Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood–brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and antiviral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two functions: inhibit P-gp efflux at the BBB and revert to monomeric therapeutic within cellular reducing environments. The prodrug dimers are potent P-gp inhibitors in cell culture and in a brain capillary model of the BBB. Significantly, these agents demonstrate anti-HIV activity in two T-cell-based HIV assays, a result that is linked to cellular reversion of the prodrug to abacavir. This strategy represents a platform technology that may be applied to other therapies with limited brain penetration due to P-glycoprotein.

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Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-glycoprotein at the Blood-Brain Barrier with Prodrug Abacavir Dimers

Black pepper (Piper nigrum L.) has been commonly utilized in food preparation and traditional medicine in several countries. Seven new amide alkaloids, pipernigramides A-G (3, 10, 38, and 41-44), a new piperic ester, pipernigrester A (48), along with 47 known compounds were isolated from the EtOH extract of P. nigrum. The inhibitory effects on nitric oxide (NO) of all compounds were then evaluated. Among the tested compounds, three of them (42-44) significantly inhibited inducible nitric oxide synthase (iNOS)-mediated NO (IC50 = 4.74 ± 0.18, 4.08 ± 0.19, and 3.71 ± 0.32 μM, respectively), and IL-1β, IL-6, TNF-α, and PGE2 release in RAW 264.7 cells stimulated by lipopolysaccharide. Moreover, 42-44 suppressed IκB degradation and further inhibited the cytosol-nucleus translocation of the p65 subunit by targeting IKK-β. In the carrageenan-induced paw edema test, 42-44 demonstrated anti-inflammatory effects as well. These results indicate that all three compounds from P.nigrum have the potential anti-inflammatory effects.

Alkaloids from Black Pepper (Piper nigrum L.) Exhibit Anti-Inflammatory Activity in Murine Macrophages by Inhibiting Activation of NF-κB Pathway.

One new coumarin, dryofracoumarin A (1), and eight known compounds 2–9 were isolated from Dryopteris fragrans (L.) Schott. Their structures were established on the basis of extensive spectroscopic data analyses and comparison with reported spectroscopic data. The new compound 1 was determined to be 8-hydroxyl-4-isopropyl-7-methyl-6-methyl-2H-benzopyran-2-one. Two dimers, trans- and cis-3-(3,4-dimethoxyphen-yl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene (compounds 8 and 9), were isolated from the Dryopteris genus for the first time. The other six were esculetin (2), isoscopoletin (3), methylphlorbutyrophenone (4), aspidinol (5), albicanol (6) and (E)-4-(3,4-dimethoxyphen-yl)but-3-en-1-ol (7). All compounds were evaluated for their cytotoxic effects by the MTT assay. Compounds 2, 3, 8 and 9 showed significantly cytotoxic effects against three cell lines (A549, MCF7 and HepG2), 1 and 5 against two cell lines (A549 and MCF7), and 6 against one cell line (MCF7). Their IC50 values ranged between 2.73 ± 0.86 μM and 24.14 ± 3.12 μM. These active compounds might be promising lead compounds for the treatment of cancer.

https://www.mdpi.com/1420-3049/19/3/3345/pdf

Compounds from Dryopteris Fragrans (L.) Schott with Cytotoxic Activity

Chronic ultraviolet radiation (UV-R) exposure causes skin disorders like erythema, edema, hyperpigmentation, photoaging and photocarcinogenesis Recent research trends of researchers have focused more attention on the identification and use of photo stable natural agents with photoprotective properties Piperine (PIP), as a plant alkaloid, is an important constituent present in black pepper (Piper nigrum), used widely in ayurvedic and other traditional medicines and has broad pharmacological properties The study was planned to photoprotective efficacy of PIP in human keratinocyte (HaCaT) cell line We have assessed the UV-R induced activation of transcription factor NF-κB in coordination with cell death modulators (Bax/Bcl-2 and p21) The LC-MS/MS analysis revealed that PIP was photostable under UV-A/UV-B exposure PIP (10μg/ml) attenuates the UV-R (A and B) induced phototoxicity of keratinocyte cell line through the restoration of cell viability, inhibition of ROS, and malondialdehyde generation Further, PIP inhibited UV-R mediated DNA damage, prevented micronuclei formation, and reduced sub-G1 phase in cell cycle, which supported against photogenotoxicity This study revealed that PIP pretreatment strongly suppressed UV-R induced photodamages Molecular docking studies suggest that PIP binds at the active site of NF-κB, and thus, preventing its translocation to nucleus In addition, transcriptional and translational analysis advocate the increased expression of NF-κB and concomitant decrease in IkB-α expression under UV-R exposed cells, favouring the apoptosis via Bax/Bcl-2 and p21 pathways However, PIP induced expression of IkB-α suppress the NF-κB activity which resulted in suppression of apoptotic marker genes and proteins that involved in photoprotection Therefore, we suggest the applicability of photostable PIP as photoprotective agent for human use

Piperine attenuates UV-R induced cell damage in human keratinocytes via NF-kB, Bax/Bcl-2 pathway: An application for photoprotection.

The current work prepared chitosan/hydroxypropyl methylcellulose (HPMC) blends and studied the possibility of chitosan/HPMC blended patches for Zingiber cassumunar Roxb. The blended patches without/with crude Z. cassumunar oil were prepared by homogeneously mixing the 3.5% w/v of chitosan solution and 20% w/v of HPMC solution, and glycerine was used as plasticizer. Then, they were poured into Petri dish and produced the blended patches in hot air oven at 70 ± 2°C. The blended patches were tested and evaluated by the physicochemical properties: moisture uptake, swelling ratio, erosion, porosity, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction, and photographed the surface and cross-section morphology under SEM technique. Herbal blended patches were studied by the in vitro release and skin permeation of active compound D. The blended patches could absorb the moisture and became hydrated patches that occurred during the swelling of blended patches. They were eroded and increased by the number of porous channels to pass through out for active compound D. In addition, the blended patches indicated the compatibility of the blended ingredients and homogeneous smooth and compact. The blended patches made from chitosan/HPMC blends provide a controlled release and skin permeation behavior of compound D. Thus, the blended patches could be suitably used for herbal medicine application.

Formulation, Physicochemical Characterization, and In Vitro Study of Chitosan/HPMC Blends-Based Herbal Blended Patches

Context: There is a need for the discovery of novel natural and semi-synthetic sunscreen that is safe and effective. Piperine has a UV absorption band of 230–400 nm with high molar absorptivity. This compound has a high potential to be developed to sunscreen.Objective: This study develops new UV protection compounds from piperine by using chemical synthesis.Materials and methods: Piperine was isolated from Piper nigrum L. (Piperaceae) fruits, converted to piperic acid by alkaline hydrolysis, and prepared as ester derivatives by chemical synthesis. The piperate derivatives were prepared as 5% o/w emulsion, and the SPF values were evaluated. The best compound was submitted to cytotoxicity test using MTT assay.Results: Piperic acid was prepared in 86.96% yield. Next, piperic acid was reacted with alcohols using Steglich reaction to obtain methyl piperate, ethyl piperate, propyl piperate, isopropyl piperate, and isobutyl piperate in 62.39–92.79% yield. All compounds were prepared as 5% oil in water em...

Development of piperic acid derivatives from Piper nigrum as UV protection agents.

Background
The rhizome of Zingiber cassumunar and the seed of Nigella sativa are two ingredients in Thai traditional medicine to relieve dysmenorrhea and adjust the menstrual cycle. Mixture of these two herbs produces three esters, namely (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl linoleate (1), (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl oleate (2) and (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl palmitate (3). The aim of this study is to examine in vitro absorption of these esters and evaluate their transport across the membrane.

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Cellular transport of anti-inflammatory pro-drugs originated from a herbal formulation of Zingiber cassumunar and Nigella sativa.

The artificial formation of three fatty acid esters, ( E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl linoleate ( 1), ( E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl oleate ( 2) and ( E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl palmitate ( 3) originating during storage by the interaction of components in Prasaplai preparation was investigated. The artifacts were not formed when 0.1 mL of water or more was added to 1.0 g of the mixture (1 : 1) of ZINGIBER CASSUMUNAR and NIGELLA SATIVA even when stored for 20 days. This result showed that water was able to stop the esterification reaction. The formation of the artifacts by chemical reaction under water-free conditions was evaluated. ( E)-4-(3,4-dimethoxyphenyl)but-3-en-1-ol was mixed with linoleic acid in the presence of anhydrous Na 2 SO 4 and stored in a dessicator for 7 days. The artifact ( 1) was formed in 6.0 % yield. It was concluded that a water-free environment is necessary for the direct chemical formation of the artificial esters.

A study on artifacts formation in the Thai traditional medicine Prasaplai.

We conducted a docking study with ArgusLab 4.0.1, a free molecular docking software, on tyrosinase inhibitors comparing with AutoDock 4 and AutoDock VINA. In this study, hydroxyl substituted 2-phenyl-naphthalenes (a group of modified structure based on oxyresveratrol and resveratrol) were docking with tyrosinase enzyme (3NQ1) with genetic algorithm (GA) in ArgusLab, AutoDock 4 and AutoDock VINA, respectively. The binding energies were correlated with the inhibition concentrations (IC 50 ) and ArgusLab performed the best linear correlation coefficient of 0.8865 while AutoDock 4 and AutoDock VINA obtained 0.6849 and 0.7805, respectively. From the results, all inhibitors stayed near the entrance of the active site to prevent the substrate binding and showed no interaction with copper atoms in the enzyme. In this study, we found that ArgusLab is an easy to use program with high-speed calculation and has an accessible user-interface even by beginners in molecular docking.

http://www.tjps.pharm.chula.ac.th/ojs/index.php/tjps/article/download/51/60

Molecular docking study of tyrosinase inhibitors using ArgusLab 4.0.1 : A comparative study

Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Botanics: Targets and Therapy 2016:6 1–9 Botanics: Targets and Therapy Dovepress

/pdf/standardization-of-prasaplai-a-thai-traditional-preparation-uhamap14gy.pdf

Prasan Tangyuenyongwatana

Papers

Development of piperic acid derivatives from Piper nigrum as UV protection agents.

Cellular transport of anti-inflammatory pro-drugs originated from a herbal formulation of Zingiber cassumunar and Nigella sativa.

A study on artifacts formation in the Thai traditional medicine Prasaplai.

Molecular docking study of tyrosinase inhibitors using ArgusLab 4.0.1 : A comparative study

Standardization of Prasaplai, a Thai traditional preparation for antidysmenorrhea