable adaptability to various environments has facilitated olive cultivation across diverse regions and agricultural scenarios. The rising global demand for olive products, coupled with climate challenges, is driving changes in cultivation methods. These changes are altering the traditional landscape and may potentially reshape the structure and composition of orchard microbial communities, which can impact productivity and stress tolerance. Bacterial and fungal communities naturally associated with plants have long been recognized as crucial for plant growth and health, serving as a vital component of sustainable agriculture. In this review, we aim to highlight the significance of olive cultivation and the impact of abiotic stresses. We update the current knowledge on the profiles of rhizosphere and root fungal and bacterial communities in olive orchards and examine how (a)biotic factors influence these communities. Additionally, we explore the potential of plant growth-promoting bacteria and fungi in enhancing olive physiological performance and stress tolerance. We identify knowledge gaps and emphasize the need for implementing new strategies. A comprehensive understanding of olive-associated microbiota will aid in developing sustainable agronomic practices to address climatic challenges and meet the growing demand for olive products.

Organic Waste from the Management of the Invasive Oxalis pes-caprae as a Source of Nutrients for Small Horticultural Crops.

The management of invasive plants is a challenge when using traditional control methods, which are ineffective for large areas, leading to the abandonment of invaded areas and the subsequent worsening of the situation. Finding potential uses for waste resulting from invaders' management could motivate their control in the long-term, concurrently providing new bio-based resources with different applications. Oxalis pes-caprae is an invasive plant, widely distributed worldwide, which spreads aggressively through bulbils, creating a dense ground cover. This study was designed to assess the potential of Oxalis aboveground waste for use as fertilizer and in ameliorating deficit irrigation effects in growing crops. Diplotaxis tenuifolia (wild rocket) seedlings were planted in pots with soil mixed with Oxalis waste at 0, 2.2 and 4.3 kg m-2 or with commercial fertilizer, left to grow for 27 days and then irrigated at 100% or 50% field capacity for 14 days. The incorporation of the Oxalis waste improved the biomass, photosynthesis, sugars, total phenols and total antioxidant capacity in the crop, achieving commercial fertilization values, as well as increasing the phosphorus in soils. However, Oxalis waste seems not to directly affect plants' relative water contents. Our results support the use of Oxalis waste as fertilizer, which can encourage the long-term control of this invasive species.

The effect of caraway oil-loaded bio-nanoemulsions on the growth and performance of barnyard grass and maize.

A proper formulation is crucial to improve the herbicidal effects of essential oils and their selectivity. In this study, we investigated the physicochemical properties of bio-based nanoemulsions (CNs) containing several concentrations of caraway (Carum carvi) essential oil stabilized with Eco Tween 80, as a surfactant, maintaining 1:1 proportions. Detailed physicochemical characteristics of the CNs revealed that their properties were most desired at 2% of the oil and surfactant, i.e., the smallest droplet size, polydispersity index, and viscosity. The CNs caused biochemical changes in maize and barnyard grass (Echinochloa crus-galli) seedlings, however, to a different extent. Barnyard grass has overall metabolism (measured as a thermal power) decreased by 39-82% when exposed to the CNs. The CNs triggered changes in the content and composition of carbohydrates in the endosperm of both species' seedlings in a dose-response manner. The foliar application of CNs caused significant damage to tissues of young maize and barnyard grass plants. The effective dose of the CN (ED50, causing a 50% damage) was 5% and 17.5% oil in CN for barnyard grass and maize tissues, respectively. Spraying CNs also decreased relative water content in leaves and affected the efficiency of photosynthesis by disturbing the electron transport chain. We found that barnyard grass was significantly more susceptible to the foliar application of CNs than maize, which could be used to selectively control this species in maize crops. However, further studies are needed to verify this hypothesis under field conditions.

Catalyst- and solvent-dependent stereodivergence in the intramolecular Et(2)Zn/Pd(0) -promoted carbonyl propargylation: mechanistic implications.

Carbonyl-tethered propargylic benzoates undergo intramolecular carbonylpropargylation upon treatment with Et2 Zn in the presence of a catalytic amount of Pd(0) with the formation of 2-alkynylcyclopentanol products. A ligand/solvent effect on the cis/trans selectivity (referring to the relative positions of alkynyl and OH groups) of ring-closure has been found. In a non-coordinating solvent (benzene), increasing the electron-donating ability of the phosphine ligand (while decreasing its dissociation ability) leads to an increased tendency towards the trans product. On the other hand, the combination of a coordinating solvent (THF) and PPh3 , an easily dissociated phosphine, results in the exclusive formation of cis products. Experimental and computational results are compatible with a divergent behavior of an allenylethylpalladium intermediate that partitions between competitive carbonyl-addition and transmetalation pathways, each leading to a different diastereoisomer. These results also suggest that the dissociating ability of the phosphine regulates that behavior.

Strategies for the Management of Aggressive Invasive Plant Species.

Current control methods for invasive alien plants (IAPs) have acceptable short-term outcomes but have proven to be unfeasible or unaffordable in the long-term or for large invaded areas. For these reasons, there is an urgent need to develop sustainable approaches to control or restrict the spread of aggressive IAPs. The use of waste derived from IAP control actions could contribute to motivating the long-term management and preservation of local biodiversity while promoting some economic returns for stakeholders. However, this strategy may raise some concerns that should be carefully addressed before its implementation. In this article, we summarize the most common methods to control IAPs, explaining their viability and limitations. We also compile the potential applications of IAP residues and discuss the risks and opportunities associated with this strategy.

Downregulated Adipose Tissue Expression of Browning Genes With Increased Environmental Temperatures.

CONTEXT: Climate change and global warming have been hypothesized to influence the increased prevalence of obesity worldwide. However, the evidence is scarce. OBJECTIVE: We aimed to investigate how outside temperature might affect adipose tissue physiology and metabolic traits. METHODS: The expression of genes involved in thermogenesis/browning and adipogenesis were evaluated (through quantitative polymerase chain reaction) in the subcutaneous adipose tissue (SAT) from 1083 individuals recruited in 5 different regions of Spain (3 in the North and 2 in the South). Plasma biochemical variables and adiponectin (enzyme-linked immunosorbent assay) were collected through standardized protocols. Mean environmental outdoor temperatures were obtained from the National Agency of Meteorology. Univariate, multivariate, and artificial intelligence analyses (Boruta algorithm) were performed. RESULTS: The SAT expression of genes associated with browning (UCP1, PRDM16, and CIDEA) and ADIPOQ were significantly and negatively associated with minimum, average, and maximum temperatures. The latter temperatures were also negatively associated with the expression of genes involved in adipogenesis (FASN, SLC2A4, and PLIN1). Decreased SAT expression of UCP1 and ADIPOQ messenger RNA and circulating adiponectin were observed with increasing temperatures in all individuals as a whole and within participants with obesity in univariate, multivariate, and artificial intelligence analyses. The differences remained statistically significant in individuals without type 2 diabetes and in samples collected during winter. CONCLUSION: Decreased adipose tissue expression of genes involved in browning and adiponectin with increased environmental temperatures were observed. Given the North-South gradient of obesity prevalence in these same regions, the present observations could have implications for the relationship of the obesity pandemic with global warming.

Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Pregnant Women of a Homogeneous Spanish Population: The Need for Revisiting the Current Vitamin Supplementation Strategies.

Polymorphisms of genes involved in the metabolism and transport of folate and cobalamin could play relevant roles in pregnancy outcomes. This study assessed the prevalence of genetic polymorphisms of folate and cobalamin metabolism-related genes such as MTHFR, MTR, CUBN, and SLC19A1 in pregnant women of a homogeneous Spanish population according to conception, pregnancy, delivery, and newborns complications. This study was conducted on 149 nulliparous women with singleton pregnancies. Sociodemographic and obstetrics variables were recorded, and all patients were genotyped in the MTHFR, MTR, CUBN, and SLC10A1 polymorphisms. The distribution of genotypes detected in this cohort was similar to the population distribution reported in Europe, highlighting that more than 50% of women were carriers of risk alleles of the studied genes. In women with the MTHFR risk allele, there was a statistically significant higher frequency of assisted fertilisation and a higher frequency of preeclampsia and preterm birth. Moreover, CUBN (rs1801222) polymorphism carriers showed a statistically significantly lower frequency of complications during delivery. In conclusion, the prevalence of genetic variants related to folic acid and vitamin B12 metabolic genes in pregnant women is related to mother and neonatal outcomes. Knowing the prevalence of these polymorphisms may lead to a personalised prescription of vitamin intake.

Immunomodulatory effect of a very-low-calorie ketogenic diet compared with bariatric surgery and a low-calorie diet in patients with excessive body weight.

BACKGROUND & AIM: Inflammation and oxidative stress are the most probable mechanistic link between obesity and its co-diseases with cancer among them. The aim of this study was to evaluate whether the nutritional ketosis and weight loss induced by a very-low-calorie ketogenic diet (VLCKD) modulates the inflammatory and oxidative stress profile, compared with a standard, balanced hypocaloric diet (LCD) or bariatric surgery (BS) in patients with obesity. METHODS: The study was performed in 79 patients with overweight or obesity and 32 normal-weight volunteers as the control group. Patients with obesity underwent a weight reduction therapy based on VLCKD, LCD or BS. The quantification of the circulating levels of a multiplexing test of cytokines and carcinogenesis/aging biomarkers, as well as of lipid peroxides and total antioxidant power, was carried out. RESULTS: First, we observed that pro-inflammatory cytokines increase, while anti-inflammatory cytokines decrease under excessive body weight. Relevantly, when patients underwent weight loss strategies, it was shown that energy-restricted and surgical strategies of weight loss induced changes in circulating cytokine and lipid peroxides. This effect was more notable in patients following the VLCKD than the LCD or BS and it was observed mainly in the ketosis phase of the intervention. Particularly, IL-11, IL-12, IL-2, INF-γ, INF-ß, Pentraxin-3 or MMP1 changed after VLCKD. Whereas, APRIL, TWEAK, osteocalcin and IL-28A increased after BS. CONCLUSION: As far as we know, this is the first study that evaluate the time-course of cytokines and oxidative stress markers after a VLCKD as compared with a standard LCD and BS. The observed results support the immunomodulatory effect of nutritional ketosis induced by a VLCKD synergistically with weight loss as a strategy to improve innate-immunity and to prevent infections and carcinogenesis in patients with obesity.

Epigenetic Effects of Healthy Foods and Lifestyle Habits from the Southern European Atlantic Diet Pattern: A Narrative Review.

Recent scientific evidence has shown the importance of diet and lifestyle habits for the proper functioning of the human body. A balanced and healthy diet, physical activity, and psychological well-being have a direct beneficial effect on health and can have a crucial role in the development and prognosis of certain diseases. The Southern European Atlantic diet, also named the Atlantic diet, is a unique dietary pattern that occurs in regions that present higher life expectancy, suggesting that this specific dietary pattern is associated with positive health effects. In fact, it is enriched with nutrients of high biological value, which, together with its cooking methods, physical activity promotion, reduction in carbon footprint, and promoting of family meals, promote these positive effects on health. The latest scientific advances in the field of nutri-epigenetics have revealed that epigenetic markers associated with food or nutrients and environmental factors modulate gene expression and, therefore, are involved with both health and disease. Thus, in this review, we evaluated the main aspects that define the Southern European Atlantic diet and the potential epigenetic changes associated with them based on recent studies regarding the main components of these dietary patterns. In conclusion, based on the information existing in the literature, we postulate that the Southern European Atlantic diet could promote healthy aging by means of epigenetic mechanisms. This review highlights the necessity of performing longitudinal studies to demonstrate this proposal.

Potential effects of nutrition-based weight loss therapies in reversing obesity-related breast cancer epigenetic marks.

Obesity is a modifiable risk factor of breast cancer and epigenetic marks were proposed as a relevant mechanistic link. These mechanisms can be remodelled by modifying lifestyle factors and this fact could be useful in the treatment of obesity-related breast cancer. This review aimed to reveal the current evidence on the effects of differences in body composition and lifestyle factors on the risk, treatment, and survival of breast cancer with a focus on the effects of weight loss therapies based on different nutrients, bioactive compounds, and Mediterranean and ketogenic diets to counteract obesity-related breast cancer epigenetic marks. This review was framed on the most relevant and recently published articles and abstracts selected in PubMed using key words related to epigenetics, lifestyle, dietary habits, nutrients, bioactive compounds, ketone bodies, and weight loss treatments in obesity and breast cancer. Several studies have demonstrated that lifestyle interventions, including dietary modifications towards a healthy diet pattern, are effective therapies to prevent the onset of breast cancer and to improve the survival after treatment. These therapies reduce the main factors associated with obesity that are links between adiposity and cancer, including oxidative stress, inflammation and epigenetic mechanisms. However, although sufficient evidence exists regarding the effects of nutrients, dietary patterns, and weight loss therapies to prevent breast cancer or to improve survival, the effects of these strategies on the oncological treatment response were less studied. This review summarises the current scientific evidence regarding these nutritional strategies as adjuvant therapies in the management of obesity-related breast cancer by remodelling epigenetic marks related to carcinogenesis.

Natural ligands of RXR receptors.

Given the role of retinoid X receptors (RXRs) as promiscuous partners of heterodimeric complexes with other members of the Nuclear Receptor (NR) superfamily, RXR ligands (rexinoids) play fundamental roles in gene transcription, since upon ligand binding either transcriptionally activate the "permissive" subclass of heterodimers or synergize with partner ligands in the "non-permissive" subclass of heterodimers. The collection of natural products thus far reported to bind RXR are described, including those discovered by high-throughput screening (HTS), mere serendipity, and a combination of those. Detailed protocols for the diastereo- and enantioselective synthesis of (R)-9-cis-13,14-dihydroretinoic acid, a putative natural RXR ligand, are provided.

ZNF577 Methylation Levels in Leukocytes From Women With Breast Cancer Is Modulated by Adiposity, Menopausal State, and the Mediterranean Diet.

The methylation levels of ZNF577 in breast tumors has been previously identified as a possible epigenetic mark of breast cancer associated with obesity. The aim of the current study was to investigate differences in methylation levels of ZNF577 depending on obesity, menopausal state and dietary pattern in blood leukocytes, a non-invasive sample. The methylation levels of ZNF577 of two CpG sites (CpGs) located in promoter and island previously identified as differentially methylated according to adiposity and menopausal state by 450 k array (cg10635122, cg03562414) were evaluated by pyrosequencing in DNA from the blood leukocytes of breast cancer patients [n = 90; n = 64 (71.1%) overweight/obesity and n = 26 (28.9%) normal-weight] and paired tumor tissue biopsies (n = 8 breast cancer patients with obesity; n = 3/5 premenopausal/postmenopausal women). Differences in methylation levels were evaluated at each CpGs individually and at the mean of the two evaluated CpGs. Adherence to the Mediterranean diet was evaluated using the MEDAS-validated questionnaire, and the consumption of food groups of interest was also evaluated using the recommended intakes of the Sociedad Española de Nutricion Comunitaria. The methylation levels of ZNF577 were correlated between paired leukocytes and breast tumor biopsies (r = 0.62; p = 0.001). Moreover, higher methylation was found in leukocytes from patients with obesity (p = 0.002) and postmenopausal patients (p = 0.022) than patients with normal-weight or premenopausal, respectively. After adjusting for the body mass index and age, higher levels of ZNF577 methylation were also found in women with greater adherence to the Mediterranean diet (p = 0.017) or specific foods. Relevantly, the methylation levels of ZNF577 showed a good ability for fish consumption detection [area under the ROC curve (AUC) = 0.72; p = 0.016]. In conclusion, the association between methylation of ZNF577 and adiposity, menopausal state, and adherence to the Mediterranean diet can be detected in the blood leukocytes. The results guarantee the need of performing further studies in longer longitudinal cohorts in order to elucidate the role of ZNF577 methylation in the association between breast cancer, adiposity and dietary patterns.