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Qualitative plant resistance mechanisms and pathogen virulence have been extensively studied since the formulation of the gene-for-gene hypothesis. The mechanisms involved in the quantitative traits of aggressiveness and plant partial resistance are less well-known. Nevertheless, they are prevalent in most plant-necrotrophic pathogen interactions, including the - interaction. Phytotoxic metabolite production by the pathogen plays a key role in aggressiveness in these interactions. The aim of the present study was to explore the link between aggressiveness and toxin production. We challenged carrot embryogenic cell cultures from a susceptible genotype (H1) and two partially resistant genotypes (I2 and K3) with exudates from strains with various aggressiveness levels. Interestingly, -resistant carrot genotypes were only affected by exudates from the most aggressive strain in our study (ITA002). Our results highlight a positive link between aggressiveness and the fungal exudate cell toxicity. We hypothesize that the fungal exudate toxicity was linked with the amount of toxic compounds produced by the fungus. Interestingly, organic exudate production by the fungus was correlated with aggressiveness. Hence, we further analyzed the fungal organic extract using HPLC, and correlations between the observed peak intensities and fungal aggressiveness were measured. One observed peak was closely correlated with fungal aggressiveness. We succeeded in purifying this peak and NMR analysis revealed that the purified compound was a novel 10-membered benzenediol lactone, a polyketid that we named 'aldaulactone'. We used a new automated image analysis method and found that aldaulactone was toxic to cultured plant cells at those concentrations. The effects of both aldaulactone and fungal organic extracts were weaker on I2-resistant carrot cells compared to H1 carrot cells. Taken together, our results suggest that: (i) aldaulactone is a new phytotoxin, (ii) there is a relationship between the amount of aldaulactone produced and fungal aggressiveness, and (iii) carrot resistance to involves mechanisms of resistance to aldaulactone.

Although different mechanisms have been proposed in the recent years, plant pathogen partial resistance is still poorly understood. Components of the chemical warfare, including the production of plant defense compounds and plant resistance to pathogen-produced toxins, are likely to play a role. Toxins are indeed recognized as important determinants of pathogenicity in necrotrophic fungi. Partial resistance based on quantitative resistance loci and linked to a pathogen-produced toxin has never been fully described. We tested this hypothesis using the Alternaria dauci-carrot pathosystem. Alternaria dauci, causing carrot leaf blight, is a necrotrophic fungus known to produce zinniol, a compound described as a non-host selective toxin. Embryogenic cellular cultures from carrot genotypes varying in resistance against A. dauci were confronted with zinniol at different concentrations or to fungal exudates (raw, organic or aqueous extracts). The plant response was analyzed through the measurement of cytoplasmic esterase activity, as a marker of cell viability, and the differentiation of somatic embryos in cellular cultures. A differential response to toxicity was demonstrated between susceptible and partially resistant genotypes, with a good correlation noted between the resistance to the fungus at the whole plant level and resistance at the cellular level to fungal exudates from raw and organic extracts. No toxic reaction of embryogenic cultures was observed after treatment with the aqueous extract or zinniol used at physiological concentration. Moreover, we did not detect zinniol in toxic fungal extracts by UHPLC analysis. These results suggest that strong phytotoxic compounds are present in the organic extract and remain to be characterized. Our results clearly show that carrot tolerance to A. dauci toxins is one component of its partial resistance.

Horizontal and polygenic resistance is race-nonspecific and, therefore, more durable, unlike vertical resistance, which is race-specific and unstable. However, this division is perhaps not so obvious since some cultivar × isolate interactions have already been observed for plant species with partial resistance. Carrot is known to be partially resistant to Alternaria dauci , but it is relevant for breeders to study cultivar × isolate interactions in order to develop durable resistant varieties. For this purpose, 12 highly diverse carrot genotypes and one segregating population were inoculated in a tunnel or in a glass house with 11 isolates of A. dauci that also represented a high diversity in terms of geographical origin, aggressiveness and genetic diversity. Disease severity values were assessed three times in the tunnel in a one-year experiment (2002) and twice in the glass house in an experiment over two consecutive years (2011 and 2012). The interaction of isolate with genotype was non-significant in the tunnel, and the same result was obtained in the glasshouse for both years of study except for the first scoring date in 2011, suggesting that the partial resistance of carrot to A. dauci is probably mainly explained by major QTLs that confer resistance to a large number of isolates and, potentially, some minor isolate-specific QTLs as well.

Although different mechanisms have been proposed in the recent years, plant pathogen partial resistance is still poorly understood. Components of the chemical warfare, including the production of plant defense compounds and plant resistance to pathogen-produced toxins, are likely to play a role. Toxins are indeed recognized as important determinants of pathogenicity in necrotrophic fungi. Partial resistance based on quantitative resistance loci and linked to a pathogen-produced toxin has never been fully described. We tested this hypothesis using the Alternaria dauci – carrot pathosystem. Alternaria dauci, causing carrot leaf blight, is a necrotrophic fungus known to produce zinniol, a compound described as a non-host selective toxin. Embryogenic cellular cultures from carrot genotypes varying in resistance against A. dauci were confronted with zinniol at different concentrations or to fungal exudates (raw, organic or aqueous extracts). The plant response was analyzed through the measurement of cytoplasmic esterase activity, as a marker of cell viability, and the differentiation of somatic embryos in cellular cultures. A differential response to toxicity was demonstrated between susceptible and partially resistant genotypes, with a good correlation noted between the resistance to the fungus at the whole plant level and resistance at the cellular level to fungal exudates from raw and organic extracts. No toxic reaction of embryogenic cultures was observed after treatment with the aqueous extract or zinniol used at physiological concentration. Moreover, we did not detect zinniol in toxic fungal extracts by UHPLC analysis. These results suggest that strong phytotoxic compounds are present in the organic extract and remain to be characterized. Our results clearly show that carrot tolerance to A. dauci toxins is one component of its partial resistance.

Horizontal and polygenic resistance is race-nonspecific and, therefore, more durable, unlike vertical resistance, which is race-specific and unstable. However, this division is perhaps not so obvious since some cultivar × isolate interactions have already been observed for plant species with partial resistance. Carrot is known to be partially resistant to Alternaria dauci, but it is relevant for breeders to study cultivar × isolate interactions in order to develop durable resistant varieties. For this purpose, 12 highly diverse carrot genotypes and one segregating population were inoculated in a tunnel or in a glass house with 11 isolates of A. dauci that also represented a high diversity in terms of geographical origin, aggressiveness and genetic diversity. Disease severity values were assessed three times in the tunnel in a one-year experiment (2002) and twice in the glass house in an experiment over two consecutive years (2011 and 2012). The interaction of isolate with genotype was non-significant in the tunnel, and the same result was obtained in the glasshouse for both years of study except for the first scoring date in 2011, suggesting that the partial resistance of carrot to A. dauci is probably mainly explained by major QTLs that confer resistance to a large number of isolates and, potentially, some minor isolate-specific QTLs as well.

ABSTRACT Purpose To explore the possibility to boost phenolic antioxidants through their structural modification by lipophilization and check the influence of such covalent modification on cellular uptake and mitochondria targeting. Methods Rosmarinic acid was lipophilized by various aliphatic chain lengths (butyl, octyl, decyl, dodecyl, hexadecyl, and octadecyl) to give rosmarinate alkyl esters which were then evaluated for their ability (i) to reduce the level of reactive oxygen species (ROS) using 2′,7′-dichlorodihydrofluorescein diacetate probe, (ii) to cross fibroblast cell membranes using confocal microscopy, and (iii) to target mitochondria using MitoTracker® Red CMXRos. Results Increasing the chain length led to an improvement of the antioxidant activity until a threshold is reached for medium chain (10 carbon atoms) and beyond which lengthening resulted in a decrease of activity. This nonlinear phenomenon—also known as the cut-off effect—is discussed here in connection to the previously similar results observed in emulsified, liposomal, and cellular systems. Moreover, butyl, octyl, and decyl rosmarinates passed through the membranes in less than 15 min, whereas longer esters did not cross membranes and formed extracellular aggregates. Besides cell uptake, alkyl chain length also determined the subcellular localization of esters: mitochondria for medium chains esters, cytosol for short chains and extracellular media for longer chains. Conclusion The localization of antioxidants within mitochondria, the major site and target of ROS, conferred an advantage to medium chain rosmarinates compared to both short and long chains. In conjunction with changes in cellular uptake, this result may explain the observed decrease of antioxidant activity when lengthening the lipid chain of esters. This brings a proof-of-concept that grafting medium chain allows the design of mitochondriotropic antioxidants.

Olive leaves are a very abundant vegetable material containing various phenolic compounds, such as secoiridoids and flavonoids, that are expected to exert strong antioxidant capacity. However, little is known about the variation of olive-leaf phenolic composition during maturation and its influence on antioxidant capacity. To answer this question, young and mature Olea Europaea L. leaves were submitted to successive extraction with dichloromethane, ethyl acetate, and methanol, then characterized by ESI-MS. It appeared that mature olive-leaf extracts contained higher levels of verbascoside isomers and glucosylated forms of luteolin, while young ones presented higher contents of oleuropein, ligstroside, and flavonoid aglycones. Moreover, antioxidant capacity evaluation using our newly developed conjugated autoxidizable triene assay showed that, in a lipid-based emulsified system, this phenolic composition variation leads to a change in the ability of extracts to counteract lipid oxidation. Mature olive-leaf extracts exhibit higher antioxidant capacity than young olive-leaf extracts. This result enables us to hypothesize that two main bioconversion scenarios may occur during maturation of olive leaves, which could explain changes observed in antioxidant capacity: (1) a bioconversion of oleuropein and ligstroside into verbascoside isomers and oleuroside, and (2) a bioconversion of flavonoid aglycones into glucosylated forms of luteolin. Finally, this study leads to a better understanding of the relationship between phenolic profile and antioxidant capacity of olive leaves.

Despite the increasing efficacy of chemotherapy, permanently unresectable colorectal liver metastases are associated with poor long-term survival. We aimed to assess whether liver transplantation plus chemotherapy could improve overall survival. TransMet was a multicentre, open-label, prospective, randomised controlled trial done in 20 tertiary centres in Europe. Patients aged 18−65 years, with Eastern Cooperative Oncology Group performance score 0−1, permanently unresectable colorectal liver metastases from resected BRAF-non-mutated colorectal cancer responsive to systemic chemotherapy (≥3 months, ≤3 lines), and no extrahepatic disease, were eligible for enrolment. Patients were randomised (1:1) to liver transplantation plus chemotherapy or chemotherapy alone, using block randomisation. The liver transplantation plus chemotherapy group underwent liver transplantation for 2 months or less after the last chemotherapy cycle. At randomisation, the liver transplantation plus chemotherapy group received a median of 21·0 chemotherapy cycles (IQR 18·0−29·0) versus 17·0 cycles (12·0−24·0) in the chemotherapy alone group, in up to three lines of chemotherapy. During first-line chemotherapy, 64 (68%) of 94 patients had received doublet chemotherapy and 30 (32%) of 94 patients had received triplet regimens; 76 (80%) of 94 patients had targeted therapy. Transplanted patients received tailored immunosuppression (methylprednisolone 10 mg/kg intravenously on day 0; tacrolimus 0·1 mg/kg via gastric tube on day 0, 6−10 ng/mL days 1–14; mycophenolate mofetil 10 mg/kg intravenously day 0 to <2 months and switch to everolimus 5−8 ng/mL), and postoperative chemotherapy, and the chemotherapy group had continued chemotherapy. The primary endpoint was 5-year overall survival analysed in the intention to treat and per-protocol population. Safety events were assessed in the as-treated population. The study is registered with ClinicalTrials.gov (NCT02597348), and accrual is complete. Between Feb 18, 2016, and July 5, 2021, 94 patients were randomly assigned and included in the intention-to-treat population, with 47 in the liver transplantation plus chemotherapy group and 47 in the chemotherapy alone group. 11 patients in the liver transplantation plus chemotherapy group and nine patients in the chemotherapy alone group did not receive the assigned treatment; 36 patients and 38 patients in each group, respectively, were included in the per-protocol analysis. Patients had a median age of 54·0 years (IQR 47·0−59·0), and 55 (59%) of 94 patients were male and 39 (41%) were female. Median follow-up was 59·3 months (IQR 42·4−60·2). In the intention-to-treat population, 5-year overall survival was 56·6% (95% CI 43·2−74·1) for liver transplantation plus chemotherapy and 12·6% (5·2–30·1) for chemotherapy alone (HR 0·37 [95% CI 0·21−0·65]; p=0·0003) and 73·3% (95% CI 59·6–90·0) and 9·3% (3·2–26·8), respectively, for the per-protocol population. Serious adverse events occurred in 32 (80%) of 40 patients who underwent liver transplantation (from either group), and 69 serious adverse events were observed in 45 (83%) of 54 patients treated with chemotherapy alone. Three patients in the liver transplantation plus chemotherapy group were retransplanted, one of whom died postoperatively of multi-organ failure. In selected patients with permanently unresectable colorectal liver metastases, liver transplantation plus chemotherapy with organ allocation priority significantly improved survival versus chemotherapy alone. These results support the validation of liver transplantation as a new standard option for patients with permanently unresectable liver-only metastases. French National Cancer Institute and Assistance Publique–Hôpitaux de Paris.

The hydrophobation of rosmarinic acid with saturated aliphatic primary alcohols of various chain lengths (methanol to eicosanol) was achieved via an acid-catalyzed esterification in the presence of a highly acidic sulfonic resin. The resulting alkyl rosmarinates were isolated, characterized and their global free radical scavenging activity was determined by the 2,2-diphenyl-1-picrylhydrazyl method in the stationary state. Only the dodecyl ester showed a stronger activity than rosmarinic acid