Thermally-responsive and reduced glutathione-sensitive folate-targeted nanocarrier based on alginate and pluronic F127 for on-demand release of methotrexate.

A specific rheumatoid arthritis (RA)-microenvironment-triggered nanocarrier for RA treatment of a first-line antirheumatic drug (Methotrexate, MTX) has been proposed. Reduced glutathione (GSH) responsivity, cystamine, was first introduced on the alginate backbone, which was then used as the bridge to connect pluronic F127 (temperature-responsive factor) and folic acid (targeting factor for active immune cells), resulting in dual-responsive triggered targeting carrier, PCAC-FA. In vitro study demonstrated that PCAC-FA was preferentially taken up by activated macrophage cells rather than normal ones, suggesting the targeting of PCAC-FA to inflamed tissue. The loading capacity of the designed carrier was 21.23 ± 0.91 %. MTX from the PCAC-FA carrier was significantly accelerated release in the presentation of glutathione or in cold shock condition, proposing the efficacy-controlled release. MTX@PCAC-FA showed excellent hemocompatibility, confirming a suitable application with parenteral administration. Notably, the acute and subacute toxicity in the mice model showed that the toxicity of MTX had significantly reduced after encapsulating in the PCAC-FA carrier. These nanoplatforms not only provide an alternative safe strategy for the clinical treatment of rheumatoid arthritis with MTX but also deliver MTX selectively and provide on-demand drug release via external and internal signals, thus emerging as a promising therapeutic option for precise RA therapy.

Injectable thermogel incorporating reactive oxygen species scavenger and nitric oxide donor to accelerate the healing process of diabetic wounds.

The healing of diabetic wounds is challenging due to redox imbalances. Herein, the thermogelling system AR-ACP hydrogel, with encapsulated biosafe nitric oxide (NO) donor L-arginine and resveratrol as an ROS scavenger, is established for sustainable wound therapy in the diabetic state. The innovated AR-ACP hydrogel dressings shows the sol-gel transition at 34 °C, allowing the hydrogel to fully cover wounds. The combination of L-arginine and resveratrol showed a prominent effect on anti-oxidative activity. The elimination of superoxide anions from the activated immune cells/oxidative cells by resveratrol maintained the NO-proangiogenic factors generated from L-arginine. Furthermore, the AR-ACP hydrogel endowed outstanding features such as haemocompatibility, non-skin irradiation as well as antibacterial activity. In the in vivo diabetic mice model, complete epidermal regeneration comparable to undamaged skin was observed with AR-ACP hydrogel. The synergy between L-arginine and resveratrol in the ACP hydrogel facilitated neovascularisation in the early stage, resulting in the higher balance in cellularity growth and collagen deposition in the dermal layer compared to control groups. Taken together, our findings demonstrate that the use of a customised ACP-based hydrogel, with the additional L-arginine and resveratrol, resulted in significant skin regeneration in the diabetic state.

In silico and in vitro studies on the anti-cancer activity of artemetin, vitexicarpin and penduletin compounds from Vitex negundo.

Vitex negundo L. (V. negundo) is one of the important medicinal and anticancer enhancer herbs. This plant is commonly used in the preparation of traditional drugs to treat numerous diseases. Inspired by the medicinal properties of this plant, the current study aimed to investigate antiproliferative potential and the primary molecular mechanisms of the apoptotic induction against human HepG2 and MCF-7 cell lines, by pure compounds isolated from targeted fractions of V. negundo which were characterized by NMR, FTIR and HRMS analysis and identified as artemetin (FLV1), vitexicarpin (FLV2), and penduletin (FLV3) compounds. The FLV1, FLV2, and FLV3 compounds were evaluated for the antiproliferative potential against HepG2 and MCF-7 cell lines by cell viability assay and exhibited IC50 values of 2.3, 23.9 and 5.6 µM and 3.9, 25.8, and 6.4 µM, respectively. In addition, those compounds increased the level of reactive oxygen species production, induced cell death occurred via apoptosis, demonstrated by Annexin V-staining cells, contributed significantly to DNA damage, and led to the activation of caspase3/caspase8 pathways.Additionally, molecular docking was also conducted to rationalize the cancer cells inhibitory and to evaluate the ability of the FLV1, FLV2, and FLV3 compounds to be developed as good drug candidates for cancers treatment.

α-Glucosidase Inhibitory Cycloartanes from the Vietnamese Combretum quadrangulare.

Leaves of Combretum quadrangulare Kurz showed potent α-glucosidase inhibition. Two new cycloartane-type triterpenes, combretic acids D and E were isolated from the bioactive fraction. The chemical structures were determined using NMR and MS methods. Combretic acid D represents for the first cycloartane having a dihydrofuran ring in the side chain. Combretic acids D and E showed significant α-glucosidase inhibition, with IC50 values of 13.9 and 30.7 µM, respectively. Combretic acid D was determined to be a non-competitive type in the kinetic study. The docking study in combination with dynamic simulations of this compound provided the molecular understanding of α-glucosidase inhibition.

Cycloartane-type triterpenoids from the whole plants of Macrosolen bidoupensis.

One new cycloartane-type triterpenoid, named macrobidoupoic acid A (as an C-24 epimeric mixture, 4a, 4 b), together with three known ones (1-3), were clarified by different chromatography from the M. bidoupensis whole plants. Triterpenoids (1, 3 & 4) were detected for the first time from the Macrosolen genus. Chemical structures of them were illuminated using HR-ESI-MS, and NMR (1 D & 2 D) assessments. The cytotoxic properties of triterpenoids (3 & 4) were examined against two human cancer cell lines (A549, and RD) by MTT assay. As results shown, triterpenoids (3 & 4) possessed moderate cytotoxic activity against A549 and RD cancer cells (IC50 ranged from 5.44 to 39.52 µM).

Acridone alkaloids from the rhizomes of Luvunga scandens (Roxb.) Buch. Ham.

The ethyl acetate extract of the rhizomes of Luvunga scandens (Roxb.) Buch. - Ham. ex Wight & Arn (Rutaceae) delivered one new acridone alkaloid named Luvungaside A (1) together with three known acridone alkaloids, namely 1,3-dihydroxy-2-methoxy-10-methyl-9-acridone (2), arborinine (3) and 1-hydroxy-3-methoxy-10-methyl-9-acridone (4). Compounds were reported for the first time from the species L. scandens applying various chromatography methods. Chemical structures were elucidated by IR, UV, HR-ESI-MS, NMR 1D & 2D experiments and comparison with the literature. The cytotoxicity and hepatoprotective activity of compounds 1-4 in human hepatoma cell line HepG2 was measured by MTT assay. At 10-100 µM, compounds expressed significant hepatoprotective effect with prevention percentage ranging from 81.1% to 194.3%, compared to the positive control quercetin displaying 49.0%.

Flavonoids with hepatoprotective activity from the leaves of Cleome viscosa L.

One new flavonol glycoside named visconoside C (1), together with seven known flavonol glycosides, quercetin 3-O-ß-d-glucopyranoside 7-O-α-l-rhamnopyranoside (2), quercetin 7-O-α-l-rhamnopyranoside (3), astragalin (4), kaempferol 3-O-(4-O-acetyl)-α-l-rhamnopyranoside (5), kaempferol 7-O-α-l-rhamnopyranoside (6), kaempferitrin (7) and kaempferol 3-O-ß-d-glucopyranoside 7-O-α-l-rhamnopyranoside (8) were isolated by various chromatography methods from the leaves of Cleome viscosa L. Their structures were elucidated by IR, UV, HR-ESI-MS and NMR (1D & 2D) experiments. The cytotoxicity and hepatoprotective activities using HepG2 human hepatoma cell line of 1 were measured by MTT assay. At the concentration of 25 µM and 50 µM, 1 showed cytotoxic activity against HepG2 cells (cell viability was decreased to 22.2 and 23.0%, respectively, compared with doxorubicin control), while at the concentration of 100 µM, 1 showed hepatoprotective activity against CCl4-induced hepatotoxicity on HepG2 cells (34.3%, compared with quercetin control).

Synthesis and Selective Cytotoxic Activities on Rhabdomyosarcoma and Noncancerous Cells of Some Heterocyclic Chalcones.

Chemically diverse heterocyclic chalcones were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against rhabdomyosarcoma (RMS) and noncancerous cell line (LLC-PK1). The influence of heteroaryl patterns on rings A and B was studied. Heterocycle functionalities on both rings, such as phenothiazine, thiophene, furan and pyridine were evaluated. Notably, the introduction of three methoxy groups at positions 3, 4, 5 on ring B appears to be critical for cytotoxicity. The best compound, with potent and selective cytotoxicity (IC50 = 12.51 µM in comparison with the value 10.84 µM of paclitaxel), contains a phenothiazine moiety on ring A and a thiophene heterocycle on ring B. Most of the potential compounds only show weak cytoxicity on the noncancerous cell line LLC-PK1.

Iron-mediated effect of alcohol on hepatocyte differentiation in HepaRG cells.

The development of alcoholic liver diseases depends on the ability of hepatocyte to proliferate and differentiate in the case of alcohol-induced injury. Our previous work showed an inhibitory effect of alcohol on hepatocyte proliferation. However, the effect of alcohol on hepatocyte differentiation has not yet been precisely characterized. In the present study, we evaluated the effect of alcohol on hepatocyte differentiation in relationship with changes of iron metabolism in HepaRG cells. This unique bipotent human cell line can differentiate into hepatocytes and biliary epithelial cells, paralleling liver development. Results showed that alcohol reduced cell viability, total protein level and enhanced hepatic enzymes leakage in differentiated HepaRG cells. Moreover, it caused cell enlargement, decreased number of hepatocyte and expression of C/EBPα as well as bile canaliculi F-actin. Alcohol increased expression of hepatic cell-specific markers and alcohol-metabolizing enzymes (ADH2, CYP2E1). This was associated with a lipid peroxidation and an iron excess expressed by an increase in total iron content, ferritin level, iron uptake as well as an overexpression of genes involved in iron transport and storage. Alcohol-induced hepatoxicity was amplified by exogenous iron via exceeding iron overload. Taken together, our data demonstrate that in differentiated hepatocytes, alcohol reduces proliferation while increasing expression of hepatic cell-specific markers. Moreover, iron overload could be one of the underlying mechanisms of effect of alcohol on the whole differentiation process of hepatocytes.