Biological Functions of Dillenia pentagyna Roxb. Against Pain, Inflammation, Fever, Diarrhea, and Thrombosis: Evidenced From in vitro, in vivo, and Molecular Docking Study.

Dillenia pentagyna Roxb. is traditionally used to treat cancer, wound healing, diabetes, and diarrhea in local tribes. This study was designed to evaluate the pharmacological potentiality of this plant. In vivo analgesic, anti-inflammatory, and antipyretic studies of the methanol extracts of D. pentagyna (MEDP) leaves were performed by using acetic acid-induced nociception, formalin-induced paw licking, and yeast-induced pyrexia assay methods, respectively. In vivo antidiarrheal activity was carried out in mice by following castor oil-induced diarrhea and gastrointestinal transit manner. In vitro thrombolytic experiment was performed employing the clot lysis activity. Besides, a molecular docking study was performed by executing the software (PyRx, Discovery Studio, and UCSF Chimera). In the acetic acid-induced writhing study, MEDP possesses significant writhing inhibition in a dose-dependent manner. It showed 50.86% of maximum inhibition of pain in the case of MEDP at a dose of 400 mg/kg body weight. In the anti-inflammatory study, maximum inhibition rate was observed at a value of 59.98 and 41.29% in early and late phases, respectively, at the dose of 400 mg/kg body weight. In the case of yeast-induced hyperpyrexia, MEDP reduced hyperpyrexia in a dose-dependent manner. In the antidiarrheal assay, MEDP moderately inhibited the occurrence of diarrhea in all the experiments. In the thrombolytic study, a moderate (17.76%) clot lysis potency has been yielded by MEDP. Again, the molecular docking simulation revealed strong binding affinities with almost all the targeted proteins. The present study suggests that the MEDP possesses remarkable pharmacological activity and this finding validated the ethnobotanical significance of D. pentagyna as the source of pain, fever, and diarrhea management agent.

Thannilignan glucoside and 2-(ß-glucopyranosyl)-3-isoxazolin-5-one derivative, two new compounds isolated from Terminalia bellirica.

Two new compounds, thannilignan 9-O-ß-glucoside (1) and 2-(ß-glucopyranosyl)-3-isoxazolin-5-one derivative (2), and seven known compounds were isolated from the methanol extract of Terminalia bellirica leaves, collected in Bangladesh. The structures of the compounds were elucidated using spectroscopic analysis. Among these isolated compounds, corilagin (3) was cytotoxic against human gastric adenocarcinoma cell line AGS at an IC50 of 20.8 µM, and ß-D-glucopyranose 1,3,6-trigallate (4) exhibited the ability to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance.

Acacienone, a terpenoid-like natural product having an unprecedented C20 framework isolated from Acacia mangium leaves.

A novel C20 natural product, acacienone (1), was isolated from the leaves of Acacia mangium collected in Bangladesh. The structure of compound 1 was elucidated by spectral studies and X-ray crystallographic analysis. Acacienone (1) possesses a terpenoid-related tetracyclic framework containing 20 carbons with biogenetically unusual structural features: (i) vicinal C1-branches at the C-3 and C-4 positions in the A ring, and (ii) a cyclopentenone D ring in an androsterone-like assembly, lacking a methyl group at the C-13 position.

Bioassay-Guided Isolation of Compounds from Datura stramonium with TRAIL-Resistance Overcoming Activity.

TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids--scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 µM, respectively in TRAIL-resistant AGS cells.

Bio-active Natural Products with TRAIL-Resistance Overcoming Activity.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent as it selectively kills cancer cells. However, TRAIL resistance limits its use as a therapeutic agent. An understanding the mechanisms responsible for TRAIL resistance and strategies to overcome it are important for its effective use as an anticancer agent. During our studies to screen natural products from medicinal plants, we identified a number of compounds with synergistic effects on TRAIL-induced apoptosis in tumor cells. This review describes our recent studies on the isolation of bioactive compounds with TRAIL-resistance overcoming activity.

Constituents from Entada scandens with TRAIL-resistance Overcoming Activity.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent because of its ability to selectively kill tumor cells. But TRAIL-resistance is a major problem of its therapy. A search for compounds for abrogating TRAIL-resistance has, thus, become an important strategy for anticancer drug discovery. In search of bioactive natural products for overcoming TRAIL-resistance, we previously reported some compounds with TRAIL-resistance overcoming activity. Bioassay guided fractionation of Entada scandens led to the isolation of four compounds (1-4). Of the isolates, compounds 1 and 3 showed moderate TRAIL-resistance overcoming activity in TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

Boehmenan, a lignan from Hibiscus ficulneus, showed Wnt signal inhibitory activity.

The Wnt signal pathway modulates numerous biological processes, and its aberrant activation is related to various diseases. Therefore, inhibition of the Wnt signal may provide an effective (or efficient) strategy for these diseases. Cell-based luciferase assay targeting the Wnt signal (TOP assay) revealed that Hibiscus ficulneus extract inhibited the Wnt signal. The activity-guided isolation of the MeOH extract of H. ficulneus stems yielded four known (1-4) lignans along with myriceric acid (5). Compounds 1-4 potently inhibited the Wnt signal with TOPflash IC50 values of 1.0, 4.5, 6.3, and 1.9 µM, respectively. Compound 1 exhibited cytotoxicity against both Wnt-dependent (HCT116) and Wnt-independent (RKO) cells. Western blot analysis showed that 1 decreased the expression of full, cytosolic and nuclear ß-catenin along with c-myc in STF/293 cells. Our results suggested that 1 may have inhibited the Wnt signal by decreasing ß-catenin levels.

Hedgehog/GLI-mediated transcriptional activity inhibitors from Crinum asiaticum.

The inhibition of the hedgehog (Hh) signaling pathway has emerged as an attractive anti-cancer strategy. As part of our continuing search for natural inhibitors of the Hh/GLI1 signaling pathway, we isolated three alkaloids (1-3) from Crinum asiaticum. Compounds 1 and 3 showed potent Hh/GLI1-mediated transcriptional inhibitory activity and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compounds 1 and 3 clearly inhibited the Hh signaling pathway by down-regulating the expression of GLI-related proteins (PTCH and BCL2) in DU145 cells.

Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium.

The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 µM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 µM.

Phenolic compounds from the bark of Oroxylum indicum activate the Ngn2 promoter.

A reporter gene assay that detects neurogenin 2 (Ngn2) promoter activity was utilized to identify compounds that induce neuronal differentiation. Ngn2 is a basic helix-loop-helix transcription factor that activates transcription of pro-neural genes. Using this assay system and an activity-guided approach, seven phenolic compounds were isolated from the methanol extract of Oroxylum indicum: 1 oroxylin A, 2 chrysin, 3 hispidulin, 4 baicalein, 5 apigenin, 6 baicalin, and 7 isoverbascoside. Compounds 1 and 2 induced an estimated 2.7-fold increase in Ngn2 promoter activity, whereas 3 increased the activity by 2.5-fold. Furthermore, 1 and 2 enhanced neuronal differentiation of C17.2 cells, which are multipotent stem cells.

Phorbol esters with wnt signal-augmenting effects isolated from Excoecaria indica.

A screening of natural products using a luciferase assay targeting the Wnt signaling pathway was carried out, and the bioassay-guided fractionation of Excoecaria indica (Euphorbiaceae) collected from Bangladesh afforded three phorbol esters (1 - 3). These compounds exhibited Wnt signal-augmenting effects with 1 causing a 25-fold increase in TCF/beta-catenin (TOP) transcriptional activity at 95 nM.

A new resin glycoside from Ipomoea maxima.

A new resin glycoside (1) was isolated from the aerial part of Ipomoea maxima, together with three known compounds, pescaprein XX (2), stoloniferin X (3), and stoloniferin IX (4). The structure of 1 was elucidated on the basis of 1D NMR spectroscopy, a fragmentation study by APCIMS, and HRESIMS analysis.

Cryptolepine, isolated from Sida acuta, sensitizes human gastric adenocarcinoma cells to TRAIL-induced apoptosis.

Bioassay guided separation of Sida acuta whole plants led to the isolation of an alkaloid, cryptolepine (1), along with two kaempferol glycosides (2-3). Compound 1 showed strong activity in overcoming TRAIL-resistance in human gastric adenocarcinoma (AGS) cells at 1.25, 2.5 and 5 µm. Combined treatment of 1 and TRAIL sensitized AGS cells to TRAIL-induced apoptosis at the aforementioned concentrations.

Cucullamide, a new putrescine bisamide from Amoora cucullata.

A new putrescine bisamide derivative named cucullamide (1) was isolated from the leaves of Amoora cucullata, together with five known natural products, dasyclamide (2), ent-2beta-hydroxymanool (3), chrysin (4), apigenin (5), and kaempferol-3-O-beta-D-glucopyranoside (6). The structure of the new isolated compound was elucidated on the basis of 1D and 2D NMR as well as high resolution-electrospray ionization (HR-ESI)-MS spectroscopic analysis.

Search for bioactive natural products from medicinal plants of Bangladesh.

In our continuous search for bioactive natural products from natural resources, we explored medicinal plants of Bangladesh, targeting cancer-related tumor necrosis factor-related apoptosis-inducing ligand-signaling pathway, along with some other biological activities such as prostaglandin inhibitory activity, 1,1-diphenyl-2-picrylhydrazyl free-radical-scavenging activity, and cell growth inhibitory activity. Along with this, we describe a short field study on Sundarbans mangrove forests, Bangladesh, in the review.

Constituents of Amoora cucullata with TRAIL resistance-overcoming activity.

In search of bioactive natural products for overcoming TRAIL resistance from natural resources, we previously reported a number of active compounds. Bioassay-guided fractionation of mangrove, Amoora cucullata, collected from Sundarbans Mangrove Forest, Bangladesh, led to the isolation of four new compounds (1-4), along with seven known compounds (5-11). Of the isolates, compounds 1, 5, 8, and 9 showed TRAIL resistance-overcoming activity, among which 8 showed the most potent activity and enhanced TRAIL-induced apoptosis in TRAIL-resistant human gastric adenocarcinoma (AGS) cells through the activation of caspase-3/7, enhancing the expression of DR4 and DR5 mRNA in AGS cells. Cell death caused by the combined treatment of 8 and TRAIL was inhibited by human recombinant DR5/Fc and DR4/Fc chimera proteins, indicating that 8 sensitizes TRAIL-resistant AGS cells to TRAIL through the induction of DR4 and DR5.

Antibacterial activity of Leonurus sibiricus aerial parts.

Different solvent extracts (carbon tetrachloride, chloroform, acetone and methanol) of Leonurus sibiricus were studied for their antibacterial activity. Carbon tetrachloride and chloroform extracts showed a broad spectrum of antibacterial activity.

Flavonoids from Sonneratia caseolaris.

According to the traditional medicinal usage of Sonneratia caseolaris, we tested the extract of S. caseolaris for antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect on thin-layer chromatography. Following activity-oriented separation, two flavonoids, luteolin (1) and luteolin 7-O-ß-glucoside (2), were isolated. Both of the compounds were found to possess antioxidant activity.

Antibacterial activity of Ludwigia adscendens.

Methanolic extract of whole plants of Ludwigia adscendens was studied for its antibacterial activity. The extract showed a broad spectrum of antibacterial activity against all the bacteria tested except Stapylococcus aureus.

Analgesic and anti-inflammatory activity of Leonurus sibiricus.

The methanolic extract of Leonurus sibiricus aerial parts injected intraperitoneally at dose of 250 and 500 mg/kg showed a significant analgesic effect in acetic acid-induced writhing in mice. Moreover, when given orally to rats at dose of 200 and 400 mg/kg, it showed a significant anti-inflammatory activity against carrageenin induced rat paw edema in rats.