Key Pharmacokinetic Parameters of 74 Pediatric Anticancer Drugs Providing Assistance in Preclinical Studies.

Novel drug treatments for pediatric patients with cancer are urgently needed. Success of drug development in pediatric oncology has been promising, but many drugs still fail in translation from preclinical to clinical phases. To increase the translational potential, several improvements have been implemented, including the use of clinically achievable concentrations in the drug testing phase. Although pharmacokinetic (PK) parameters of numerous investigated drugs are published, a comprehensive PK overview of the most common drugs in pediatric oncology could guide preclinical trial design and improve the translatability into clinical trials. A review of the literature was conducted for PK parameters of 74 anticancer drugs, from the drug sensitivity profiling library of the INdividualized Therapy FOr Relapsed Malignancies in Childhood (INFORM) registry. PK data in the pediatric population were reported and complemented by adult parameters when no pediatric data were available. In addition, blood-brain barrier (BBB)-penetration assessment of drugs was provided by using the BBB score. Maximum plasma concentration was available for 73 (97%), area under the plasma concentration-time curve for 69 (92%), plasma protein binding for 66 (88%), plasma half-life for 57 (76%), time to maximum concentration for 54 (72%), clearance for 52 (69%), volume of distribution for 37 (49%), lowest plasma concentration reached by the drug before the next dose administration for 21 (28%), and steady-state concentration for 4 (5%) of drugs. Pediatric PK data were available for 48 (65%) drugs. We provide a comprehensive review of PK data for 74 drugs studied in pediatric oncology. This data set can serve as a reference to design experiments more closely mimicking drug PK conditions in patients, and may thereby increase the probability of successful clinical translation.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Evaluation of the effects of 10% and 30% gluconolactone chemical peel on sebum, pH, and TEWL.

BACKGROUND: Gluconolactone (GLA) exhibits antioxidant and moisturizing effects. It also presents soothing effects, protects elastin fibers from UV-induced degradation, and improves the function of the skin barrier. AIMS: Evaluation of skin parameters such as pH, transepidermal water loss (TEWL), sebum levels before, during, and after a series of applications of 10% and 30% GLA chemical peel in a split-face model. MATERIALS AND METHODS: The study involved 16 female subjects. Three split-face procedures were performed using two concentrations of GLA solution applied on two sides of the face. The skin parameters were measured before treatments and 7 days after the last procedure at four measurement sites on either side of the face, that is, on the forehead, around the eye, on the cheek, and on the nose wing. RESULTS: Measurement of sebum demonstrated some statistically significant changes between sebum levels in the cheeks after a series of treatments. The pH measurement showed that the pH value was reduced after each treatment at all measurement points. The level of TEWL after treatments was significantly lower around the eyes, on the left forehead, and on the right cheek. There were no significant differences between the use of different concentrations of the GLA solution. CONCLUSIONS: The results of the study show that GLA has a significant influence on lowering skin pH and TEWL. GLA also has seboregulatory properties.

Split-face evaluation: Gluconolactone plus oxybrasion versus gluconolactone plus microneedling. The effects on skin parameters.

BACKGROUND: The application of polyhydroxy acids and alpha-hydroxy acids to the skin is often used in cosmetology. To enhance the effect of gluconolactone chemical peeling, a combined method including water-oxygen oxybrasion or microneedle mesotherapy can be used. OBJECTIVES: To evaluate skin parameters such as hydration, sebum, pH and TEWL after application of a 10% gluconolactone chemical peel in combination with oxybrasion and microneedling. MATERIALS AND METHODS: Twenty-one Caucasian women participated in the study. A series of three split face treatments was carried out at 1-week intervals. Oxybrasion was performed on the right side of the face and micro-needle mesotherapy on the left side. A 10% gluconolactone solution was applied to the entire face. Before the first and third treatments and 2 weeks after the last treatment, skin parameters were evaluated. Photographic documentation was also made before and after the treatment series. RESULTS AND CONCLUSION: Evaluation of skin parameters using Courage & Khazaka 580 Multi Probe Adapter probes (Courage + Khazaka electronic GmbH, Cologne, Germany) showed an increase in hydration and a decrease in sebum, pH and TEWL for both treatments. There were no statistically significant differences between the treatments. Combining chemical peeling of gluconolactone with oxybrasion and microneedle mesotherapy is a good method to seal the hydrolipid barrier and increase skin hydration.

Objective, measurable assessment of the elasticity of the skin around the eyes following the carboxytherapy treatment.

BACKGROUND: Carboxytherapy is one of the most popular procedures used in dermatology. The treatments are known to be minimally invasive and highly effective for various skin disorders. Therefore, the research carried out in the paper is purposeful and addresses an important area of aesthetic therapies. AIMS: Objective, apparatus-based assessment of the effect of carboxytherapy on skin elasticity around the eyes. PATIENTS/METHODS: The study included a group of 39 Caucasian individuals aged 35-55 years. Participants were subjected to a series of five carboxytherapy treatments of eye area at weekly intervals. The Cutometer measuring probe was used to assess skin elasticity. Additionally, photographic documentation was out using the Fotomedicus system. RESULTS: In this study, statistically significant increase in R2 parameter was found as the result of applied treatment. This parameter is considered to be the most important indicator of changes in skin elasticity. In 29 out of 39 subjects, the carboxytherapy treatment significantly improved skin tension and elasticity. Such therapy may also exert a beneficial effect on flexibility since in 28 participants the favorable change in the R7 parameter was visible. CONCLUSIONS: The objective analysis of the impact of carboxytherapy treatment on parameters determining skin elasticity revealed that this therapy can be used as an anti-aging method in the eye area. Obtained results are in agreement with other biochemical, histological, and photographical documentation analyses of the effect of carboxytherapy on skin, performed by independent researchers.

The correlation between the severity of symptoms and the thickness of the fat fold in cellulite-affected areas-A pilot study.

OBJECTIVE: The aim of the study was to assess the correlation between the cellulite severity and the thickness of the fat fold. MATERIAL AND METHODS: The study comprised 62 women aged 22 to 26 years. A palpation and visual evaluation of cellulite severity was performed on the basis of the Nurnberger and Muller classification, and the thickness of adipose tissue (fatty tissue) was measured with the use of a skinfold caliper. RESULTS: The H0 hypothesis was rejected in favor of the H1 hypothesis (p < 0.001) in the chi-square independence test; therefore, a relationship between the thickness of the adipose tissue fold and the severity of cellulite was confirmed. Moreover, on the basis of obtained results, the hypothesis of the independence of the studied variables (p < 0.0000001) was also rejected. It can be concluded that there is an association between the thickness of adipose tissue and the degree of cellulite. Moreover, the values of the obtained coefficients are greater than zero (the correlation is positive), and the obtained Spearman's R (0.89) and Kendall's tau (0.79) values indicate a very strong correlation between the studied variables. CONCLUSIONS: On the basis of obtained results and their statistical analysis, we can state that there is a relationship between the degree of cellulite and the thickness of the fat fold-the degree of cellulite increases with the increase in the thickness of the measured fat fold.

Ferulic acid - A novel topical agent in reducing signs of photoaging.

Continuous production of reactive oxygen species, induced by UV radiation, is one of the main mechanisms contributing to skin photoaging. Therefore, the use of novel superior antioxidants, which ferulic acid belongs to, is an innovative treatment option. The aim of this study was to evaluate the effect of 14% ferulic acid peel on skin hydration, topography, the level of melanin, and the severity of erythema, in people with skin photoaging symptoms. Twenty women aged 45-60, received eight treatments of chemical peeling in 1-week intervals. Efficacy was measured using The Multi Probe Adapter (MPA) Systems (Courage + Khazaka electronic GmbH, Köln, Germany). The measurements were taken before, 8, and 12 weeks after the first treatment. Additionally, the photo documentation was made with Fotomedicus (Elfo) and VISIA® Complexion Analysis System (Canfield Scientific, Inc.). The objective evaluation showed statistically significant improvement in all measured skin parameters p < 0.05). The best results of skin hydration and melanin level were observed right after the end of the series (p < 0.001). The best improvement in erythema reduction was noted a month after the last treatment (p < 0.0001). At the control, untreated point none of the probes showed statistically significant changes. In conclusion, a series of treatments with 14% ferulic acid peel has a significant bleaching, erythema-reducing, and moisturizing activity. The results achieved by apparatus, are reflected by photo documentation. The effects achieved during a series persist over time.

Two superior antioxidants: Ferulic acid and ascorbic acid in reducing signs of photoaging-A split-face comparative study.

The assessment of the signs of photoaging in mexametric (melanin and erythema index), corneometric (hydration level), and cutometric (elasticity) examination after the treatment with ascorbic acid and ferulic acid. This study was conducted in a group of 20 women aged 39-61 (mean age 54), with Fitzpatrick skin types II and III. The study included a series of eight treatments performed once a week. Two layers of peeling, based on 14% ferulic acid (left half of the face) and 12% l-ascorbic acid serum (right half of the face) were applied. To determine skin parameters: moisture, elasticity, melanin level, and erythema intensity, the Multi Probe Adapter Systems (Courage + Khazaka electronic GmbH, Köln, Germany) were used. Additionally, before and after the series of treatments, photographs were taken with the standardized photographic system Fotomedicus (Elfo®). The results of mexametric measurement for melanin level and erythema intensity were statistically significant (p < 0.0001) for both acids. Slightly greater lightening of the skin was demonstrated for ascorbic acid. The results of corneometric measurement of hydration level for ferulic acid and ascorbic acid were both statistically significant (p < 0.0001). First beneficial changes in improved elasticity could be observed as early as after 8 weeks but the increase in flexibility grew with time (after 12 weeks). These changes affected both acids and all measurement points. The changes in parameters were highly statistically significant (p < 0.0001). Based on the conducted research, it is not possible to state which of the tested acids is more effective in reducing the symptoms of photoaging. Both acids (ascorbic and ferulic), which have a high antioxidant potential, affect the measurable parameters of the skin: pigmentation (melanin index), erythema (erythema index), skin hydration, and elasticity.

The eye area as the most difficult area of activity for esthetic treatment.

Eyes area is of high importance in esthetic dermatology. This area is one of the most difficult for procedures. Skillful treatment can significantly improve the quality of patients' life. The aim of the study was to present and differentiate a variety of changes observed in the eye area and factors stimulating their appearance and enhancing intensity. This article also presents treatment methods in the field of esthetic dermatology, which are used in the in the following problems: eyelid edema, fatty bags under the eyes, vascular circles under the eyes, pigment shadows, periorbital melanosis, structural shadows, tear trough, wrinkles and loss of skin elasticity and dry skin around the eyes. Their correct diagnosis requires the knowledge of the characteristics of the skin structure within the eye area and also the mechanisms responsible for disorders in its functioning. Many patients and people performing procedures, limit the problems within eye area to a generalized division into shadows, swelling and wrinkles under the eyes and probably to one selected form of therapy. However, as it has been shown in this review, the variety of defects is large. Actions in case of problems with skin around the eyes require a systemic, multi-specialist.

Efficacy of fractional laser, radiofrequency and IPL rejuvenation of periorbital region.

The purpose of this study was to assess skin elasticity, the reduction in the number and the depth of wrinkles and changes in the other skin defects (bags under the eyes, dark circles under the eyes, skin hyperpigmentation in the ageing eye area following the use of non-ablative fractional laser, bipolar radiofrequency and intense pulsed light). Moreover, the study was also comparison which device brought better results than the others. This study included 71 patients (66 women, 5 men), aged 33-63 years (the average age was 45.81 years) with skin phototypes II and III. Twenty-four patients received five treatment sessions with a 1410-nm non-ablative fractional laser in 2-week intervals, 23 patients received five treatment sessions with a bipolar radiofrequency in 1-week intervals and 24 patients received five treatment sessions with an intense pulsed light in 2-week intervals. The treatment was applied on the skin in the eye area. The Cutometer (Courage + Khazaka electronic) reference test was used as an objective method for the assessment of skin elasticity. A questionnaire was used to compare baseline state with changes that occurred after the series of treatment sessions. The results of cutometric measurements of R2, R6 and R7 parameters and the results of questionnaires indicated that non-ablative fractional laser therapy, bipolar radiofrequency and intense pulsed light improved skin elasticity. Of the three treatments, the most significant percentage improvement in the R6 parameter was demonstrated by non-ablative fractional laser therapy which gave better final results than the other methods (p < 0.0001). No other statistically significant relationships were found between RF and IPL. In the (subjective) opinion of study participants (questionnaire), all used methods resulted in the reduction of the amount and the depth of wrinkles. However, they did not observe significant impact of individual treatment method on the signs of skin ageing, including discolorations within eye area, bags (fatty hernia), dark circles (vascular/pigmentary) and oedema (predisposition to water retention). Non-ablative fractional laser therapy, bipolar radiofrequency and intense pulsed light improved skin elasticity and the reduction of wrinkles. The most significant improvement of elasticity was demonstrated by laser therapy. It seems necessary to expand the group with the effect of individual treatments against bags and dark circles under the eyes.

Ligation of newly replicated DNA controls the timing of DNA mismatch repair.

Mismatch repair (MMR) safeguards genome stability through recognition and excision of DNA replication errors.1-4 How eukaryotic MMR targets the newly replicated strand in vivo has not been established. MMR reactions reconstituted in vitro are directed to the strand containing a preexisting nick or gap,5-8 suggesting that strand discontinuities could act as discrimination signals. Another candidate is the proliferating cell nuclear antigen (PCNA) that is loaded at replication forks and is required for the activation of Mlh1-Pms1 endonuclease.7-9 Here, we discovered that overexpression of DNA ligase I (Cdc9) in Saccharomyces cerevisiae causes elevated mutation rates and increased chromatin-bound PCNA levels and accumulation of Pms1 foci that are MMR intermediates, suggesting that premature ligation of replication-associated nicks interferes with MMR. We showed that yeast Pms1 expression is mainly restricted to S phase, in agreement with the temporal coupling between MMR and DNA replication.10 Restricting Pms1 expression to the G2/M phase caused a mutator phenotype that was exacerbated in the absence of the exonuclease Exo1. This mutator phenotype was largely suppressed by increasing the lifetime of replication-associated DNA nicks, either by reducing or delaying Cdc9 ligase activity in vivo. Therefore, Cdc9 dictates a window of time for MMR determined by transient DNA nicks that direct the Mlh1-Pms1 in a strand-specific manner. Because DNA nicks occur on both newly synthesized leading and lagging strands,11 these results establish a general mechanism for targeting MMR to the newly synthesized DNA, thus preventing the accumulation of mutations that underlie the development of human cancer.

Inactivation of folylpolyglutamate synthetase Met7 results in genome instability driven by an increased dUTP/dTTP ratio.

The accumulation of mutations is frequently associated with alterations in gene function leading to the onset of diseases, including cancer. Aiming to find novel genes that contribute to the stability of the genome, we screened the Saccharomyces cerevisiae deletion collection for increased mutator phenotypes. Among the identified genes, we discovered MET7, which encodes folylpolyglutamate synthetase (FPGS), an enzyme that facilitates several folate-dependent reactions including the synthesis of purines, thymidylate (dTMP) and DNA methylation. Here, we found that Met7-deficient strains show elevated mutation rates, but also increased levels of endogenous DNA damage resulting in gross chromosomal rearrangements (GCRs). Quantification of deoxyribonucleotide (dNTP) pools in cell extracts from met7Δ mutant revealed reductions in dTTP and dGTP that cause a constitutively active DNA damage checkpoint. In addition, we found that the absence of Met7 leads to dUTP accumulation, at levels that allowed its detection in yeast extracts for the first time. Consequently, a high dUTP/dTTP ratio promotes uracil incorporation into DNA, followed by futile repair cycles that compromise both mitochondrial and nuclear DNA integrity. In summary, this work highlights the importance of folate polyglutamylation in the maintenance of nucleotide homeostasis and genome stability.

The assessment of the effects of the combination of microdermabrasion and cavitation peeling in the therapy of seborrhoeic skin with visible symptoms of acne punctata.

Objective: The aim of this study was to assess objectively the effects of the combination of corundum microdermabrasion and cavitation peeling in the therapy of seborrheic skin with visible symptoms of acne punctata. Material and methods: The study involved a group of nine women. A series of six treatments with the combination of microdermabrasion and cavitation peeling were performed within facial skin at 10-14 days intervals. Corneometric measurements examining skin hydration level and sebumetric measurements analyzing skin sebum level were made before the series of treatments and after second, fourth and sixth procedure in five facial areas. Clinical assessment of the efficacy of the therapy was performed on the basis of photographic documentation (Fotomedicus). Anonymous questionnaires were used in order to evaluate patients' satisfaction rate. Results: Statistically significant improvement in skin sebum level was observed in all examined areas (forehead p = 0.002; nose p = 0.001, chin p = 0.01, left cheek p = 0.009, right cheek p = 0.007). In case of skin hydration, significant improvement was found only in the area of chin (p = 0.03). 78% of participants estimated that the improvement was in the range of 55-70%, while 22% of participants of 75-100%. The reduction in the amount and visibility of comedones and pimples were demonstrated on the basis of questionnaire and photographic documentation. Conclusions: Combined microdermabrasion and cavitation peeling treatments improve the condition of seborrheic skin.

Antioxidant Properties of Ferulic Acid and Its Possible Application.

Ferulic acid has low toxicity and possesses many physiological functions (anti-inflammatory, antioxidant, antimicrobial activity, anticancer, and antidiabetic effect). It has been widely used in the pharmaceutical, food, and cosmetics industry. Ferulic acid is a free radical scavenger, but also an inhibitor of enzymes that catalyze free radical generation and an enhancer of scavenger enzyme activity. Ferulic acid has a protective role for the main skin structures: keratinocytes, fibroblasts, collagen, elastin. It inhibits melanogenesis, enhances angiogenesis, and accelerates wound healing. It is widely applied in skin care formulations as a photoprotective agent, delayer of skin photoaging processes, and brightening component. Nonetheless, its use is limited by its tendency to be rapidly oxidized.

Is skin microneedling a good alternative method of various skin defects removal.

Skin microneedling accelerates the process of skin regeneration through the creation of numerous microinjuries which emerge when skin is deeply punctured with very thin needles. The whole procedure evokes various reactions which can be divided into three major phases: inflammation, proliferation, and remodeling. It activates platelet growth factors which are responsible for the stimulation of fibroblasts to produce collagen and elastin. Moreover, skin breakdown enhances penetration of active ingredients. Treatment can be performed with the use of different devices, all equipped with needles of various lengths. Due to the fact that skin microneedling stimulates the synthesis of significant rebuilding and structural skin elements (collagen, elastin, proteoglycan), it is used in the treatment of many skin defects of different etiologies (e.g., photoaging, wrinkles, loss of elasticity, hypo- or hypertrophic scars, pigmentation changes, infraorbital dark circles, teleangiectasia, stretch marks, cellulite, alopecia, and vitiligo). In order to accelerate postsurgical regeneration and/or to enhance effects, microneedling is combined with the application of UV light (photodynamic therapy with ALA), LED light, platelet-rich plasma, chemical peels, stem cells, retinoids and other pharmaceuticals, and vitamins. High effectiveness, limited number of side effects, and short recovery time, make skin microneedling a popular cosmetic, and medical treatment.

Is carboxytherapy a good alternative method in the removal of various skin defects?

Carbon dioxide is a physiologic compound present in our body, mainly as a result of cellular metabolism. The frequency of carboxytherapy use by dermatologists and cosmetologists increased significantly in the second half of the 20th century due to the fact that it improves blood circulation within skin tissues. This article focuses on the use of carboxytherapy in case of various skin problems, such as stretch marks, scars, loss of elasticity, redundancy of fatty tissue, cellulite, morphea, and alopecia. The review of sparse studies that are available indicate increasing interest in this method.

Development of a Highly Sensitive FcMito qPCR Assay for the Quantification of the Toxigenic Fungal Plant Pathogen Fusarium culmorum.

Fusarium culmorum is a ubiquitous, soil-borne fungus (ascomycete) causing foot and root rot and Fusarium head blight on cereals. It is responsible for yield and quality losses as well as grain contamination with mycotoxins, which are a potential health hazard. An extremely sensitive mitochondrial-based qPCR assay (FcMito qPCR) for quantification of F. culmorum was developed in this study. To provide specificity, the FcMito assay was successfully validated against 85 F. culmorum strains and 53 isolates of 30 other fungal species. The assay efficiency and sensitivity were evaluated against different F. culmorum strains with various amounts of pure fungal DNA and in the presence of background wheat DNA. The results demonstrated the high efficiency of the assay (97.2⁻106.0%, R²-values > 0.99). It was also shown that, in the presence of background DNA, 0.01 pg of fungal template could be reliably quantified. The FcMito assay was used to quantify F. culmorum DNA using 108 grain samples with different trichothecene levels. A significant positive correlation was found between fungal DNA quantity and the total trichothecene content. The obtained results showed that the sensitivity of the FcMito assay was much higher than the nuclear-based qPCR assay for F. culmorum.

Cutometric assessment of elasticity of skin with striae distensae following carboxytherapy.

OBJECTIVE: The aim of the study was to evaluate the effectiveness of carboxytherapy in the treatment of striae distensae. Additionally, discomfort and side effects associated with the treatment were assessed. MATERIALS AND METHODS: This study involved 15 women aged 22-40 years. They underwent 3 sessions of carboxytherapy at one-week intervals. Treatment was performed in skin area within stretch marks located on stomach, buttocks, and thighs. Cutometric probe was used to evaluate skin elasticity. Four measurements were performed-immediately before each treatment and one month after the last session. Photographic documentation was made before and after a series of treatment to perform clinical evaluation of changes in skin condition. RESULTS: Statistical analysis of results obtained with the use of Cutometer (R2 and R8 parameters) demonstrated that carboxytherapy significantly improved skin elasticity within stretch marks (P < .05). The analysis of photographic documentation revealed 58% improvement in stretch mark visibility. The width and length of stretch marks decreased, and their color became more like the natural color of the skin. Carboxytherapy is associated with moderate pain/discomfort. The occurrence of hematoma is the main side effect of this procedure. CONCLUSIONS: Carboxytherapy seems to be an effective method of reducing stretch marks. This procedure is safe, and it can be performed without the risk of complications. Moreover, it does not require special postoperative convalescence. Photographic documentation is a method of assessment of aesthetic procedures effectiveness, which is complementary to other objective methods (eg, the use of MPA probes).

Sinapic Acid Affects Phenolic and Trichothecene Profiles of F. culmorum and F. graminearum Sensu Stricto.

Plant-derived compounds for reducing the mycotoxin load in food and feed have become a rapidly developing research field of importance for plant breeding efforts and in the search for natural fungicides. In this study, toxigenic strains of Fusarium culmorum and F. graminearum sensu stricto were exposed to sinapic acid on solid YES media at levels close to those reported in wheat bran. Fusaria produced phenolic acids, whose accumulation was decreased by exogenous sinapic acid. Strains exposed to the lowest doses of sinapic acid showed more efficient reduction of phenolic acid production than fungi kept at higher concentrations of this compound. Fungi reduced exogenous sinapic acid, leading to the formation of syringic aldehyde. Treatment with sinapic acid led to a dramatic accumulation of its parent compound ferulic acid, presumably due to inhibition of the further conversion of this phenolic compound. Exogenous sinapic acid decreased the production of trichothecenes by fungi. Higher doses of sinapic acid resulted in more efficient reduction of mycotoxin accumulation in the media. Gene expression studies of Tri genes responsible for trichothecene biosynthesis (Tri4, Tri5 and Tri10) proved that the inhibition of mycotoxin production by sinapic acid occurred at the transcriptional level. Fusaria respond to sinapic acid by stimulation of ergosterol biosynthesis.

trans-Cinnamic and Chlorogenic Acids Affect the Secondary Metabolic Profiles and Ergosterol Biosynthesis by Fusarium culmorum and F. graminearum Sensu Stricto.

Plant-derived compounds limiting mycotoxin contamination are currently of major interest in food and feed production. However, their potential application requires an evaluation of their effects on fungal secondary metabolism and membrane effects. In this study, different strains of Fusarium culmorum and F. graminearum sensu stricto were exposed to trans-cinnamic and chlorogenic acids on solid YES media. Fusaria produced phenolic acids, whose accumulation was lowered by exogenous phenolic compounds. In addition, fungi reduced exogenous phenolic acids, leading either to their conversion or degradation. trans-Cinnamic acid was converted to caffeic and ferulic acids, while chlorogenic acid was degraded to caffeic acid. The latter underwent further degradation to protocatechuic acid. Fungal-derived trans-cinnamic acid, as the first intermediate of the shikimate pathway, increased after chlorogenic acid treatment, presumably due to the further inhibition of the conversion of trans-cinnamic acid. Exogenous trans-cinnamic and chlorogenic acid displayed the inhibition of mycotoxin production by Fusaria, which appeared to be largely dependent on the phenolic compound and its concentration and the assayed strain. Exogenous phenolic acids showed different effects on ergosterol biosynthesis by fungi. It was found that the production of this membrane sterol was stimulated by trans-cinnamic acid, while chlorogenic acid negatively impacted ergosterol biosynthesis, suggesting that phenolic acids with stronger antifungal activities may upregulate ergosterol biosynthesis by Fusaria. This paper reports on the production of phenolic acids by Fusaria for the first time.