Auxin regulated metabolic changes underlying sepal retention and development after pollination in spinach.

BACKGROUND: Pollination accelerate sepal development that enhances plant fitness by protecting seeds in female spinach. This response requires pollination signals that result in the remodeling within the sepal cells for retention and development, but the regulatory mechanism for this response is still unclear. To investigate the early pollination-induced metabolic changes in sepal, we utilize the high-throughput RNA-seq approach. RESULTS: Spinach variety 'Cornel 9' was used for differentially expressed gene analysis followed by experiments of auxin analog and auxin inhibitor treatments. We first compared the candidate transcripts expressed differentially at different time points (12H, 48H, and 96H) after pollination and detected significant difference in Trp-dependent auxin biosynthesis and auxin modulation and transduction process. Furthermore, several auxin regulatory pathways i.e. cell division, cell wall expansion, and biogenesis were activated from pollination to early developmental symptoms in sepals following pollination. To further confirm the role auxin genes play in the sepal development, auxin analog (2, 4-D; IAA) and auxin transport inhibitor (NPA) with different concentrations gradient were sprayed to the spinach unpollinated and pollinated flowers, respectively. NPA treatment resulted in auxin transport weakening that led to inhibition of sepal development at concentration 0.1 and 1 mM after pollination. 2, 4-D and IAA treatment to unpollinated flowers resulted in sepal development at lower concentration but wilting at higher concentration. CONCLUSION: We hypothesized that sepal retention and development might have associated with auxin homeostasis that regulates the sepal size by modulating associated pathways. These findings advanced the understanding of this unusual phenomenon of sepal growth instead of abscission after pollination in spinach.

Long-term safety and exploratory efficacy of fevipiprant in patients with inadequately controlled asthma: the SPIRIT randomised clinical trial.

BACKGROUND: The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites. METHODS: SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits. RESULTS: In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks' treatment, while 163 received ≥ 104 weeks' treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies. In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor. CONCLUSIONS: In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517 .

Drug Targeting of Plasminogen Activator Inhibitor-1 Inhibits Metabolic Dysfunction and Atherosclerosis in a Murine Model of Metabolic Syndrome.

OBJECTIVE: Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome. Approach and Results: LDL receptor-deficient (ldlr-/-) mice were fed a Western diet high in cholesterol, fat, and sucrose to induce obesity, metabolic dysfunction, and atherosclerosis. Western diet triggered significant upregulation of PAI-1 expression compared with normal diet controls. Addition of a pharmacological PAI-1 inhibitor (either PAI-039 or MDI-2268) to Western diet significantly inhibited obesity and atherosclerosis formation for up to 24 weeks without attenuating food consumption. Pharmacological PAI-1 inhibition significantly decreased macrophage accumulation and cell senescence in atherosclerotic plaques. Recombinant PAI-1 stimulated smooth muscle cell senescence, whereas a PAI-1 mutant defective in LRP1 (LDL receptor-related protein 1) binding did not. The prosenescent effect of PAI-1 was blocked by PAI-039 and R2629, a specific anti-LRP1 antibody. PAI-039 significantly decreased visceral adipose tissue inflammation, hyperglycemia, and hepatic triglyceride content without altering plasma lipid profiles. CONCLUSIONS: Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an LRP1-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.

A Study of the Effect of Cyclosporine on Fevipiprant Pharmacokinetics and its Absolute Bioavailability Using an Intravenous Microdose Approach.

This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for C max, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for C max, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied intravenous microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic drug-drug interaction understanding.

Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids.

Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d) or twice-daily (2, 25, 75 or 150 mg b.i.d) fevipiprant (n=782), montelukast 10 mg q.d (n=139) or placebo (n=137). All patients received inhaled budesonide 200 µg b.i.dFevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d and 75 mg b.i.d groups, with no clinically meaningful differences between q.d and b.i.d Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments.Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted.

Effects of indole-3-acetic acid on arsenic uptake and antioxidative enzymes in Pteris cretica var. nervosa and Pteris ensiformis.

A hydroponic experiment was conducted to investigate the effects of indole-3-acetic acid (IAA) on arsenic (As) uptake and antioxidative enzymes in fronds of Pteris cretica var. nervosa (As hyperaccumulator) and Pteris ensiformis (non-hyperaccumulator). Plants were exposed to 2 mg L-1 As(III), As(V) or dimethylarsinic acid (DMA) and IAA concentrations for 14 d. The biomass and total As in the plants significantly increased at 30 mg L-1 IAA. Superoxide dismutase (SOD) activities significantly increased with IAA addition. Catalase (CAT) activities showed a significant increase in P. ensiformis exposed to three As species at 30 or 50 mg L-1 IAA but varied in P. cretica var. nervosa. Peroxidase (POD) activities were unchanged in P. ensiformis except for a significant decrease at 50 mg L-1 IAA under As(III) treatment. However, a significant increase was observed in P. cretica var. nervosa at 10 mg L-1 IAA under As(III) or DMA treatment and at 50 mg L-1 IAA under As(V) treatment. Under DMA stress, malondialdehyde contents in fronds of P. cretica var. nervosa showed a significant decrease at 10 mg L-1 IAA but remained unchanged in P. ensiformis. Therefore, IAA enhanced As uptake and frond POD activity in P. cretica var. nervosa under As stress.

Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVß3 integrin cross talk.

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) regulates angiogenesis via effects on extracellular matrix proteolysis and cell adhesion. However, no previous study has implicated PAI-1 in controlling vascular endothelial growth factor (VEGF) signaling. We tested the hypothesis that PAI-1 downregulates VEGF receptor-2 (VEGFR-2) activation by inhibiting a vitronectin-dependent cooperative binding interaction between VEGFR-2 and αVß3. APPROACH AND RESULTS: We studied effects of PAI-1 on VEGF signaling in human umbilical vein endothelial cells. PAI-1 inhibited VEGF-induced phosphorylation of VEGFR-2 in human umbilical vein endothelial cells grown on vitronectin, but not on fibronectin or collagen. PAI-1 inhibited the binding of VEGFR-2 to ß3 integrin, VEGFR-2 endocytosis, and intracellular signaling pathways downstream of VEGFR-2. The anti-VEGF effect of PAI-1 was mediated by 2 distinct pathways, one requiring binding to vitronectin and another requiring binding to very low-density lipoprotein receptor. PAI-1 inhibited VEGF-induced angiogenesis in vitro and in vivo, and pharmacological inhibition of PAI-1 promoted collateral arteriole development and recovery of hindlimb perfusion after femoral artery interruption. CONCLUSIONS: PAI-1 inhibits activation of VEGFR-2 by VEGF by disrupting a vitronectin-dependent proangiogenic binding interaction involving αVß3 and VEGFR-2. These results broaden our understanding of the roles of PAI-1, vitronectin, and endocytic receptors in regulating VEGFR-2 activation and suggest novel therapeutic strategies for regulating VEGF signaling.

Effect of low frequency pulsed magnetic field on gravitropic response and cell elongation in coleoptiles of maize seedlings.

The effect of pulsed magnetic field (PMF) on gravitropic response, endogenous growth and growth in the presence of indole-3-acetic acid (IAA) was studied in coleoptiles of maize (Zea mays L.) seedlings. Medium pH changes, measured simultaneously with growth of coleoptile segments, were also determined. In seedlings grown in the presence of PMF, elongation growth of coleoptiles was inhibited by 16%, while growth of roots and mesocotyls did not depend on PMF. Magnetic field also inhibited (by 36%) the gravitropic response of maize seedlings. However, when PMF was applied only during gravistimulation (within 6 h), it suppressed the gravitropic reaction only by 8% at 6 h. It was also found that endogenous growth and IAA-induced growth of maize coleoptile segments excised from seedlings treated with the PMF was stimulated by 52% and 30%, respectively, as compared to control (segments untreated with the PMF). Values of medium pH, measured simultaneously with growth, indicated that PMF-treated coleoptile segments extruded much more protons than untreated segments. In contrast, coleoptile segments treated with the PMF and subsequently incubated in the presence of IAA extruded 2.5-fold less protons as compared to segments treated with IAA only. The data presented here have been discussed with consideration of mechanisms by which auxin (IAA) regulates plant cell growth.

Auxin induces cell proliferation in an experimental model of mammalian renal tubular epithelial cells.

Indole-3-acetic acid is the main auxin produced by plants and plays a key role in the plant growth and development. This hormone is also present in humans where it is considered as a uremic toxin deriving from tryptophan metabolism. However, beyond this peculiar aspect, the involvement of auxin in human pathophysiology has not been further investigated. Since it is a growth hormone, we evaluated its proliferative properties in an in vitro model of mammalian renal tubular epithelial cells. We employed an experimental model of renal tubular epithelial cells belonging to the LLC-PK1 cell line that is derived from the kidney of healthy male pig. Growth effects of auxin against LLC-PK1 cell lines were determined by a rapid colorimetric assay. Increasing concentrations of auxin (to give a final concentration from 1 to 1000 ng/mL) were added and microplates were incubated for 72 h. Each auxin concentration was assayed in four wells and repeated four times. Cell proliferation significantly increased, compared to control cells, 72 h after addition of auxin to cultured LLC-PK1 cells. Statistically significant values were observed when 100 ng/mL (p < 0.01) and 1000 ng/mL (p < 0.05) were used. In conclusion, auxin influences cell growth not only in plants, where its role is well documented, but also in mammalian cell lines. This observation opens new scenarios in the field of tissue regeneration and may stimulate a novel line of research aiming at investigating whether this hormone really influences human physiology and pathophysiology and in particular, kidney regeneration.

In vitro effect of FGIN-1-27, a ligand to 18 kDa mitochondrial translocator protein, in human osteoblast-like cells.

Ligands of 18 kDa mitochondrial translocator protein (TSPO) differ in their cellular effects. We hypothesize that different TSPO ligands might exert different cellular responses. Therefore, following previous studies that showed different cellular responses to two specific TSPO ligands, PK 11195 and protoporphyrin IX, in human osteoblast-like cells in vitro, we now report the cellular response to another specific TSPO ligand, FGIN-1-27 (10(-5) M) (MW 436 kDa), in order to characterize the effects of each TSPO ligand. We found in primary culture of the human osteoblast-like cells that cell numbers were decreased by an average of 30% (p < 0.001) following exposure to 10(-5) M of FGIN-1-27 in comparison to vehicle controls. Cellular [(18)F]-FDG incorporation and ATP content were suppressed, by an average of 43% (p < 0.001) and 83% (p < 0.001), respectively. Mitochondrial mass and ΔΨm increased by an average of 26% (p < 0.01) and 425% (p < 0.0001) respectively. Lactate dehydrogenase activity was enhanced in culture media by 60% (p < 0.05), indicating overall cell death, while no increase in apoptotic levels was observed. Cellular proliferation, as determined by BrdU assay, was not affected. Synthesis of mRNA of TSPO, VDAC 1, and hexokinase 2 decreased in 0.3, 0.3 and 0.5 fold respectively, with accompanying decreases in protein expression of TSPO and Voltage Dependent Anion Channel 1 by 23% (p < 0.001) and 98% (p < 0.001), respectively, but without changes in hexokinase 2 protein expression. Thus it appears that 10(-5) M FGIN-1-27 reduces cell viability, cell metabolism, and mitochondrial function. Previously we found similar effects of PK 11195 on mitochondrial function and cell metabolism and of protoporphyrin IX on cell death in primary osteoblast-like cells.

Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459.

BACKGROUND: The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. A study was conducted to determine the effect of lower once daily doses of OC000459 and to define the phenotype of subjects most responsive to treatment. METHODS: Adult subjects (percentage of predicted forced expiratory volume in 1 s (FEV1 ) 60-85%) were randomized to OC000459 at three dose levels (25 mg once daily, 200 mg once daily or 100 mg twice daily) or placebo for 12 weeks (n = 117-125 per group, full analysis set). The primary endpoint was the change from baseline in prebronchodilator FEV1 , and secondary endpoints included Asthma Control Questionnaire (ACQ) and Standardised Asthma Quality of Life Questionnaire [AQLQ(S)], and incidence of exacerbations and respiratory tract infections. RESULTS: OC459 caused a significant improvement in FEV1 compared with placebo at a dose of 25 mg once daily (P = 0.028). A similar increase was observed in the other dose groups, and the mean change in FEV1 in the pooled dose groups at endpoint was 95 ml greater than placebo (P = 0.024). In a post hoc analysis of atopic eosinophilic subjects with uncontrolled asthma, a mean increase in FEV1 of 220 ml was observed compared with placebo (P = 0.005). The mean increase in FEV1 was more marked in younger subjects in this group: for subjects aged ≤40 years, there was a mean increase of 355 ml compared with placebo (P = 0.007). Improvements in ACQ and AQLQ(S) were observed in both the full analysis set and the atopic eosinophilic subgroup. There was a lower incidence of exacerbations and respiratory infections in subjects treated with OC000459. There were no drug-related serious adverse events. CONCLUSIONS: OC000459 is a safe and effective oral anti-inflammatory agent, which achieved clinically meaningful improvements in lung function and asthma control in allergic asthmatics with an eosinophil-dominant form of the disease. A dose of 25 mg given once daily was as effective as the higher doses studied.

Expression and regulation of pear 1-aminocyclopropane-1-carboxylic acid synthase gene (PpACS1a) during fruit ripening, under salicylic acid and indole-3-acetic acid treatment, and in diseased fruit.

In plants, the level of ethylene is determined by the activity of the key enzyme 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS). A gene encoding an ACC synthase protein was isolated from pear (Pyrus pyrifolia). This gene designated PpACS1a (GenBank accession no. KC632526) was 1488 bp in length with an open reading frame (ORF) encoding a protein of 495 amino acids that shared high similarity with other pear ACC synthase proteins. The PpACS1a was grouped into type-1 subfamily of plant ACS based on its conserved domain and phylogenetic status. Real-time quantitative PCR indicated that PpACS1a was differentially expressed in pear tissues and predominantly expressed in anthers. The expression signal of PpACS1a was also detected in fruit and leaves, but no signal was detected in shoots and petals. Furthermore, the PpACS1a expression was regulated during fruit ripening. In addition, the PpACS1a gene expression was regulated by salicylic acid (SA) and indole-3-acetic acid (IAA) in fruit. Moreover, the expression of the PpACS1a was up-regulated in diseased pear fruit. These results indicated that PpACS1a might be involved in fruit ripening and response to SA, IAA and disease.

[Role of the expansin genes NtEXPA1 and NtEXPA4 in the regulation of cell extension during tobacco leaf growth].

The tobacco plant genes NtEXPA1 and NtEXPA4 encode the α-expansin proteins involved in the regulation of cell growth and extension. We examined the levels of expression of these genes in various plant organs and under the effect of exogenous phytohormones. The highest levels of NtEXPA1 expression were registered in the terminal bud and in the young growing leaves and flowers. NtEXPA1 expression ceased once the leaves stopped growing. The NtEXPA4 gene showed a similar expression profile, except for higher levels of mRNA in the leaves. In young leaves located near the terminal bud, high levels of NtEXPA1 and NtEXPA4 are induced by auxins. In the lower leaves, expansin expression is differentially regulated by brassinosteroids, which inhibit NtEXPA1 and upregulate NtEXPA4. We further showed that expression of the transgenic ARGOS-LIKE results in upregulation of NtEXPA1 and a reduction in the NtEXPA4 mRNA. In turn, overexpression of NtEXPA1 resulted in an increased size of the leaves and stems because of the larger size of the individual cells.

Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, Th2-type inflammatory disease. Chemoattractant receptor-homologous molecule on Th2 cells (CRTH2) is a prostaglandin D(2) (PGD(2)) receptor, expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, that mediates chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and would be expected to suppress eosinophilic tissue inflammation. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE. METHODS: In this randomized, double-blind, placebo-controlled trial, 26 adult patients (m/f = 22/4; mean age 41 years, range 22-69 years) with active EoE, dependent or resistant to corticosteroids, were treated either with 100 mg OC000459 (n = 14) or placebo (n = 12) twice daily. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary end point was the reduction in esophageal eosinophil infiltration. RESULTS: After an 8-week OC000459 treatment, the esophageal eosinophil load decreased significantly, from 114.83 to 73.26 eosinophils per high-power field [(eos/hpf), P = 0.0256], whereas no reduction was observed with placebo (102.80-99.47 eos/hpf, P = 0.870). With OC000459, the physician's global assessment of disease activity improved from 7.13 to 5.18 (P = 0.035). OC000459 likewise reduced extracellular deposits of eosinophil peroxidase and tenascin C, the effects not seen with placebo. No serious adverse events were observed. CONCLUSIONS: An 8-week treatment with the CRTH2-antagonist, OC000459, exerts modest, but significant, anti-eosinophil and beneficial clinical effects in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE and is well tolerated.

A comparative split-face study of photodynamic therapy with indocyanine green and indole-3-acetic acid for the treatment of acne vulgaris.

BACKGROUND: Recently, photodynamic therapy (PDT) using a variety of light sources and photosensitizers has been used for the treatment of acne vulgaris. PDT with aminolaevulinic or methylaminolaevulinic acid has also been used in clinical trials as a treatment for acne, but adverse effects such as pain, erythema and pustular eruption are common. Indocyanine green (ICG) and indole-3-acetic acid (IAA), newer photosensitizers, are known to have minimal adverse effects. OBJECTIVES: This study was designed to compare the safety and efficacy of PDT using ICG and PDT using IAA in the treatment of mild to moderate acne vulgaris. METHODS: In this prospective, single-blind, clinical trial, 34 patients with mild to moderate acne were treated with IAA with green light (520 nm) on half of the face and with ICG with near-infrared radiation (805 nm) on the other half. The procedure was carried out five times at 1-week intervals. RESULTS: With regard to acne lesions (inflammatory and noninflammatory) and sebum secretion, there were statistically significant reductions at each time point compared with the baseline values (P < 0·05). However, there were no statistically significant differences between the two treatment types (P > 0·05). Both ICG-PDT and IAA-PDT showed better responses for inflammatory lesions than for noninflammatory lesions (P < 0·05). Subjective satisfaction score were statistically significant at 4 and 5 weeks of treatment as well as at 1, 2 and 3 months follow-up (P < 0·05). CONCLUSIONS: Both PDT with ICG and PDT with IAA are safe and effective for the treatment of mild to moderate acne vulgaris.

Indole-3-acetic acid: a potential new photosensitizer for photodynamic therapy of acne vulgaris.

BACKGROUND AND OBJECTIVES: ALA (5-aminolevulinic acid) photodynamic therapy (PDT) is a new treatment option for acne. However, it needs a relatively long incubation period and adverse effects are common. Indole-3-acetic acid (IAA) is not toxic by itself but produces free radicals with ultraviolet B. In this study we examined the potential of IAA as a photosensitizer for acne treatment. MATERIALS AND METHODS: Free radical formation was measured after visible light irradiation of IAA. Antimicrobial effect was evaluated by assessing growth suppression of Propionibacterium acnes and Staphylococcus aureus after IAA PDT. To evaluate the histological changes, skin biopsies were performed on nude mice skin after IAA PDT. To evaluate the clinical efficacy of IAA PDT, 14 acne patients were treated with the following IAA PDT regimen: three times each with a 15 minutes incubation period and a 2-week interval. The number of inflammatory lesions and the amount of sebum secretion were then assessed. RESULTS: IAA produced free radicals with green light irradiation. Importantly, IAA lost its photosensitizing ability after exposure to certain amount of light. This implies IAA PDT would not require post-procedure photo-protection. The growth of P. acnes and S. aureus were significantly suppressed with IAA PDT. In addition, IAA PDT treated skin showed destruction of follicular ostia epithelium. Interestingly, there was no significant difference between a 4 hours and a 30 minutes incubation, which means that longer absorption time is not necessary for IAA PDT. In the clinical study, inflammatory lesions and sebum secretion were significantly reduced. The procedure was painless and no adverse effect was observed. Photo-protection was not performed and there were no further phototoxic responses. CONCLUSIONS: IAA PDT has therapeutic effects on acne via its antimicrobial activities, its sebum-reducing effect and through relieving follicular occlusion. It is a very simple and safe treatment option for acne.

Radial water transport in arbuscular mycorrhizal maize plants under drought stress conditions is affected by indole-acetic acid (IAA) application.

Drought stress is one of the most devastating abiotic stresses, compromising crop growth, reproductive success and yield. The arbuscular mycorrhizal (AM) symbiosis has been demonstrated to be beneficial in helping the plant to bear with water deficit. In plants, development and stress responses are largely regulated by a complex hormonal crosstalk. Auxins play significant roles in plant growth and development, in responses to different abiotic stresses or in the establishment and functioning of the AM symbiosis. Despite these important functions, the role of indole-3acetic acid (IAA) as a regulator of root water transport and stress response is not well understood. In this study, the effect of exogenous application of IAA on the regulation of root radial water transport in AM plants was analyzed under well-watered and drought stress conditions. Exogenous IAA application affected root hydraulic parameters, mainly osmotic root hydraulic conductivity (Lo), which was decreased in both AM and non-AM plants under water deficit conditions. Under drought, the relative apoplastic water flow was differentially regulated by IAA application in non-AM and AM plants. The effect of IAA on the internal cell component of root water conductivity suggests that aquaporins are involved in the IAA-dependent inhibition of this water pathway.

Infertility induced by auxin in PX627 Caenorhabditis elegans does not affect mitochondrial functions and aging parameters.

Caenorhabditis elegans is widely used for aging studies. 5-Fluoro-2´-deoxyuridine (FUdR) is commonly used to control offspring. While larvae are stopped from further development, also mitochondrial DNA and function may be affected. Since mitochondria and longevity are closely related, the use of FUdR may falsify possible studies. PX627, an auxin inducible infertility strain to control offspring, allows mitochondrial investigations during senescence without FUdR toxicity.Longevity and health parameters were assessed in 2- and 10-day old nematodes wild-type N2 and PX627 treated with FUdR or auxin, respectively. Mitochondrial membrane potential, energetic metabolites and reactive oxygen species levels, were determined. mRNA expression levels of key genes involved were quantified using quantitative real-time PCR.FUdR significantly increased lifespan and health parameters, as well as, mitochondrial function compared to untreated controls and auxin treated PX627. Although a decrease in all parameters could be observed in aged nematodes, this was less severe after FUdR exposure. Glycolysis was significantly up-regulated in aged PX627 compared to N2. Expression levels of daf-16, sir-2.1, aak-2, skn-1, atp-2 and atfs-1 were regulated accordingly.Hence, auxin in PX627 might be a good alternative to control progeny, for mitochondrial- and longevity-related investigations in nematodes.

Design of stable magnetic hybrid nanoparticles of Si-entrapped HRP.

Hybrid and composite nanoparticles represent an attractive material for enzyme integration due to possible synergic advantages of the structural builders in the properties of the nanobiocatalyst. In this study, we report the synthesis of a new stable hybrid nanobiocatalyst formed by biomimetic silica (Si) nanoparticles entrapping both Horseradish Peroxidase (HRP) (EC 1.11.1.7) and magnetic nanoparticles (MNPs). We have demonstrated that tailoring of the synthetic reagents and post immobilization treatments greatly impacted physical and biocatalytic properties such as an unprecedented ~280 times increase in the half-life time in thermal stability experiments. The optimized nanohybrid biocatalyst that showed superparamagnetic behaviour, was effective in the batch conversion of indole-3-acetic acid, a prodrug used in Direct Enzyme Prodrug Therapy (DEPT). Our system, that was not cytotoxic per se, showed enhanced cytotoxic activity in the presence of the prodrug towards HCT-116, a colorectal cancer cell line. The strategy developed proved to be effective in obtaining a stabilized nanobiocatalyst combining three different organic/inorganic materials with potential in DEPT and other biotechnological applications.

The effects of IBA on the composition of maize root cell walls.

Auxin is one of the crucial plant hormones which stimulates and controls cell and plant growth. The effects of auxin IBA (indole-3-butyric acid) during 10-days on maize plants growth in controlled conditions (hydroponic, 16-h photoperiod, 70% humidity, 25/20 °C temperature), depended on its concentration in the substrate. A high concentration (10-7 M) of IBA inhibited root growth, evoked the development of apoplasmic barriers (Casparian bands and suberin lamellae) closer to the root apex, and elevated the amount of lignin in roots. A low concentration (10-11 M) of IBA stimulated root growth but affected neither the development of apoplasmic barriers, nor the amount of lignin. Auxin in a 10-8 M concentration influenced the root growth to a minimal extent compare to the control, and it was the non-effective concentration. Plant cell walls as cell structures ensure cell enlargement and plant growth, and have to react to auxin stimulus by modification of their components. We found the most significant changes in the composition of the PF III fraction (lignocellulosic complex) of the cell wall. The presence of auxin in the substrate affected all three components of this fraction - Klason lignin and both the by acid (2 M TFA) non-hydrolysable and the hydrolysable parts of this complex. The ratio of the non-hydrolysable part to the Klason lignin increased from 1.3 to 3.3 with increasing auxin concentrations in the substrate. This may be related to the deposition of polysaccharides and lignin in the cell wall, which help maintain the specific tensile stress of, and turgor pressure on, the cell walls.