The Systems of Naringenin with Solubilizers Expand Its Capability to Prevent Neurodegenerative Diseases

Background: Naringenin (NAR) is a flavonoid with excellent antioxidant and neuroprotective potential that is limited by its low solubility. Thus, solid dispersions with β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropylmethylcellulose (HPMC), and microenvironmental pH modifiers were prepared. Methods: The systems formation analysis was performed by X-Ray Powder Diffraction (XRPD) and Fourier-transform infrared spectroscopy (FT-IR). Water solubility and dissolution rates were studied with a pH of 1.2 and 6.8. In vitro permeability through the gastrointestinal tract (GIT) and the blood-brain barrier (BBB) was assessed with the parallel artificial membrane permeability assay (PAMPA) assay. The antioxidant activity was studied with the 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and cupric ion reducing antioxidant capacity (CUPRAC) assays, while in vitro enzymes studies involved the inhibition of acetylcholinesterase, butyrylcholinesterase, and tyrosinase. For the most promising system, in silico studies were conducted. Results: NAR solubility was increased 458-fold by the solid dispersion NAR:HP-β-CD:NaHCO3 in a mass ratio of 1:3:1. The dissolution rate was elevated from 8.216% to 88.712% in a pH of 1.2 and from 11.644% to 88.843% in a pH of 6.8 (within 3 h). NAR GIT permeability, described as the apparent permeability coefficient, was increased from 2.789 × 10−6 cm s−1 to 2.909 × 10−5 cm s−1 in an acidic pH and from 1.197 × 10−6 cm s−1 to 2.145 × 10−5 cm s−1 in a basic pH. NAR BBB permeability was established as 4.275 × 10−6 cm s−1. The antioxidant activity and enzyme inhibition were also increased. Computational studies confirmed NAR:HP-β-CD inclusion complex formation. Conclusions: A significant improvement in NAR solubility was associated with an increase in its biological activity.

A Model for the Apparent Gas Permeability of Shale Matrix Organic Nanopore Considering Multiple Physical Phenomena

The flow of shale gas in nano scale pores is affected by multiple physical phenomena. At present, the influence of multiple physical phenomena on the transport mechanism of gas in nano-pores is not clear, and a unified mathematical model to describe these multiple physical phenomena is still not available. In this paper, an apparent permeability model was established, after comprehensively considering three gas flow mechanisms in shale matrix organic pores, including viscous slippage Flow, Knudsen diffusion and surface diffusion of adsorbed gas, and real gas effect and confinement effect, and at the same time considering the effects of matrix shrinkage, stress sensitivity, adsorption layer thinning, confinement effect and real gas effect on pore radius. The contribution of three flow mechanisms to apparent permeability under different pore pressure and pore size is analyzed. The effects of adsorption layer thinning, stress sensitivity, matrix shrinkage effect, real gas effect and confinement effect on apparent permeability were also systematically analyzed. The results show that the apparent permeability first decreases and then increases with the decrease of pore pressure. With the decrease of pore pressure, matrix shrinkage, Knudsen diffusion, slippage effect and surface diffusion effect increase gradually. These four effects will not only make up for the permeability loss caused by stress sensitivity and adsorption layer, but also significantly increase the permeability. With the decrease of pore radius, the contribution of slippage flow decreases, and the contributions of Knudsen diffusion and surface diffusion increase gradually. With the decrease of pore radius and the increase of pore pressure, the influence of real gas effect and confinement effect on permeability increases significantly. Considering real gas and confinement effect, the apparent permeability of pores with radius of 5 nm is increased by 13.2%, and the apparent permeability of pores with radius of 1 nm is increased by 61.3%. The apparent permeability model obtained in this paper can provide a theoretical basis for more accurate measurement of permeability of shale matrix and accurate evaluation of productivity of shale gas horizontal wells.

Evaluation on Intestinal Permeability of Phlorotannins Using Caco-2 Cell Monolayers

Among the phlorotannins of seaweed polyphenols, eckols which have a dibenzodioxin linkage are known to have various physiological functions. The purpose of this study was to investigate the intestinal epithelial absorption of eckols using Caco-2 cell monolayers of the small intestinal membrane model. Each compound permeated from the apical (AP) side to the basolateral (BL) side in the monolayers was identified and quantitated by liquid chromatography-mass spectrometry with electrospray ionization. In the transport assays using five types of eckols (eckol, fucofuroeckol A, phlorofucofuroeckol A, dieckol, and 8,8'-bieckol), only the monomeric eckol showed limited transepithelial absorption with relatively small apparent permeability values (0.30 ± 0.04 × 10−8 cm/s). Analyzing the Hanks’ balanced salt solution in the receiver on the BL side showed that phloroglucinol was detected in all experimental sections using eckols, and it's concentration increased with time over the course of the incubation. The other molecules corresponding to the unconjugated and conjugated metabolites of eckols were not detected in the AP and BL sides through the assays. These results suggest that eckols, including monomeric eckol, may be decomposed into phloroglucinol in the intestinal epithelium and the resulting phloroglucinol permeates to the BL side.

Influence of a Laser Irradiation and Laser Scribing on Magnetic Properties of GO Silicon Steels Sheets Using a Nanosecond Fiber Laser

Improving the performance of electrical steels within the magnetic circuits is essential to save energy. The domain refinement through local surface treatment by laser is an effective technique to reduce the iron losses in grain-oriented iron silicon steels. To interpret the mechanism of this technique, we have quantitatively studied the impact of nanosecond pulse laser treatment on the magnetic properties of grain-oriented Fe(3%wt)Si sheets. We measured the total power loss and apparent permeability of the samples using a Single-Sheet Tester (SST). The laser treatment resulted in a loss reduction of up to 24% compared to the average power loss of standard samples at 50 Hz. At mid-induction levels, the reduction was also accompanied by an improvement in apparent permeability. A dynamic magnetic behavior law was used to identify a dynamic property Λ including information on density, surface area and wall mobility and another internal permeability property µ representative of static field and magnetization characteristics. Lastly, we presented the behavior of these properties under different laser treatment.

Absorption and Transport Characteristics and Mechanisms of Carnosic Acid

Carnosic acid (CA) is a phenolic diterpenoid mainly found in rosemary and sage. CA has been reported to possess health-beneficial effects in various experimental settings. Herein, a mouse experiment and Caco-2 single-cell model were used to understand the absorption and transport characteristics of CA. First, we determined the tissue distribution of CA in mice, following an oral gavage at a physiologically relevant dose. We found that CA was bioavailable systemically and present locally in the digestive tract, especially in the cecum and colon. Next, we thought to characterize the absorption and transport of CA in the Caco-2 cell monolayer model of the intestinal epithelial barrier. In the Caco-2 cell model, CA exhibited a moderate permeability and was subjected to a mild efflux. Moreover, the apparent permeability coefficient (Papp) of CA transported across Caco-2 cell monolayers was significantly changed when the inhibitors of specific active transporter and passive diffusion were added to cells, suggesting that the absorption and transport of CA involved both passive and active transportation. The present study is an important first step towards understanding the absorption, transport, and metabolic mechanisms of CA. This could provide the scientific basis for developing CA-containing functional foods or dietary supplements with improved bioavailability.

EFECTO DE UN SURFACTANTE NO IONICO EN LA PERMEABILIDAD DE BUTORFANOL A TRAVES DE MUCOSA NASAL EQUINA

Implementation of intranasal administration for the delivery of drugs with site of action into the central nervous system, such as butorphanol, became a potential choice in equine medicine. In this study, using Franz-diffusion cells the in vitro permeation rate through respiratory and olfactory equine nasal mucosa of two butorphanol formulations was estimated and compared. Both formulations had the same composition, was the exception for formulation 2, that contained 2, 5 x 10 -4 M of a non-ionic surfactant (tween 80). Butorphanol administered dose was 24, 4 mg/cm2. Plots of the cumulative amounts of butorphanol against time were constructed, where maximum flux values at the steady state (Jss), apparent permeability coefficients (Kp) and lag-time (tlag) were estimated. The Jss and Kp show that permeation of butorphanol through olfactory mucosa is different than respiratory mucosa. Moreover, Jss for formulation 2 was higher than formulation 1 in both anatomical areas, probably for the effect of the surfactant. The present results are promising to carry on with the development of formulation of butorphanol for intranasal administration.

EXTH-16. LP-184, A NOVEL ALKYLATING AGENT, IS EFFECTIVE IN GLIOBLASTOMA

Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to prolong survival of patients with newly diagnosed MGMT-methylated GBM. Blood-brain barrier permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT unmethylated GBM) are desperately needed. Lantern Pharma is currently developing LP-184, a hydroxyurea methyl acylfulvene derivative of irofulven guided by its AI platform RADRⓇ analysis showing that tumor cell sensitivity to LP-184 correlates positively with genes commonly upregulated in GBM and either associated with TMZ resistance (e.g. MGMT, UGDH) or tumor promotion (e.g. EGFR, ANXA2). In an in vitro 3D model that mimics the human BBB, the apparent permeability for LP-184 was 1.53E-04 cm/s at 30 minutes, comparable to 1.72E-04 cm/s for TMZ under identical conditions. LP-184 predominantly alkylates DNA at 3’-adenine predicting insensitivity to MGMT expression. In vitro cell toxicity assays in a panel of GBM cell lines and neurospheres reveal an IC50 range of 30 - 400 nM with the MGMT unmethylated cell line LN-18 being among the most sensitive. A single cycle of LP-184 (4 mg/kg, i.v, every other day X 4 doses) induced rapid and near complete regression of subcutaneous U87 xenografts pre-established in immune-deficient mice and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 xenografts (p < 0.0001). LP-184-induced DNA damage is associated with synthetic lethality in tumor cell lines with decreased expression of Nucleotide Excision Repair (NER) genes. Furthermore, interrogation of clinical databases for expression of 112 NER genes revealed that 25 - 37% of clinical GBM clusters in a low NER expression subgroup, predicting high sensitivity of low NER GBM subsets to LP-184. These findings identify LP-184 as a promising new alkylating agent and support its further development for GBM therapy.

2D-to-3D image translation of complex nanoporous volumes using generative networks

Image-based characterization offers a powerful approach to studying geological porous media at the nanoscale and images are critical to understanding reactive transport mechanisms in reservoirs relevant to energy and sustainability technologies such as carbon sequestration, subsurface hydrogen storage, and natural gas recovery. Nanoimaging presents a trade off, however, between higher-contrast sample-destructive and lower-contrast sample-preserving imaging modalities. Furthermore, high-contrast imaging modalities often acquire only 2D images, while 3D volumes are needed to characterize fully a source rock sample. In this work, we present deep learning image translation models to predict high-contrast focused ion beam-scanning electron microscopy (FIB-SEM) image volumes from transmission X-ray microscopy (TXM) images when only 2D paired training data is available. We introduce a regularization method for improving 3D volume generation from 2D-to-2D deep learning image models and apply this approach to translate 3D TXM volumes to FIB-SEM fidelity. We then segment a predicted FIB-SEM volume into a flow simulation domain and calculate the sample apparent permeability using a lattice Boltzmann method (LBM) technique. Results show that our image translation approach produces simulation domains suitable for flow visualization and allows for accurate characterization of petrophysical properties from non-destructive imaging data.

Pharmacokinetics and brain distribution studies of 6-hydroxykynurenic acid and its structural modified compounds

Objectives 6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant. Methods Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats. Key findings The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration. Conclusions The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment.