(R)-(-)-Xanthorrhizol inhibits the migration and invasion of triple-negative breast cancer cells by suppressing matrix metalloproteinases via the NF-kB signaling pathway.

(R)-(-)-Xanthorrhizol is a bioactive sesquiterpenoid and major chemical constituent of Curcuma zanthorrhiza rhizomes. It was reported to have many pharmacological activities including nephroprotective, hepatoprotective, antimicrobial, anti-inflammatory, antioxidant, antihypertensive, antihyperglycemic, antiplatelet, estrogenic, and antiestrogenic properties. (R)-(-)-Xanthorrhizol was also investigated for the antiproliferative activity against many cancer cells including breast, lung, liver, ovarian, and colon cancer. It was also revealed to have a potential effect on TNBC cells MDA-MB-231. Considering the previous studies, this study has aimed to investigate the anti-migratory and anti-invasive properties as well as possible molecular mechanisms behind these properties. The findings of (R)-(-)-xanthorrhizol on MDA-MB-231 cell migration and invasion demonstrated significant inhibition at three different concentrations in a concentration-dependent manner which was observed in the scratch, transwell migration, and invasion assays. Further investigation of the molecular mechanism using gelatin zymography revealed that (R)-(-)-xanthorrhizol prevented cell migration and invasion of breast cancer cells through the inhibition of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression. Western blot analysis indicated that the inhibition of matrix metalloproteinases is possibly the result of the inhibition of phosphorylation in the NF-kB signaling pathway. These findings corroborate (R)-(-)-xanthorrhizol to proceed for the further studies as a possible future drug candidate for cancer patients.

Bioactive compounds from Curcuma aeruginosa and the effect of comosone II on the migration and invasion of breast cancer cells.

Bioassay-guided separation afforded furanodienone 1,10-epoxide (9) as the new compound, curcolone (10) as partially described compound and ten known compounds; germacrone (1), furanodienone (2), curzerenone (3), curcumenol (4), zederone (5), comosone II (6), (1E,4E,8R)-8-hydroxygermacra-1(10),4,7(11)-trieno-12,8-lactone (7), 13-hydroxygermacrone (8), curcuzederone (11) and demethoxycurcumin (12). The study showed that germacrone, furanodienone, curzerenone, comosone II, 13-hydroxygermacrone, curcuzederone and demethoxycurcumin are the bioactive compounds of C. aeruginosa rhizomes. Comosone II significantly inhibited MDA-MB-231 cell migration and invasion through the inhibition of MMP-9 enzyme. The present study may lead to further anticancer studies of comosone II and supports the traditional uses of C. aeruginosa rhizomes.

Bioactive chemical constituents from Curcuma caesia Roxb. rhizomes and inhibitory effect of curcuzederone on the migration of triple-negative breast cancer cell line MDA-MB-231.

Rhizomes of Curcuma caesia are traditionally used to treat cancer in India. The aim is to isolate chemical constituents from C. caesia rhizomes through bioassay-guided fractionation. The extract, hexanes and chloroform fractions showed effect on MCF-7 and MDA-MB-231cells in cell viability assay. The chromatographic separation afforded germacrone (1), zerumbone (2), furanodienone (3), curzerenone (4), curcumenol (5), zederone (6), curcumenone (7), dehydrocurdione (8) from hexanes fraction and curcuminol G (9), curcuzederone (10), (1S, 10S), (4S,5S)-germacrone-1 (10), 4-diepoxide (11), wenyujinin B (12), alismoxide (13), aerugidiol (14), zedoarolide B (15), zedoalactone B (16), zedoarondiol (17), isozedoarondiol (18) from chloroform fraction. This is first report of compounds 2, 9-13, 15-18 from C. caesia. The study demonstrated compounds 1-4 and 10 are the bioactive compounds. The effect of curcuzederone (10) on MDA-MB-231 cell migration showed significant inhibition in scratch and Transwell migration assays. The results revealed that curcuzederone could be a promising drug to treat cancer.

Ethnobotanical study and phytochemical profiling of Heptapleurum hypoleucum leaf extract and evaluation of its antimicrobial activities against diarrhea-causing bacteria.

BACKGROUND: Due to the development of superbugs as a result of unprescribed and frequent use of antibiotics in recent years, an alternate form of medicine had to be introduced. In light of this global threat, researchers all over the world have been gravitating towards herbal medicines. In order to find out new ways of saving the planet using medicinal plants, ethnobotanical studies must be carried out. Concerning this, an ethnobotanical study has been done in this paper to identify potential medicinal plants in Rangamati, Bangladesh. RESULTS: For the ethnobotanical survey, randomized 104 people were interviewed and 62 different plant species were found to treat 19 different kinds of diseases and 84% of people reported to be completely recovered. Furthermore, among the 19 diseases found, the majority of them were common cold, abdominal pain or gastric, diarrhea, and dysentery. From the 62 different plant species, Heptapleurum hypoleucum, used for the treatment of diarrhea, was selected for conducting further studies due to its heavy use as reported by the tribal people. In this study, the aqueous, ethanol, and methanol extracts of Heptapleurum hypoleucum were subjected to microbial susceptibility assays using the agar well diffusion method. The test microorganisms were Salmonella typhi, Streptococcus pneumoniae, Staphylococcus aureus, Shigella flexneri, and Escherichia coli. Among these, the most susceptible organisms were Staphylococcus aureus (21 mm) and Salmonella typhi (19 mm) in the ethanolic extract. Also, the methanolic extract showed an inhibition zone of 13 mm against E. coli, which was more than that of the antibiotic's (11 mm). Phytochemical screening of the plant revealed that it contains alkaloids, phenols, steroids, and flavonoids, but lacks saponins and tannins. CONCLUSION: To combat the rising threat of antibiotic resistance, ethnoscience needs to be consolidated with modern biotechnological techniques to make the most use of the vast amount of natural resources. The findings of this study indicate that Heptapleurum hypoleucum, an ethnobotanical medicinal plant, has shown comparable antimicrobial activity with commercial antibiotics against several diarrhea-causing pathogens and also contains several medically important phytochemicals.

Catechinic acid, a natural polyphenol compound, extends the lifespan of Caenorhabditis elegans via mitophagy pathways.

Catechinic acid (CA), widely present in tea and fruits, has vital biological and pharmacological properties. CA plays an important role in the regulation of lifespan. However, the mechanism behind its anti-aging properties remains poorly characterized. In the present study, Caenorhabditis elegans (C. elegans) was used as a model organism. It was found that CA induced mitophagy which prevented the accumulation of dysfunctional mitochondria with age and profoundly extended lifespan. Notably, CA significantly improved the fitness of aging worms, particularly the treatment slowed age-related decline in observed spontaneous movements. Furthermore, CA was found to eliminate dysfunctional mitochondria in the gut and muscle cells, and demonstrated that the lifespan-prolonging effects of CA can be attributed to mitophagy along with the likely regulation of the genes bec-1 and pink-1. The results of this study indicated that pharmacologically induced mitophagy has a profound impact on aging, providing a novel therapeutic intervention against aging and age-related diseases.

Inhibitory Activity of Extract, Fractions, and Compounds from Zingiber montanum Rhizomes on the Migration of Breast Cancer Cells.

Zingiber montanum rhizomes are traditionally used for the treatment of numerous human ailments. The present study was carried out to investigate the inhibitory activity of the crude extract, chromatographic fractions, and purified compounds from Z. montanum rhizomes on the migration of MDA-MB-231 cells. The effect of the extract on cell migration was investigated by a scratch assay, which showed significant inhibition in a concentration-dependent manner. Vacuum liquid chromatography on silica gel afforded four fractions (Frs. 1 - 4), which were tested on cell migration in the scratch assay. Frs. 1 and 2 showed the most significant inhibition of MDA-MB-231 cell migration. The effect of the most potent fraction (Fr. 2) was further confirmed in a transwell migration assay. The study of Frs. 1 and 2 by gelatin zymography showed significant inhibition of MMP-9 enzyme activity. Chromatographic separation of Frs. 1 and 2 afforded buddledone A (1: ), zerumbone (2: ), (2E,9E)-6-methoxy-2,9-humuradien-8-one (3: ), zerumbone epoxide (4: ), stigmasterol (5: ), and daucosterol (6: ). In a cell viability assay, compounds 1:  - 4: inhibited the viability of MDA-MB-231 cells in a concentration-dependent manner. The study of buddledone A (1: ) and zerumbone epoxide (4: ) on cell migration revealed that 4: significantly inhibited the migration of MDA-MB-231 cells in both scratch and transwell migration assays. The results of the present study may lead to further molecular studies behind the inhibitory activity of zerumbone epoxide (4: ) on cell migration and support the traditional use of Z. montanum rhizomes for the treatment of cancer.

A Strategy toward Icetexane Natural Products.

Icetexane diterpenoids are richly complex polycyclic natural products that have been described with a variety of biological activities. We report here a general synthetic approach toward the 6-7-6 tricyclic core structure of these interesting synthetic targets based on a two-step enolate alkylation and ring-closing metathesis reaction sequence.

Somatically expressed germ-granule components, PGL-1 and PGL-3, repress programmed cell death in C. elegans.

We previously reported that germline apoptosis in C. elegans increased by loss of PGL-1 and PGL-3, members of a family of constitutive germ-granule components, from germ cells in adult hermaphrodite gonads. In this study, we found that somatic apoptosis was reduced in synthetic multivulva class B (synMuv B) mutants due to ectopic expression of PGL-1 and PGL-3 in the soma. In synMuv B-mutant somatic cells, CED-4 expression level was reduced due to ectopic expression of PGL-1. Furthermore, in contrast to wild type, somatic apoptosis in synMuv B mutants increased following DNA damage in a SIR-2.1-dependent manner. Intriguingly, somatic apoptosis was repressed not only in synMuv B mutants but also by ectopically expressing pgl-1 and/or pgl-3 transgenes in wild-type somatic cells. Our study demonstrates that germ-granule components, PGL-1 and PGL-3, can serve as negative regulators of apoptosis not only in the germline but also in the soma in C. elegans.

Caffeine Induces the Stress Response and Up-Regulates Heat Shock Proteins in Caenorhabditis elegans.

Caffeine has both positive and negative effects on physiological functions in a dose-dependent manner. C. elegans has been used as an animal model to investigate the effects of caffeine on development. Caffeine treatment at a high dose (30 mM) showed detrimental effects and caused early larval arrest. We performed a comparative proteomic analysis to investigate the mode of action of high-dose caffeine treatment in C. elegans and found that the stress response proteins, heat shock protein (HSP)-4 (endoplasmic reticulum [ER] chaperone), HSP-6 (mitochondrial chaperone), and HSP-16 (cytosolic chaperone), were induced and their expression was regulated at the transcriptional level. These findings suggest that high-dose caffeine intake causes a strong stress response and activates all three stress-response pathways in the worms, including the ER-, mitochondrial-, and cytosolic pathways. RNA interference of each hsp gene or in triple combination retarded growth. In addition, caffeine treatment stimulated a food-avoidance behavior (aversion phenotype), which was enhanced by RNAi depletion of the hsp-4 gene. Therefore, up-regulation of hsp genes after caffeine treatment appeared to be the major responses to alleviate stress and protect against developmental arrest.

Antinociceptive principle from Curcuma aeruginosa.

BACKGROUND: The rhizome of Curcuma aeruginosa Roxb (Zingiberaceae) has been used as a traditional folk medicine for the treatment of rheumatic disorders in Bangladesh. The aim of the current study was the bioassay-guided isolation and purification of an antinociceptive principle from the methanol extract of C. aeruginosa rhizomes. METHODS: The antinociceptive activity was determined using acetic acid induced writhing and formalin induced licking in the Swiss albino mice to investigate central and peripheral antinociceptive principle of C. aeruginosa rhizomes. Vacuum Liquid Chromatography (VLC) and open column chromatography were used for separation. Crystallization was used for the purification of the isolated compound germacrone (1). Diclofenac (10 mg/kg) and aspirin (100 mg/kg) were used as positive control and 5% carboxymethyl cellulose (CMC) in distilled water (10 ml/kg) for negative control were used in the acetic acid induced writhing and formalin induced licking methods. RESULTS: The methanol extract exhibited 37.50 and 45.31% inhibition of writhing; 33.27 and 38.13% inhibition of licking in the first phase and 69.72, 73.71% inhibition of licking in the second phase at doses of 200 and 400 mg/kg, respectively. VLC of the extract yielded five fractions (Fr. 1 to Fr. 5). Fr. 1 exhibited 33.98% inhibition that was comparably higher than other fractions (Fr. 2 to Fr. 5) at a dose of 100 mg/kg. Column chromatography of Fr. 1 generated five fractions (SF. 1 to SF. 5). Fraction SF.3 exhibited 46.88% inhibition that was most potent among the other fractions at a dose of 50 mg/kg. Crystallization of the fraction SF.3 yielded germacrone (1), a cyclic sesquiterpene. Germacrone (1) showed 22.66, 34.77 and 51.17% inhibition of writhing at doses of 10, 20 and 40 mg/kg, respectively; 30.43 and 37.53% inhibition in the initial phase and 32.27 and 60.96% inhibition in the second phase of licking at doses of 200 and 400 mg/kg, respectively. CONCLUSION: Germacrone (1) showed a potent activity in both writhing and licking methods that indicates the compound as a central and peripheral antinociceptive principle of C. aeruginosa rhizomes with possible anti-inflammatory activity.

Analgesic principle from Curcuma amada.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Curcuma amada has been used as a folk medicine for the treatment of rheumatic disorders in the northern part of Bangladesh and has also used for the treatment of inflammation and fever in the Ayurvedic and Unani systems of medicine. Aim of the study was to investigate the analgesic principle of the MeOH extract of the rhizome of Curcuma amada by an in vivo bioassay guided chromatographic separation and purification, and the structure elucidation of the purified compound by spectroscopic methods. MATERIALS AND METHODS: Dried powder of Curcuma amada rhizomes was extracted with MeOH. The analgesic activity of the crude extract and its chromatographic fractions as well as the purified compound itself was evaluated by the acetic acid induced writhing method and the formalin induced licking test in Swiss albino mice. The MeOH extract was separated by chromatographic methods and the pure active compound was purified by crystallization in hexanes. The structure of the pure compound was then elucidated by spectroscopic methods. RESULTS: The MeOH extract of Curcuma amada exhibited 41.63% and 45.53% inhibitions in the acetic acid induced writhing method at doses of 200mg/kg and 400mg/kg, respectively. It also exerted 20.43% and 28.50% inhibitions in early phase at doses of 200mg/kg and 400mg/kg, respectively, and 30.41% and 42.95% inhibitions in late phase at doses of 200mg/kg and 400mg/kg, respectively in the formalin induced licking test. Vacuum Liquid Chromatography (VLC) of crude extract yielded five fractions and Fr. 1 was found to have the most potent analgesic activity with inhibitions of 36.96% in the acetic acid induced writhing method and 47.51% (early phase), 39.50% (late phase) in the formalin induced licking test at a dose of 200mg/kg. Column chromatography of Fr. 1 on silica gel generated seven fractions (SF. 1-SF. 7). SF. 2 showed the most potent activity with inhibition of 49.81% in the acetic acid induced writhing method at a dose of 100mg/kg. Crystallization of SF. 2 yielded (1) (zederone, 520mg). It showed statistically significant inhibitions of 38.91% and 52.14% in the acetic acid induced writhing method at doses of 20mg/kg and 40mg/kg, respectively. Moreover, it also showed statistically significant inhibitions of 27.79% and 29.93% (early phase) and of 38.24% and 46.08% (late phase) in the formalin induced licking test at doses of 20mg/kg and 40mg/kg, respectively. CONCLUSION: Isolation and characterization of zederone (1) as analgesic principle of Curcuma amada corroborate its use in Ayurvedic, Unani and folk medicines for the treatment of rheumatic disorders and also contributing to its pharmacological validation.

Selectivity, Compatibility, Downstream Functionalization, and Silver Effect in the Gold and Palladium Dual-Catalytic Synthesis of Lactones.

The chemo- and regioselectivity and functional group compatibility in gold and palladium cooperatively catalyzed cross-coupling reactions were determined in the synthesis of lactones; the selectivity in the gold and palladium dual-metal catalysis system was distinct from that available for the same class of substrates in systems with only gold catalysis or only palladium catalysis rather than dual catalysis. The dual-catalytic rearrangement reaction selectively promoted oxidative addition at the C-O bond over the C-Br bond, providing a useful C-Br bond handle for downstream functionalization showcased via Suzuki-Miyaura and Sonogashira coupling reactions. Product classes were expanded from isocoumarins to three previously unpublished ring classes: pyrone, indolepyrone, and furopyrone.

Palladium-nanoparticle-catalyzed 1,7-palladium migration involving C-H activation, followed by intramolecular amination: regioselective synthesis of N1-arylbenzotriazoles and an evaluation of their inhibitory activity toward indoleamine 2,3-dioxygenase.

A sulfur-modified gold-supported palladium material (SAPd) has been developed bearing palladium nanoparticles on its surface. Herein, we report for the first time the use of SAPd to affect a Pd-nanoparticle-catalyzed 1,7-Pd migration reaction for the synthesis of benzotriazoles via C-H bond activation. The resulting benzotriazoles were evaluated in terms of their inhibitory activity toward indoleamine 2,3-dioxygenase.

Mechanistic Studies of Gold and Palladium Cooperative Dual-Catalytic Cross-Coupling Systems.

Double-label crossover, modified-substrate, and catalyst comparison experiments in the gold and palladium dual-catalytic rearrangement/cross-coupling of allenoates were performed in order to probe the mechanism of this reaction. The results are consistent with a cooperative catalysis mechanism whereby 1) gold activates the substrate prior to oxidative addition by palladium, 2) gold acts as a carbophilic rather than oxophilic Lewis acid, 3) competing olefin isomerization is avoided, 4) gold participates beyond the first turnover and therefore does not serve simply to generate the active palladium catalyst, and 5) single-electron transfer is not involved. These experiments further demonstrate that the cooperativity of both gold and palladium in the reaction is essential because significantly lower to zero conversion is achieved with either metal alone in comparison studies that examined multiple potential gold, palladium, and silver catalysts and precatalysts. Notably, employment of the optimized cocatalysts, PPh3AuOTf and Pd2dba3, separately (i.e., only Au or only Pd) results in zero conversion to product at all monitored time points compared to quantitative conversion to product when both are present in cocatalytic reactions.

Ligand-free Suzuki-Miyaura coupling with sulfur-modified gold-supported palladium in the synthesis of a conformationally-restricted cyclopropane compound library with three-dimensional diversity.

A conformationally restricted privileged structure library with stereochemical diversity for a "fragment growth" methodology comprising 90 compounds was designed and systematically and efficiently synthesized using sulfur-modified Au-supported Pd (SAPd)-catalyzed ligand-free Suzuki-Miyaura coupling of vinyl iodide promoted by microwave and subsequent amidation in liquid-phase combinatorial chemistry as key reactions. Evaluation of the compounds with a 20-kinase panel indicated the usefulness of this "fragment growth" methodology for finding hit library compounds for fragment-based drug discovery.

In Silico Molecular Characterization of Cysteine Protease YopT from Yersinia pestis by Homology Modeling and Binding Site Identification.

Plague is a major health concern and Yersinia pestis plays the central causal role in this disease. Yersinia pestis has developed resistance against the commonly available drugs. So, it is now a key concern to find a new drug target. Cysteine protease YopT enzyme is an important factor used by Yersinia pestis for pathogenesis in its host and it has the anti-phagocytic function of removal of C-termini lipid modification. The 3D structure of cysteine protease YopT of Yersinia pestis was determined by means of homology modeling through multiple alignments followed by intensive optimization and validation. The modeling was done by Phyre 2 and refined by ModRefiner. The obtained model was verified with structure validation programs such as PROCHECK, verify 3D and ERRAT for reliability. Interacting partners and active sites were also determined. PROCHECK analysis showed that 93% of the residues are in the most favored region, 5.9% are in the additional allowed region and 1.1% are in the generously allowed region of the Ramachandran plot. The verify 3D value of 0.78 indicates that the environmental profile of the model is good. SOPMA is employed for calculation of the secondary structural features of cysteine protease YopT. Active site determination through CASTp proposes that this protein can be utilized as a potential drug target. However, these findings should further be confirmed by wet lab studies for a targeted therapeutic agent design against Yersinia pestis.

Comparative assessment on in vitro antioxidant activities of ethanol extracts of Averrhoa bilimbi, Gymnema sylvestre and Capsicum frutescens.

BACKGROUND: Averrhoa bilimbi, Gymnema sylvestre and Capsicum frutescens are medicinal plants commonly used as traditional medicine for the treatment of various diseases. The present study was designed to investigate the antioxidant activities of Ethanolic extract of A. bilimbi, G. sylvestre and C. frutescens. MATERIALS AND METHODS: The antioxidant activity of the extracts were evaluated using total phenolic and flavonoid contents, ferric reducing power and the free radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH). RESULTS: Total phenolic and flavonoid contents were higher in G. sylvestre (53.63636 ± 0.454545 mg/g gallic acid equivalent) and C. frutescens (26.66667 ± 2.081666 mg/g quercetin equivalent) respectively. Reducing power of the crude ethanol extracts increased with the concentrations of the extracts and all the extracts showed moderate free radical scavenging activity against DPPH. The plant extract displayed moderate phenolic and flavonoid contents compared to gallic acid and quercetin equivalent respectively, whereas also exhibited significant scavenging of DPPH radical and reducing power compared with ascorbic acid as standard. CONCLUSION: Our study suggests that G. sylvestre has significant antioxidant activity. The antioxidant compound of this plant might be a therapeutic candidate against oxidative stress related diseases. Different sub-fraction of A. bilimbi and C. frutescens should be studied further to assess the effect. Further study is necessary for isolation and characterization of the active antioxidant agents for better treatment.

An in silico approach to design potential siRNA molecules for ICP22 (US1) gene silencing of different strains of human herpes simplex 1.

BACKGROUND: The herpes simplex virus (HSV-1) is a virus that manifests itself in viral infection with painful, watery blisters in the skin or on the genitals as well as mucous membrane such as the mouth or lips. During an outbreak, the disease is contagious particularly and is irredeemable with present technology. Genetic studies of HSV-1 have shown that ICP22 (US1) gene is an immediate early gene and is responsible for genome replication and also has contribution in viral infection. METHOD: For disease diagnosis, ICP22 (US1) gene may be suitable target. Viral activity can be controlled through RNA interference technology, a significant method for the post-transcriptional gene silencing. However, in different viral isolates there is a genetic variability; it is very challenging to design possible siRNA molecules which can silence the respective target genes. The work was done by using various computational tools as similarity search, target alignment, secondary structure prediction and RNA interaction evaluation. RESULT: In our study two effective siRNA molecules for ICP22 (US1) gene silencing of seven different strains of HSV-1 were rationally designed and authenticated using computational methods, which might lead to knockdown the viral activity. CONCLUSION: siRNA molecules were foreseen against ICP22 (US1) gene of different strains of HSV-1 as effective aspirant using computational methods. Thus, the approach may deliver a vision for the chemical synthesis of antiviral RNA molecule for treatment of HSV-1, at genomic level.

Development of second generation gold-supported palladium material with low-leaching and recyclable characteristics in aromatic amination.

An improved process for the preparation of sulfur-modified gold-supported palladium material [SAPd, second generation] is presented. The developed preparation method is safer and generates less heat (aqueous Na2S2O8 and H2SO4) for sulfur fixation on a gold surface, and it is superior to the previous method of preparing SAPd (first generation), which requires the use of the more heat-generating and dangerous piranha solution (concentrated H2SO4 and 35% H2O2) in the sulfur fixation step. This safer and improved preparation method is particularly important for the mass production of SAPd (second generation) for which the catalytic activity was examined in ligand-free Buchwald-Hartwig cross-coupling reactions. The catalytic activities were the same between the first and second generation SAPds in aromatic aminations, but the lower palladium leaching properties and safer preparative method of second generation SAPd are a significant improvement over the first generation SAPd.