BA Treatment Research Articles

Mitigation of salinity stress by exogenous application of cytokinin in faba bean (Vicia faba L.)

Soil salinity limits agricultural land use and crop productivity, thereby a major threat to global food safety. Plants treated with several phytohormones including cytokinins were recently proved as a powerful tool to enhance plant’s adaptation against various abiotic stresses. The current study was designed to investigate the potential role of 6-benzyladenine (BA) to improve broad bean (Vicia faba L.) salinity tolerance. The salt-stressed broad bean plantlets were classified into two groups, one of which was sprayed with water and another was sprayed with 200 ppm of BA. Foliar applications of BA to salt-exposed plants promoted the growth performance which was evidenced by enhanced root-shoot fresh and dry biomass. Reduced proline was strongly connected to the enhanced soluble proteins and free amino acids contents, protecting plant osmotic potential following BA treatment in salt-stressed broad bean. BA balanced entire mineral homeostasis and improved mineral absorption and translocation from roots to shoots, shoots to seeds and roots to seeds in salt-stressed plants. Excessive salt accumulation increased malondialdehyde level in leaves creating oxidative stress and disrupting cell membrane whereas BA supplementation reduced lipid peroxidation and improved oxidative defence. BA spray to salinity-stressed plants also compensated oxidative damage by boosting antioxidants defence mechanisms, as increased the enzymatic activity of superoxide dismutase, catalase, peroxidase and ascorbate peroxidase. Moreover, clustering heatmap and principal component analysis revealed that mineral imbalances, osmotic impairments and increased oxidative damage were the major contributors to salts toxicity, on the contrary, BA-augmented mineral homeostasis and higher antioxidant capacity were the reliable markers for creating salinity stress tolerance in broad bean. In conclusion, the exogenous application of BA alleviated the antagonistic effect of salinity and possessed broad bean to positively regulate the osmoprotectants, ion homeostasis, antioxidant activity and finally plant growth and yield, perhaps suggesting these easily-accessible and eco-friendly organic compounds could be powerful tools for the management of broad bean growth as well as the development of plant resiliency in saline prone soils.

The Morphological Responses of Calendula officinalis L. “Radio” to the Foliar Application of Benzyladenine and Different Light Spectra

Pot marigold is a valuable medicinal plant with great decorative value. Three combinations of light (white (W)—170 μmol m−2 s−1, white + blue (W+B)—230 μmol m−2 s−1, white + red (W+R)—230 μmol m−2 s−1) were used to analyse the influence of a diversified light spectrum on the morphological traits and flowering of Calendula officinalis L. “Radio”. The effect of foliar treatment of the plants with 6-benzyladenine (BA) at concentrations of 100, 150 and 200 mg dm−3 at all the light spectrum combinations was analysed. BA had negative influence on the earliness of florescence and delayed it even by more than 10 days. W+B light intensified the delay, whereas red light partly reduced it. The BA treatment had the greatest influence on the biometric traits of the plants at the initial period of their development. W+B light significantly inhibited the growth of the plants. A high share of red light in the spectrum positively affected the Fv/Fm value, the relative chlorophyll content and the percentage of dry matter in the plants. When the amount of blue or red light in the spectrum increased, it was possible to obtain specific biometric traits of Calendula without the BA treatment.

Effects of plant growth regulators and polyamines on bract longevity in Bougainvillea buttiana

There are no reports on plant growth regulators (PGR) or polyamines being used to stimulate bract longevity in bougainvillea species, yet understanding how PGR and polyamines influence bougainvillea bract phenology is important for flower profitability. Potted bougainvillea plants in four different bract development stages based on bract diameter were pre-treated with salicylic acid (SA) at a concentration of 0.5 mM combined with 1-naphthaleneacetic acid (NAA, 0.13 mM), gibberellic acid (GA, 0.29 mM), and 6-benzylaminopurine (BA, 0.22 mM) in 100 mL mixtures. Three 100 mL polyamine treatments [diamine putrescine (Put), triamine spermidine (Spd), and tetraamine spermine (Spm)] at 1 mM were also individually sprayed on bougainvillea bracts. Control bracts were sprayed only with water. Different PGR combinations and single polyamine treatments acted differently on bract longevity and endogenous 1-aminocylopropane-1-carboxylic acid (ACC) content, and each combination and single polyamine was not equally significant in regard to coordinating a response to ACC regulation. In combined chemical treatments, maximum and significantly prolonged bract longevity in all stages were detected in the SA + NAA + GA + BA treatment compared to controls and other combinations, and longevity increased as bract stage progressed. A strong synergistic interaction was observed between SA and NAA regarding bract longevity and ACC levels. Moreover, Put also significantly prolonged bract longevity and remarkably reduced endogenous ACC content at all stages, this effect increasing as bract stage progressed compared to Spd, Spm, and controls. Therefore, the effects of SA + NAA + GA + BA and single Put (1 mM) applied to bougainvillea bracts for increasing longevity in the nursery offers insight into re-vegetation, landscaping programs, and cultivation in gardens.

Effect of bempedoic acid on uric acid and gout in 3621 patients with hypercholesterolemia: pooled analyses from phase 3 trials

Abstract Background Bempedoic acid (BA), an oral ATP-citrate lyase inhibitor, significantly lowers low-density lipoprotein cholesterol levels in patients with hypercholesterolemia. In clinical trials of BA, small mean increases in uric acid have been reported. BA weakly inhibits organic anion transporter 2 (OAT2) in vitro, which may account for small elevations in serum uric acid. Purpose To assess uric acid levels and incidence of gout with BA treatment. Methods Data were pooled from 4 randomized (2:1), double-blind studies of BA (180 mg daily) vs placebo for 12 weeks to 52 weeks in patients with hypercholesterolemia on stable background lipid-lowering therapy. Safety assessments included adverse events of special interest (elevation in uric acid levels, gout) and laboratory assessments. Results A total of 2424 patients treated with BA and 1197 patients on placebo were included in this analysis. Mean (SD) baseline uric acid levels were 6.0 (1.4) mg/dL for both groups. History of gout was reported by 5.2% (127/2424) and 5.8% (69/1197) in the BA and placebo groups, respectively. At week 12, mean (SD) serum uric acid levels (% change from baseline) increased from baseline with BA treatment by 0.82 (0.97) mg/dL (14.8%) vs –0.02 (0.82) mg/dL (0.67%) for placebo. Elevations in serum uric acid levels typically occurred within the first 4 weeks of treatment, remained stable during treatment, and returned to baseline after treatment discontinuation. Gout was reported in 1.4% (BA) and 0.4% (placebo) of patients, and hyperuricemia was reported in 1.7% (BA) and 0.6% (placebo) of patients. Other potential clinical consequences of elevated uric acid levels (eg, events associated with nephrolithiasis), were similar between groups (0.7% vs 0.8%). In both groups, patients who reported gout during the studies were more likely to have a medical history of gout or elevated baseline uric acid levels (Table). Few patients discontinued treatment due to gout (n=1, <0.1% [BA]) or uric acid increases (n=2, <0.1% [BA]). Conclusion Mean increases in uric acid levels were small, remained stable while patients continued to receive treatment, were infrequently associated with AEs, and were reversible on discontinuation of BA Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.

Long-term safety and efficacy of bempedoic acid in patients at high risk of atherosclerotic cardiovascular disease: results from the CLEAR Harmony open-label extension study

Abstract Background Bempedoic acid (BA) is an oral first-in-class, ATP-citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) levels in adults with hypercholesterolemia. In the phase 3 CLEAR Harmony study (NCT02666664, n=2230), BA 180 mg for 52 weeks significantly lowered LDL-C at week 12 compared with placebo and was maintained for 52 weeks in hypercholesterolemic patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) on stable, maximally tolerated statins. Purpose To report long-term safety, tolerability, and efficacy of BA from the CLEAR Harmony open-label extension (OLE) study (NCT03067441). Methods After completing the 52-week placebo-controlled CLEAR Harmony study, patients immediately entered the OLE and received BA for 78 weeks, followed by a 4-week washout period; the potential cumulative exposure to BA was 2.5 years. The primary endpoint was long-term safety of BA in the OLE. Results A total of 1462 patients enrolled in the OLE (BA n=970; placebo n=492 from CLEAR Harmony). At OLE baseline, mean (SD) age was 66.9 (8.7) years, 73.9% were male, 96.3% had ASCVD, 3.7% had HeFH with or without ASCVD, and all were receiving statins (93.5% moderate or high intensity). At baseline of CLEAR Harmony, patients had mean (SD) LDL-C of 102.9 (29.9) mg/dL (BA) and 99.0 (24.2) mg/dL (placebo). The majority of OLE patients (86.2%, n=1260) completed 78 weeks of BA treatment. At week 12 and 78 of OLE treatment, respectively, mean LDL-C lowering from CLEAR Harmony baseline was –14.9% and –14.4%. A total of 1143 patients (78.2%) reported a treatment-emergent adverse event (TEAE), and 299 (20.5%) reported a serious TEAE. TEAEs of special interest, determined by the therapeutic area or prior observations in preclinical or early clinical studies, occurred at similar rates as CLEAR Harmony (creatine kinase elevations, 1.8%; gout, 2.6%; hepatic enzyme elevations, 2.0%; hypoglycemia, 1.2%; muscular disorders, 8.5%; neurocognitive disorders, 0.9%; new onset/worsening diabetes mellitus, 5.5%; renal disorders, 2.8%) with biochemical changes that were stable over the course of the study and approached baseline levels after treatment discontinuation. Overall, 114 patients (7.8%) reported a TEAE leading to discontinuation of BA (most common: myalgia [0.6%], muscle spasm [0.5%]). Conclusion Durable lipid lowering was observed through 78 weeks of BA treatment and patient adherence to BA therapy was high (86.2%). Overall safety during the OLE was similar to results reported in the 52-week-long CLEAR Harmony study and the overall BA phase 3 clinical program, with no new safety findings. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics, Inc., funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.

Clinical research on behavioral activation as treatment for post‐traumatic stress disorder: A brief review and meta‐analysis

AbstractBehavioral activation (BA), an effective treatment for depression, has recently been receiving attention as a possible intervention for PTSD. BA interventions could be particularly useful in treating underserved populations (i.e., individuals with lower socioeconomic status). A literature search was conducted, which identified seven outcome studies that examined the effectiveness of stand‐alone BA treatment for individuals with PTSD. All studies identified for this brief review demonstrated clinically significant reductions in PTSD symptoms using BA as an intervention. A meta‐analysis of these few studies revealed a nonsignificant effect (Cohen's d = 0.713, p = .512) despite reporting an average symptom reduction of 25.8%. Other studies utilizing BA treatment for PTSD do so in tandem with other interventions and were excluded from analysis. This brief review summarizes the literature on the use of BA as a stand‐alone treatment for PTSD and suggests that future research seek to confirm the usefulness of BA as a potential treatment modality for mental health‐care providers treating individuals with PTSD.

Effects of plant growth regulators applications on induction of lateral branching in Oregon Spur apple nursery trees

The study presents the influence of 6-benzayladenine alone and in combination with gibberellic acid on growth and lateral branching of one-year-old ‘Oregon Spur’ apple nursery trees grafted on MM-106 rootstock. Different concentrations of BA and BA+GA3 (200, 300, 400, 500, 600 and 700 ppm) were applied three times at one week interval during second vegetative growth. Investigation reveal that Oregon Spur have strong apical dominance and plant applied with growth regulators resulted in a significant increase in number of feathers (0.58 to 6.18 per tree) compared to untreated control (0.18 per tree). However, BA alone has more significant effect on number of feathers (1.45 to 6.18 per tree) than BA+GA3 (0.58 to 4.35 per tree). Maximum number of feathers (6.18 per tree) has been obtained with 500 ppm BA treatment. This treatment also resulted in more uniform feather length (2.58 short and 2.55 medium length lateral branches per tree) and correct distribution of feathers along the trunk (20.63 cm branching zone) with appropriate average feathers crotch angle (54.74° from vertical). Furthermore, this treatment resulted in 100 per cent feathered trees compared to none in control and 2.88 trunk and mean feather diameter ratio compared to 1.54 in control. Some treatments with BA had a negative influence on the tree height. Whereas, most treatments increased trunk diameter and crotch angle compared to control.

Transcriptomically Guided Mesendoderm Induction of Human Pluripotent Stem Cells Using a Systematically Defined Culture Scheme.

SummaryHuman pluripotent stem cells (hPSCs) are an essential cell source in tissue engineering, studies of development, and disease modeling. Efficient, broadly amenable protocols for rapid lineage induction of hPSCs are of great interest in the stem cell biology field. We describe a simple, robust method for differentiation of hPSCs into mesendoderm in defined conditions utilizing single-cell seeding (SCS) and BMP4 and Activin A (BA) treatment. BA treatment was readily incorporated into existing protocols for chondrogenic and endothelial progenitor cell differentiation, while fine-tuning of BA conditions facilitated definitive endoderm commitment. After prolonged differentiation in vitro or in vivo, BA pretreatment resulted in higher mesoderm and endoderm levels at the expense of ectoderm formation. These data demonstrate that SCS with BA treatment is a powerful method for induction of mesendoderm that can be adapted for use in mesoderm and endoderm differentiation.

Reversible phase transition enabled by binary Ba and Ti-based surface modification for high voltage LiCoO2 cathode

As a popular commercialized cathode material in lithium-ion batteries, the cycle life, practical reversible capacity, and rate capabilities of LiCoO2 (LCO) at high voltage are limited owning to structural irreversibility and surface side reactions. Here, we employ a binary Ba and Ti-based hybrid surface treatment on LiCoO2 (LCO@BT) by facile wet chemical routes. This strategy integrates the advantages of both interface particle doping and surface coating as the layered structure of LCO is stabilized by a binary hybrid surface treatment, and the modified layer promotes the surface Li+ diffusivity and protects the LCO cathode from steady corrosion induced by surface side reaction. On the basis of in-situ NMR characterizations, it is found that after the first electrochemical delithiation/lithiation the phase reversibly changes from O3–I-type in LCO@BT and back to O3–I-type LxCO@BT (0.98 ≤ x＜1) rather than to a two-phase domain of O3–I and O3-II phase in uncoated LxCO (x＜0.98). The target material is achievable in displaying an initial discharge capacity of 190.5 mAh g−1 and delivers a high capacity retention of 90.29% (172 mAh g−1) at 0.2C after 100 cycles which is superior to most LiCoO2 cathodes that are operated at high cut-off voltage of 4.5V.

Bakuchiol suppresses oestrogen/testosterone-induced Benign Prostatic Hyperplasia development through up-regulation of epithelial estrogen receptor β and down-regulation of stromal aromatase

Estrogens and androgens play critical roles during benign prostatic hyperplasia (BPH) development. Estrogen receptors (ERs), androgen receptor (AR) and aromatase, the key conversion enzyme of androgen to estrogen, are thought to be the effective targets for BPH treatment. Bakuchiol (Ba)-containing herb Psoralea corylifolia has been long-termed used for BPH patients in traditional Chinese medicine while the role and regulatory mechanism of Ba involved remain unclear. Human prostatic cell lines WPMY-1 and BPH-1 and oestrodial/testosterone-induced BPH rats were used as the in vitro and in vivo models. Ba significantly inhibited the proliferation of WPMY-1 and BPH-1 cells. In E2/T-induced BPH model, Ba treatment also significantly inhibited the enlargement of prostate, decreased PI values, reduced the thickness of periglanular smooth muscle layer, and down-regulated the expressions of PCNA and smooth muscle cell marker α-SMA, all of which were highly induced in BPH rats. Moreover, the basal and PGE2-induced expressions of aromatase were reduced in Ba-stimulated WPMY-1 cells, while the expression of ERβ was highly increased in Ba-stimulated BPH-1 cells, both of which are consistent with the findings in Ba group in vivo. Ba induced ERE activity in BPH-1 cells as E2 did; however, silence of ERβ not ERα, blocked Ba-induced ERE activity while E2 still exhibited the significant ERE activity, indicating the regulation of estrogen signaling by Ba is particularly via ERβ. In conclusion, by down-regulation of stromal aromatase and up-regulation of epithelial ERβ, Ba contributes to the balance of estrogen and androgen signaling and further inhibits BPH development.

Étude préliminaire de l’effet de l’activation comportementale sur les biais attentionnels envers l’information émotionnelle à valence positive et négative

ObjectivesBehavioural activation improves mental health and psychological functioning, especially among patients with depression. Behavioural activation is associated with the improvement of several mechanisms, such as activation, avoidance, and environmental reward. Behavioural activation may also improve cognitive control abilities. Finally, studies on neurological changes suggested an improvement of the functioning of reward structures in response to positive stimuli after a BA treatment. Yet, uncertainty abounds regarding the putative mechanisms of behavioural activation. Prominent cognitive models of depression posit that attentional bias for negative and positive information may play an important role in the maintenance of a depressive mood. Inspired by these models and the results by the mentioned above, we investigated the impact of behavioural activation treatment for depression on attentional selectivity for sad and positive materials. We predicted that (1) attention to sad faces would be reduced after the intervention, (2) attention to happy faces would be enhanced after the intervention, and finally (3) the intervention would improve depressive symptomatology, activation, avoidance and environmental reward. Materials and methodEight undergraduate students with medium to moderate depressive symptoms participated in a six-week behavioural activation intervention. A dot-probe task with happy and sad faces and self-report questionnaires focused on depression, activation, avoidance, and environmental reward were administered before and after the intervention. ResultsDepression, avoidance, and environmental reward scores improved after treatment with large effect sizes. Behavioural activation likewise improves attentional bias for positive faces. However, there was no attentional bias for sad faces at either evaluation time. ConclusionThe preliminary nature of our findings notwithstanding, this study is the first to provide evidence of behavioural activation impact on attentional selectivity vis-à-vis positive material.

Laboratory Scale Investigations on Heap (Bio)leaching of Municipal Solid Waste Incineration Bottom Ash

Municipal solid waste incineration bottom ash (MSWI BA) is the main output of the municipal solid waste incineration process, both in mass and volume. It contains some heavy metals that possess market value, but may also limit the utilization of the material. This study illustrates a robust and simple heap leaching method for recovering zinc and copper from MSWI BA. Moreover, the effect of autotrophic and acidophilic bioleaching microorganisms in the system was studied. Leaching yields for zinc and copper varied between 18–53% and 6–44%, respectively. For intensified copper dissolution, aeration and possibly iron oxidizing bacteria caused clear benefits. The MSWI BA was challenging to treat. The main components, iron and aluminum, dissolved easily and unwantedly, decreasing the quality of pregnant leach solution. Moreover, the physical nature and the extreme heterogeneity of the material caused operative requirements for the heap leaching. Nevertheless, with optimized parameters, heap leaching may offer a proper solution for MSWI BA treatment.

MICROPROPAGATION AND PLOIDY STABILITY OF Lippia lacunosa Mart. & Schauer: AN ENDANGERED BRAZILIAN MEDICINAL PLANT

Lippia lacunosa is a Brazilian savanna plant that belongs to the Verbenaceae family. It has been used in folk medicine as a treatment for different diseases. This species represents an endangered Brazilian medicinal plant, and this is the first report documenting a reliable protocol for the in vitro propagation and regeneration of L. lacunosa. Axenic explants were cultivated in MS medium containing different concentrations of naphthalene acetic acid (NAA) to induce root growth. The mean shoot length and the number of roots were highest with 0.06 mg·L-1 NAA. The highest number of buds in shoot regeneration was induced with 2 mg·L-1 6-benzylaminopurine (BA). To obtain a long-term culture, the dwarf shoots were elongated on MS media containing 0.5 mg·L-1 BA alternated with MS containing 2 mg·L-1 BA every 40 days. In the present protocol, the long-term shoots retained the ability to root even after long periods of BA treatment. In addition, we evaluated the nuclear DNA content and ploidy levels, including the occurrence of endopolyploidy, in long-term micropropagated plant leaves using flow cytometry analysis. The plants propagated in vitro over several years possessed nuclear DNA contents ranging from 2.940 to 3.095 pg, and no differences in DNA content were found among in vitro plants or between these plants and the control (L. lacunosa from a greenhouse with a DNA content of 3.08 pg). The flow cytometry analysis also demonstrated that there was no polyploidization. The present study will be useful for biotechnological approaches and provides the first estimate of the nuclear DNA content of this species using flow cytometry.

Exogenous application of GA3 inactively regulates axillary bud outgrowth by influencing of branching-inhibitors and bud-regulating hormones in apple (Malus domestica Borkh.).

Although gibberellin (GA) has been reported to control branching, little is known about how GA mediates signals regulating the outgrowth of axillary buds (ABs). In the current study, the effect of the exogenous application of 5.0mM GA3 on ABs outgrowth on 1-year-old 'Nagafu No. 2'/T337/M. robusta Rehd. apple trees was investigated and compared to the bud-activating treatments, 5mM BA or decapitation. Additionally, the expression of genes related to bud-regulating signals and sucrose levels in ABs was examined. Results indicated that GA3 did not promote ABs' outgrowth, nor down-regulate the expression of branching repressors [MdTCP40, MdTCP33, and MdTCP16 (homologs of BRANCHED1 and BRC2)], which were significantly inhibited by the BA and decapitation treatments. MdSBP12 and MdSBP18, the putative transcriptional activators of these genes, which are expressed at lower levels in BA-treated and decapitated buds, were up-regulated in the GA3 treatment in comparison to the BA treatment. Additionally, GA3 did not up-regulate the expression of CK response- and auxin transport-related genes, which were immediately induced by the BA treatment. In addition, GA3 also up-regulated the expression of several Tre6P biosynthesis genes and reduced sucrose levels in ABs. Sucrose levels, however, were still higher than what was observed in BA-treated buds, indicating that sucrose may not be limiting in GA3-controlled AB outgrowth. Although GA3 promoted cell division, it was not sufficient to induce AB outgrowth. Conclusively, some branching-inhibiting genes and bud-regulating hormones are associated with the inability of GA3 to activate AB outgrowth.

Improved optical and structural properties of nonpolar a-plane AlGaN epi-layers after Cp2Mg and NH3 treatments

The optical and structural properties of non-polar a-plane Al0.4Ga0.6N epi-layers were improved significantly with the assistance of a bicyclopentadienyl-magnesium (Cp2Mg) and ammonia (NH3) (BA) treatment. The defects-related emission was remarkably suppressed with the introduced BA treatment. Moreover, the crystalline quality could be improved significantly using a BA treatment at a relatively low-temperature (LT), whereas the anisotropy in crystalline quality could be suppressed remarkably using a BA treatment at a relatively high-temperature (HT). In fact, the full width at half maximum values in the X-ray rocking curves measured along c- and m-directions were found to be decreased by approximately 15.5% and 56.0%, respectively, with the introduction of both LT-BA and HT-BA treatments. Meanwhile, the root-mean-square value measured with an atomic force microscope was decreased from 7.1 to 3.3 nm due to the LT-BA and HT-BA treatments.

Anti-diabetic effect of betulinic acid on streptozotocin-nicotinamide induced diabetic male mouse model

ABSTRACT Diabetes is a metabolic disease caused by abnormal insulin secretion or action. In the present study, the effects of betulinic acid (BA, a triterpene) are evaluated on glucose, α-amylase and plasma insulin levels, insulin resistance and the histopathology of pancreatic islets in streptozotocin-nicotinamide (STZ-NA) diabetic mice. Seventy adult male NMRI mice were randomly divided into seven groups: control, sham, diabetic, diabetic treated with BA (10, 20 and 40 mg/kg) and diabetic treated with metformin (200 mg/kg). Diabetes was induced in mice by intraperitoneal injection of streptozotocin 50 mg/kg after a dose of nicotinamide 120 mg/kg. Two weeks after treatment with BA, blood samples were collected for measuring glucose, α-amylase and insulin levels, and the pancreas was isolated for histopathology evaluation. Diabetes reduced the number and diameter of pancreatic islets, and increased α-amylase and insulin resistance. BA treatment reduced blood glucose, α-amylase and improved insulin sensitivity as well as pancreas histopathology. In addition, BA showed stronger effects on the pancreatic histology and insulin resistance compared to the metformin group.

Abstract 2874: Benzaldehyde inhibits the multiple signals in cancer by suppressing the binding activity of overexpressed 14-3-3ζ and represses the pRb/E2F transcriptional pathway

Abstract Benzaldehyde (BA) is the simplest aromatic aldehyde composed of only benzene ring and aldehyde. It is constituents of many fruits and flavor essence. Anti-cancer effect of BA was first reported in 1980, and multi institutional clinical trials by using derivatives of BA were performed in 1980's in Japan. However, clinical study was aborted due to the policy and strategic change in the company. Only the safety of the compound was confirmed. Given that we had multiple effective clinical cases including pancreatic cancers and chemo-resistant non Hodgkin lymphoma, we attempted to elucidate the mechanism of anti-cancer effect of BA. We have previously reported that BA inhibits cancer-related multiple pathways such as PI3K/AKT/mTOR, STAT3, NFκB and ERK, leading to cell death and growth suppression in BA sensitive pancreatic cancer cell line BxPC3, but not in normal cells. We found that such mechanism is based on the BA-mediated inhibition of 14-3-3ζ binding to its client proteins. To further analyze the BA-mediated regulation of 14-3-3ζ, we generated HEK293 cells overexpressing 14-3-3ζ and confirmed that BA suppressed mTOR pathway in the 14-3-3ζ expressing HEK293 cells but not in parental HEK293 cells. Furthermore, we found that depletion of 14-3-3ζ suppresses mTOR signal in BxPC3 and BA-induced reduction of phosphorylation of mTOR signal proteins. Moreover, we performed microarray analysis on three pancreatic cancer cell lines (BxPC-3, AsPC1, PANC1) and found that stress response genes were upregulated in BxPC-3 cells by BA treatment. E2F2 and E2F targeted genes and histone cluster genes in 6p22 were suppressed in not only BxPC-3 but also BA low-sensitive PANC1. We confirmed that BA treatment suppresses the expression of E2F2 and E2F target genes. Of note, protein levels of pRb and cyclin D were also suppressed by BA treatment. Those data suggest that BA inhibits overexpressed 14-3-3ζ mediated multiple signaling pathway and consequently represses pRB/E2F and E2F target genes, resulting in inhibition of cell cycle progression, DNA replication and DNA repair. We propose that those mechanisms can explain why this safe compound is effective for refractory cancers. Citation Format: Jun Saitoh, Hideyuki Saya. Benzaldehyde inhibits the multiple signals in cancer by suppressing the binding activity of overexpressed 14-3-3ζ and represses the pRb/E2F transcriptional pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2874.

Identification of candidate genes mediating apple fruit-cracking resistance following the application of gibberellic acids 4 + 7 and the cytokinin 6-benzyladenine

Calyx-end cracking in 'Pink Lady' apple is treated by a solution of gibberellic acids 4 and 7 (GA4+7) and the cytokinin 6-benzyladenine (BA). Although the GA4+7 and BA mixture is applied early in apple fruit development, it mitigates cracking that becomes evident in the mature fruit, implying a long-term treatment effect. The reduced incidence of peel cracking is associated with increased epidermal cell density, which is maintained until fruit maturation. Presently, the expression of genes that have been previously reported to be associated with epidermal cell patterning and cuticle formation, or cracking resistance, was monitored in the peel during fruit development and following GA4+7 and BA treatment. For most of the genes whose expression is naturally upregulated during fruit development, the early GA4+7 and BA treatment maintained or further increased the high expression level in the mature peel. Where the expression of a gene was downregulated during development, no change was detected in the treated mature peel. Gene-networking analysis supported the interaction between gene clusters of cell-wall synthesis, cuticle formation and GA signaling. Overall, the data suggested that the GA4+7 and BA treatment did not modify developmental cues, but promoted or enhanced the innate developmental program.

Effects of stem-injected gibberellins and 6-benzylaminopurine on phytohormone profiles and cone yield in two lodgepole pine genotypes

Stem-injection of plant growth regulators into ramets of two lodgepole pine genotypes altered endogenous phytohormones and metabolites in long-shoot buds, and in one of the genotypes, dramatically increased female cone yield. Effects of exogenously applied gibberellins (GAs) and 6-benzylaminopurine (BA) on profiles of phytohormones and some of their metabolites relative to controls in long-shoot buds of lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.) were analyzed during cone bud initiation and differentiation. Differential responses in phytohormones and in cone yield were observed in ramets of the two tested genotypes (478 and 276) to stem-injected mixtures of GA4 and GA7 (GA4/7) and /or BA. Injected GA4/7 affected bud concentrations of GA4 and GA7. Injected PGRs, with the exception of BA injection, decreased concentrations of abscisic acid (ABA) and ABA glucose-ester at week 5 and/or week 7. Internal concentrations of trans-zeatin riboside (t-ZR) increased in response to all treatments at week 3 in genotype 276. In genotype 478, t-ZR only increased with treatments of BA or GA4/7 plus BA. Dihydrozeatin riboside concentrations increased in response to GA4/7 plus BA treatment at week 7 in genotype 276. Concentrations of isopentenyl adenosine declined with treatments of GA4/7 and GA4/7 plus BA in genotype 276 at week 5. In genotype 478, a similar decrease was caused by GA4/7 plus BA treatment. For both genotypes, the highest ratio of zeatin-type cytokinins to isopentenyl-type cytokinins occurred at weeks 5 and 7 after injection with GA4/7 plus BA. Stem-injection of GA4/7, especially in combination with BA, increased female cone yields significantly in genotype 276, but not in genotype 478.

Enhanced Thermal Stability in Perovskite Solar Cells by Assembling 2D/3D Stacking Structures.

Two-dimensional (2D) perovskites have been shown to be more stable than their three-dimensional (3D) counterparts due to the protection of the organic ligands. Herein a method is introduced to form 2D/3D stacking structures by the reaction of 3D perovskite with n-Butylamine (BA). Different from regular treatment with n-Butylammonium iodide (BAI) where 2D perovskite with various layers form, the reaction of BA with MAPbI3 only produce (BA)2PbI4, which has better protection due to more organic ligands in (BA)2PbI4 than the mixture of 2D perovskites. Compared to BAI treatment, BA treatment results in smoother 2D perovskite layer on 3D perovskites with a better coverage. The photovoltaic devices with 2D/3D stacking structures show much improved stability in comparison to their 3D counterparts when subjected to heat stress tests. Moreover, the conversion of defective surface into 2D layers also induces passivation of the 3D perovskites resulting in an enhanced efficiency.