Honokiol Crosses BBB and BCSFB, and Inhibits Brain Tumor Growth in Rat 9L Intracerebral Gliosarcoma Model and Human U251 Xenograft Glioma Model

BACKGROUND: Gliosarcoma is one of the most common malignant brain tumors, and anti-angiogenesis is a promising approach for the treatment of gliosarcoma. However, chemotherapy is obstructed by the physical obstacle formed by the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Honokiol has been known to possess potent activities in the central nervous system diseases, and anti-angiogenic and anti-tumor properties. Here, we hypothesized that honokiol could cross the BBB and BCSFB for the treatment of gliosarcoma. METHODOLOGIES: We first evaluated the abilities of honokiol to cross the BBB and BCSFB by measuring the penetration of honokiol into brain and blood-cerebrospinal fluid, and compared the honokiol amount taken up by brain with that by other tissues. Then we investigated the effect of honokiol on the growth inhibition of rat 9L gliosarcoma cells and human U251 glioma cells in vitro. Finally we established rat 9L intracerebral gliosarcoma model in Fisher 344 rats and human U251 xenograft glioma model in nude mice to investigate the anti-tumor activity. PRINCIPAL FINDINGS: We showed for the first time that honokiol could effectively cross BBB and BCSFB. The ratios of brain/plasma concentration were respectively 1.29, 2.54, 2.56 and 2.72 at 5, 30, 60 and 120 min. And about 10% of honokiol in plasma crossed BCSFB into cerebrospinal fluid (CSF). In vitro, honokiol produced dose-dependent inhibition of the growth of rat 9L gliosarcoma cells and human U251 glioma cells with IC(50) of 15.61 µg/mL and 16.38 µg/mL, respectively. In vivo, treatment with 20 mg/kg body weight of honokiol (honokiol was given twice per week for 3 weeks by intravenous injection) resulted in significant reduction of tumor volume (112.70±10.16 mm(3)) compared with vehicle group (238.63±19.69 mm(3), P = 0.000), with 52.77% inhibiting rate in rat 9L intracerebral gliosarcoma model, and (1450.83±348.36 mm(3)) compared with vehicle group (2914.17±780.52 mm(3), P = 0.002), with 50.21% inhibiting rate in human U251 xenograft glioma model. Honokiol also significantly improved the survival over vehicle group in the two models (P<0.05). CONCLUSIONS/SIGNIFICANCE: This study provided the first evidence that honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. It suggested a significant strategy for offering a potential new therapy for the treatment of gliosarcoma

Effects of (<i>S</i>)-Carvone and Gibberellin on Sugar Accumulation in Potatoes during Low Temperature Storage

Potato tubers (Solanum tuberosum L.) are usually stored at low temperature, which can suppress sprouting and control the occurrence of diseases. However, low temperatures lead potatoes to easily suffer from cold-induced sweetening (CIS), which has a negative effect on food processing. The aim of this research was to investigate potential treatments on controlling CIS in potatoes during postharvest storage. &#8220;Atlantic&#8222; potatoes were treated with gibberellin and (S)-carvone, respectively, and stored at 4 &#176;C for 90 days. The results showed that gibberellin can significantly accelerate sprouting and sugar accumulation by regulating expressions of ADP-glucose pyrophosphorylase (AGPase), granule-bound starch synthase (GBSS), &#946;-amylase (BAM1/2), UDP-glucose pyrophosphorylase (UGPase) and invertase inhibitor (INH1/2) genes. The opposite effects were found in the (S)-carvone treatment group, where CIS was inhibited by modulation of the expressions of GBSS and INH1/2 genes. In summary, gibberellin treatment can promote sugar accumulation while (S)-carvone treatment has some effects on alleviating sugar accumulation. Thus, (S)-carvone can be considered as a potential inhibitor of some of the sugars which are vital in controlling CIS in potatoes. However, the chemical concentration, treatment time, and also the treatment method needs to be optimized before industrial application

Phytic Acid Treatment Inhibits Browning and Lignification to Promote the Quality of Fresh-Cut Apples during Storage

Browning and lignification often occur in fresh-cut apple processing, leading to quality deterioration and limiting the shelf life of products. In this study, 0.8% (v/v) phytic acid was used to improve the quality and shelf life of fresh-cut apples. From the results, the browning was inhibited by the phytic acid treatment and the browning index (BI) of the control fruit was 1.62 times that of phytic acid treatment at 2 d of storage. The lignin content in phytic acid-treated fruit significantly decreased at 2, 4, and 6 d of storage compared to the control. Phytic acid treatment also reduced H2O2 and malonaldehyde (MDA) contents, which may indicate lighter membrane damage to apples. Compared with the control, the polyphenol oxidase (PPO) and peroxidase (POD) activities decreased while superoxide dismutase (SOD) and catalase (CAT) activities increased in phytic acid-treated fruit. Consistent with the lignin content, the activities of phenylpropane metabolism-related enzymes phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H), and 4-coumarate: CoA ligase (4CL) were inhibited by phytic acid treatment. In conclusion, phytic acid alleviated the browning and lignification of fresh-cut apples by reducing PPO and POD activities, maintaining cell membrane integrity, and inhibiting phenylpropane metabolism

UV-C treatment promotes quality of early ripening apple fruit by regulating malate metabolizing genes during postharvest storage.

Early ripening apples are usually used for fresh marketing because of short storage life, although they are with high acid and low sugar contents. Understanding the malate metabolism in fleshy fruit and underpinning process during ripening is crucial for particular crop improvement where acidity is a concern for direct consumption or further processing. In this research, a traditional Chinese apple cultivar 'Hongyu', which belongs to early ripening apple cultivar, were freshly harvested at commercial maturity stage (120 Days after full bloom) and used for different storage temperature (4°C, 20°C) and UV-C treatment (following storage at 20°C after treatment). Simple sugars (glucose, sucrose, and fructose) and organic acids (malic, and oxalic) were assessed after 14 d of storage. Compared to fruits stored at 20°C, the malate content in fruits stored at 4°C significantly higher, while it was decreased significantly in UV-C treated fruits stored at 20°C after 14 d of storage. The sugar content was almost similar throughout the UV-C-treated fruits and fruits stored at different temperature. The higher ratios of total sugars to total organic acids in UV-C treated fruits after 14 d suggest that UV-C treatment has the potential to improve the taste of early ripening apple cultivars. Considering the significant difference in malate the samples at 14 d of storage were subjected for RNA-seq analysis. Transcriptome analysis revealed that the phenomena underlying this change were governed by metabolism of malate by the regulation of NADP-malic enzyme (NADP-ME) and phosphoenolpyruvate carboxylase kinase (PEPCK) in apple during postharvest storage. This transcriptome profiling results have specified the transcript regulation of malate metabolism and lead to possible taste improvement without affecting the other fruit quality attributes

Exogenous Gibberellic Acid Ameliorates Chilling Injury in Peach (<i>Prunus persica</i> L.) by Improving the Antioxidant System

Currently, several studies have demonstrated that cold stress can cause the accumulation of reactive oxygen species (ROS) in fruit. However, little is known about the roles of gibberellic acid (GA3) on the antioxidant system in the mitochondria of fruit. To explore the molecular basis of GA3 interference with the chilling tolerance of fruit, ‘Jinqiuhongmi’ peach fruit was treated with 0.1 mmol L−1 GA3 after harvest. Exogenous GA3 treatment relieved the chilling injury of postharvest peach fruit with a lower cold injury index and higher antioxidant level. In addition, GA3 delayed the senescence of peaches by reducing the firmness, respiratory action, and ethylene production. The antioxidant enzyme activities were elevated, including superoxide dismutase (SOD) and catalase (CAT). Moreover, GA3-treated peaches exhibited lower hydrogen peroxide (H2O2) and malondialdehyde (MDA) in comparison with the control. These results showed that the application of 0.1 mmol L−1 of GA3 enhanced the chilling resistance of peach fruit by regulating the antioxidant system

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta-analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR-Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock-out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta-analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2-year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked-out using CRISPR-Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock-out osteosarcoma cells. NSC59984 also showed similar anti-tumor effects as CRISPR-Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock-out or inhibition of mutant TP53 decreased the expression of the oncogene IGF-1R, anti-apoptotic proteins Bcl-2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. (c) 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Re

Chromophoric Fingerprinting of Brown Carbon from Residential Biomass Burning

Emissions from residential biomass burning are a significant source of atmospheric brown carbon (BrC). In this study, we used liquid chromatography-photodiode array-high resolution tandem mass spectrometry to investigate the chromophoric fingerprinting of BrC emitted from residential biomass burning. In total, 59 major chromophores were identified, which accounted for 49-85% of the total light absorption of BrC (averaged between 300 and 500 nm) for different samples. These chromophores include furans, lignin pyrolysis products, coumarins, flavonoids, stilbenes, N-containing aromatic compounds, and unsubstituted or oxygenated polycyclic aromatic hydrocarbons, of which some are newly reported as BrC species (e.g., stilbenes and substituted phenyl cyanates). Among the chromophores identified, seven are common to all samples while some are specific to certain biofuel or burning conditions. For instance, 3,3'-dimethoxyquercetin from wheat burning, p-hydroxybenzaldehyde and apigenin from maize smoldering, 4-nitro-2-vinylphenol from maize flaming, and nodakenetin and anthanthrene from wood flaming are specific to the fuel type or burning condition. The identified optical markers will be essential for understanding atmospheric chemical and optical processes of biomass burning BrC in future studies, while the source-specific chromophore profiles developed in this study are a prerequisite for apportioning the biofuel types and burning conditions, which is a key for estimating source-specific radiative forcing