Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia. The exact pathophysiology of this disease remains incompletely understood and safe and effective therapies are required. AD is highly correlated with neuroinflammation and oxidative stress in brain causing neuronal loss. Nuclear factor of activated B-cells (NF-κB) is involved in physiological inflammatory processes and thus representing a promising target for inflammation-based AD therapy. Phytochemicals are able to interfere with the NF-κB pathway. They inhibit the phosphorylation or the ubiquitination of signaling molecules, and thus, inhibit the degradation of IκB. The translocation of NF-κB to the nucleus and subsequent tr…

Adaptogens in chemobrain (Part I): Plant extracts attenuate cancer chemotherapy-induced cognitive impairment – Transcriptome-wide microarray profiles of neuroglia cells

Abstract Background Cancer chemotherapy-induced cognitive impairments are presumably associated with undesirable effects of chemotherapy on physiological functions of brain cells. Adaptogens are natural compounds or plant extracts increasing an organism's adaptability and survival in stress. They exhibited neuroprotective effects and increased cognitive functions in clinical studies in human beings. Hypothesis We hypothesized that selected adaptogenic plant extracts attenuate or prevent cancer chemotherapy-induced cognitive impairments. Aim We assessed the effects of selected adaptogenic herbal extracts on FEC (fixed combination 5-fluorouracil, epirubicin and cyclophosphamide) induced chang…

Both Phenolic and Non-phenolic Green Tea Fractions Inhibit Migration of Cancer Cells.

Green tea consumption is associated with chemoprevention of many cancer types. Fresh tea leaves are rich in polyphenolic catechins, which can constitute up to 30% of the dry leaf weight. While the polyphenols of green tea have been well investigated, it is still largely unknown, whether or not non-phenolic constituents also reveal chemopreventive and anti-metastatic effects. In this study, we investigated the effects of a fraction of green tea rich in phenolic compounds (PF), a non-phenolic fraction (NPF), which contains glyceroglycolipids (GGL), and a pure glyceroglycolipid compound isolated from the non-phenolic fraction in human cancer. Dried green tea leaves were extracted and applied t…

GH57 amylopullulanase from Desulfurococcus amylolyticus JCM 9188 can make highly branched cyclodextrin via its transglycosylation activity.

Abstract Desulfurococcus amylolyticus is an anaerobic and hyperthermophilic crenarchaeon that can use various carbohydrates as energy sources. We found a gene encoding a glycoside hydrolase family 57 amylolytic enzymes (DApu) in a putative carbohydrate utilization gene cluster in the genome of D. amylolyticus . This gene has an open reading frame of 1,878 bp and consists of 626 amino acids with a molecular mass of 71 kDa. Recombinant DApu (rDApu) completely hydrolyzed pullulan to maltotriose by attacking α-1,6-glycosidic linkages, and was able to produce glucose and maltose from soluble starch and amylopectin. Although rDApu showed no activity toward α-cyclodextrin (CD) and β-CD, maltooctao…

Cytotoxic bufadienolides from the leaves of a medicinal plant Melianthus comosus collected in South Africa.

Abstract From the leaves of South African medicinal plant Melianthus comosus, four previously undescribed bufadienolides, 16β-formyloxymelianthugenin (1), 2β-acetoxymelianthusigenin (2), 2β-hydroxy-3β,5β-di-O-acetylhellebrigenin (3), and 2β-acetoxy-5β-O-acetylhellebrigenin (4) were isolated together with two known bufadienolides. The structural elucidation of the compounds was based on 1D and 2D NMR spectroscopy, high-resolution mass spectrometry, and other spectroscopic methods. The relative configurations were determined by single-crystal X-ray crystallography analysis and NOESY correlations. The isolated compounds displayed strong cytotoxicity against MCF-7 breast cancer cells, sensitive…

Antiproliferative activity against leukemia cells of sesquiterpene lactones from the Turkish endemic plant Centaurea drabifolia subsp. detonsa

The apolar organic extract obtained from aerial parts of Centaurea drabifolia Sibth. & Sm. subsp. detonsa (Bornm.) Wagenitz, growing wild in Turkey, was investigated for the first time for its secondary metabolite composition. Seven sesquiterpene lactones belonging to the guaiane class (1-7), including the new compound 4, along with a fatty acid lactone derivative (8), were isolated. The structures of these compounds were established by spectroscopic analysis, including 2D NMR spectroscopic techniques, with the stereostructure of the new guaiane 4 determined with the help of MTPA derivatization. Cytotoxic activities of compounds 1-7 were evaluated against two cancer cell lines, namely acute…

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compo…

Mbandakamine-Type Naphthylisoquinoline Dimers and Related Alkaloids from the Central African Liana Ancistrocladus ealaensis with Antiparasitic and Antileukemic Activities.

Four new dimeric naphthylisoquinoline alkaloids, michellamine A5 (2) and mbandakamines C–E (4–6), were isolated from the Congolese plant Ancistrocladus ealaensis, along with the known dimer mbandakamine A (3). They represent constitutionally unsymmetric dimers, each consisting of two 5,8′-coupled naphthylisoquinoline monomers. While the molecular halves of michellamine A5 (2) are linked via C-6′ of both of the naphthalene moieties, i.e., via the least-hindered positions, so that the central biaryl axis is configurationally unstable and not an additional element of chirality, the mbandakamines 3–6 possess three consecutive stereogenic axes. Their monomeric units are linked through an unprece…

Access to new highly potent antileukemia, antiviral and antimalarial agents via hybridization of natural products (homo)egonol, thymoquinone and artemisinin

Hybridization of natural products has high potential to further improve their activities and may produce synergistic effects between linked pharmacophores. Here we report synthesis of nine new hybrids of natural products egonol, homoegonol, thymoquinone and artemisinin and evaluation of their activities against P. falciparum 3D7 parasites, human cytomegalovirus, sensitive and multidrug-resistant human leukemia cells. Most of the new hybrids exceed their parent compounds in antimalarial, antiviral and antileukemia activities and in some cases show higher in vitro efficacy than clinically used reference drugs chloroquine, ganciclovir and doxorubicin. Combined, our findings stress the high pot…

Role of TCTP for Cellular Differentiation and Cancer Therapy

The translationally controlled tumor protein (TCTP) is a highly conserved protein that is regulated due to a high number of extracellular stimuli. TCTP has an important role for cell cycle and normal development. On the other side, tumor reversion and malignant transformation have been associated with TCTP. TCTP has been found among the 12 genes that are differentially expressed during mouse oocyte maturation, and an overexpression of this gene was reported in a wide variety of different cancer types. Its antiapoptotic effect is indicated by the interaction with several proapoptotic proteins of the Bcl-2 family and the p53 tumor suppressor protein. In this article, we draw attention to the …

Ancistrocyclinones A and B, unprecedented pentacyclic N,C-coupled naphthylisoquinoline alkaloids, from the Chinese liana Ancistrocladus tectorius

Two unique pentacyclic N,C-coupled naphthylisoquinolines, the ancistrocyclinones A (5) and B (6), were discovered in the Chinese liana Ancistrocladus tectorius. Furthermore, six known, likewise N,C-coupled alkaloids, viz., ancistrocladinium A (7a) and its mono- and bisphenolic analogs 8a and 9a were isolated, along with their atropo-diastereomers 7b, 8b, and 9b. The stereostructures of 5 and 6 were determined by HRESIMS, 1D and 2D NMR, oxidative degradation, and ECD calculations. The pentacyclic ancistrocyclinones A (5) and B (6) are structurally similar to berberine alkaloids - yet arising from a most different biosynthetic pathway: they are apparently formed by N,C-coupling of their polyk…

Pharmacogenomics of Scopoletin in Tumor Cells

Drug resistance and the severe side effects of chemotherapy necessitate the development of novel anticancer drugs. Natural products are a valuable source for drug development. Scopoletin is a coumarin compound, which can be found in several Artemisia species and other plant genera. Microarray-based RNA expression profiling of the NCI cell line panel showed that cellular response of scopoletin did not correlate to the expression of ATP-binding cassette (ABC) transporters as classical drug resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2). This was also true for the expression of the oncogene EGFR and the mutational status of the tumor suppressor gene, TP53. However, mutations in the RAS onc…

Curcumin downregulates expression of opioid-related nociceptin receptor gene (OPRL1) in isolated neuroglia cells.

Abstract Background: Curcumin (CC) exerts polyvalent pharmacological actions and multi-target effects, including pain relief and anti-nociceptive activity. In combination with Boswellia serrata extract (BS), curcumin shows greater efficacy in knee osteoarthritis management, presumably due to synergistic interaction of the ingredients. Aim: To elucidate the molecular mechanisms underlying the analgesic activity of curcumin and its synergistic interaction with BS. Methods: We performed gene expression profiling by transcriptome-wide mRNA sequencing in human T98G neuroglia cells treated with CC (Curamed), BS, and the combination of CC and BS (CC-BS; Curamin), followed by interactive pathways a…

Synthesis and cytotoxic activity of new artemisinin hybrid molecules against human leukemia cells

A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20-28 showed IC50 values in the range of 0.019µM-0.192µM against CCRF-CEM cells and between 0.345µM and 7.159µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC50 value of 0.019±0.001µM and 0.345±0.031µM, respectively. A relatively low cross resistance to hybrids 20-28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to al…

Synergy assessment of fixed combinations of Herba Andrographidis and Radix Eleutherococci extracts by transcriptome-wide microarray profiling

Abstract Background Generally accepted, but insufficiently proved, the concept of synergy is based on an assumption that combining of two biologically active substances is justified because the combination is more active and less harmful than the ingredients. Hypothesis Analysis of RNA microarray of isolated neuroglia cells and the comparison the number of genes deregulated by plant extracts and their fixed herbal formulation might be a useful tool/method for assessment of synergistic and antagonistic interactions of herbal extracts in human organism. Aim The primary aim of this study was to extend a new method of assessment of synergistic and antagonistic interactions of herbal extracts in…

Antileukemic ancistrobenomine B and related 5,1′-coupled naphthylisoquinoline alkaloids from the Chinese liana Ancistrocladus tectorius

A striking feature of the metabolite pattern of the Southeast Asian liana Ancistrocladus tectorius (Ancistrocladaceae) is the predominance of 5,1′-coupled naphthylisoquinoline alkaloids. About 20 alkaloids of this coupling type have so far been discovered in this plant species. Here, we report on the isolation of four new 5,1′-linked naphthylisoquinolines from the twigs and stems of A. tectorius. Two of them, the ancistrobenomines B (5) and C (6), belong to the very rare group of alkaloids with a fully dehydrogenated isoquinoline portion. Likewise unusual for naphthylisoquinoline alkaloids is the presence of a hydroxymethylene group at C-3. Within the large class of meanwhile ca. 180 such n…

Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation.

The 6-epimer of the plakortide H acid (1), along with the endoperoxides plakortide E (2), plakortin (3), and dihydroplakortin (4) have been isolated from a sample of the Caribbean sponge Plakortis halichondrioides. To perform a comparative study on the cytotoxicity towards the drug-sensitive leukemia CCRF-CEM cell line and its multi-drug resistant subline CEM/ADR5000, the acid of plakortin, namely plakortic acid (5), as well as the esters plakortide E methyl ester (6) and 6-epi-plakortide H (7) were synthesized by hydrolysis and Steglich esterification, respectively. The data obtained showed that the acids (1, 2, 5) exhibited potent cytotoxicity towards both cell lines, whereas the esters s…

Two new flavonoids from Dracaena usambarensis Engl.

Abstract Investigations of the root extract of Dracaena usambarensis Engl. for anticancer principles led to the characterization of one new homoisoflavonoid, (3S)-3,4ʹ,5,6-tetrahydroxy-7-methoxyhomoisoflavanone (1) and a new retrodihydrochalcone, 4ʹ,4-dihydroxy-2,3-dimethoxydihydrochalcone (2) along with six previously reported compounds, including two homoisoflavonoids, 7-O-methyl-8-demethoxy-3-hydroxy-3,9-dihydropunctatin (3) and loureiriol (4); a phenolic amide, 3-(4ʹʹʹ-hydroxyphenyl)-N-[2ʹ-(4ʹʹ-hydroxyphenyl)-2ʹ-methoxyethyl]acrylamide (5); a spirostane, 25S-spirosta-1,4-dien-3-one (6) and two steroids, stigmasterol (7) and stigmasterol 3-O-β-D-glucopyranoside (8). The structures of 1-8…

Phytochemical characterization and biological activities of green tea (Camellia sinensis) produced in the Azores, Portugal

Abstract Background Green tea is not only one of the most widely consumed beverages worldwide, but is also known for its health promoting and therapeutic effects. Green tea is cultivated in areas with high humidity and acidic soils in China, Indonesia and Japan. Those places have well-marked dry and rainy seasons. In opposite, Azores have a climate with constant average annual rainfall and, unlike eastern regions, relatively constant air humidity throughout the year. While a brand implemented on the Portuguese market, the quality of green tea produced in Azores must be guaranteed. Quality control measures based on phytochemical determination of the chemical composition and biological activi…

Total Synthesis and Biological Investigation of (−)‐Artemisinin: The Antimalarial Activity of Artemisinin Is not Stereospecific

Here, we describe an efficient and diversity-oriented entry to both (-)-artemisinin (1) and its natural antipode (+)-artemisinin, starting from commercially and readily available S-(+)- and R-(-)-citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug-sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistan…

AMG900 as novel inhibitor of the translationally controlled tumor protein

Abstract Introduction Cancer is one of the leading causes of death worldwide. Classical cytotoxic chemotherapy exerts high side effects and low tumor selectivity. Translationally controlled tumor protein (TCTP) is a target for differentiation therapy, a promising, new therapeutic approach, which is expected to be more selective and less toxic than cytotoxic chemotherapy. The aim of the present investigation was to identify novel TCTP inhibitors. Methods We performed in silico screening and molecular docking using a chemical library of more than 31,000 compounds to identify a novel inhibitor of TCTP. We tested AMG900 in vitro for binding to TCTP by microscale thermophoresis and co-immunoprec…

Ancistectorine D, a naphthylisoquinoline alkaloid with antiprotozoal and antileukemic activities, and further 5,8'- and 7,1'-linked metabolites from the Chinese liana Ancistrocladus tectorius

From the twigs and stems of the Chinese liana Ancistrocladus tectorius (Ancistrocladaceae), two new 5,8'-coupled naphthylisoquinolines, ancistectorine D (5) and its 6-O-demethyl derivative 6, were isolated, along with two new 7,1'-linked alkaloids, 6-O-methylancistectorine B1 (7) and ancistectorine B2 (8). Two further compounds, ancistroealaine A (4) and 6-O-demethyl-8-O-methyl-7-epi-ancistrobrevine D (10), already known from related Asian and African Ancistrocladus species, were discovered for the first time in A. tectorius. The structure elucidation was achieved by spectroscopic analysis including HRESIMS, 1D and 2D NMR, and by chemical (oxidative degradation) and chiroptical (circular di…

Epidermal Growth Factor Receptors and Downstream Signalling Pathways as Cancer Treatment Targets for Medicinal Plants

Totalsynthese und Untersuchung der biologischen Aktivität von (−)‐Artemisinin – die Antimalaria‐Aktivität von Artemisinin ist nicht stereospezifisch

Teratogenicity and Developmental Toxicity of Herbal Products

Developmental toxicology and research in teratogenicity focus on xenobiotic substances that damage embryos and fetuses and lead to death, growth retardation, and/or malformation of offspring. While considerable information has been acquired about synthetic drugs and environmental xenobiotics, much less is known about the teratogenicity of herbal products. In this chapter we report on some major topics of developmental toxicity and teratogenicity, and discuss the safety of a few selected medicinal herbs in this context, i.e., Artemisia annua L., Caulophyllum thalictroides (L.) Michx., Echinacea spec,. Glycyrrhiza spec., herbs derived from Chinese medicine, Hypericum perforatum L., Panax gins…

Adaptogens in chemobrain (Part III): Antitoxic effects of plant extracts towards cancer chemotherapy-induced toxicity - transcriptome-wide microarray analysis of neuroglia cells.

Abstract Background Toxicity of chemotherapeutics is a serious problem in cancer therapy. Adaptogens are known to increase adaptability and survival organisms. Aim The aim of this study was to assess the effects of selected adaptogenic herbal extracts on FEC (fixed combination of 5-fluorouracil, epirubicin and cyclophosphamide) induced changes in transcriptome-wide microarray profiles of neuroglia cells. Another task of the study was to identify those genes, which are associated with FEC-induced hepato-, cardio– and nephrotoxicity to predict potential effects of andrographolide (AND), Andrographis herb, Eleutherococcus roots genuine extracts (ES), their fixed combination (AE) and the combin…

Adaptogens in chemobrain (Part II): Effect of plant extracts on chemotherapy-induced cytotoxicity in neuroglia cells

Abstract Background Cancer chemotherapy-induced cognitive impairments are apparently associated with harmful effects on physiological functions of brain cells. Adaptogens, are known to exhibit neuroprotective effects and to increase cognitive functions in clinical studies. In our previous study (Seo et al., 2018), we demonstrated that selected adaptogenic extracts significantly attenuate cytostatic-induced regulation of more than 100 genes involved in the activation of neuronal death and inhibiting neurogenesis. Neuroprotective and cytoprotective activities of adaptogens rise the question about their possible impact on cytostatic effects of a chemotherapeutic combination of 5-fluorouracil, …

Synthesis and biological evaluation of a D-ring-contracted analogue of lamellarin D

A D-ring contracted analogue of the strongly cytotoxic marine pyrrole alkaloid lamellarin D was synthesized and investigated for its antiproliferative action towards a wild type and a multidrug resistant (MDR) cancer cell line. The compound was found to inhibit tumor cell growth at submicromolar concentrations and showed a lower relative resistance in the MDR cell line than the antitumor drug camptothecin to which lamellarin D shows cross resistance and with which lamellarin D shares the same binding site.

Repurposing of Bromocriptine for Cancer Therapy

Bromocriptine is an ergot alkaloid and dopamine D2 receptor agonist used to treat Parkinson’s disease, acromegaly, hyperprolactinemia, and galactorrhea, and more recently diabetes mellitus. The drug is also active against pituitary hormone-dependent tumors (prolactinomas and growth-hormone producing adenomas). We investigated, whether bromocriptine also inhibits hormone-independent and multidrug-resistant (MDR) tumors. We found that bromocriptine was cytotoxic towards drug-sensitive CCRF-CEM, multidrug-resistant CEM/ADR5000 leukemic cells as well as wild-type or multidrug-resistant ABCB5-transfected HEK293 cell lines, but not sensitive or BCRP-transfected multidrug-resistant MDA-MB-231 brea…

Cytotoxicity of fagaramide derivative and canthin-6-one from Zanthoxylum (Rutaceae) species against multidrug resistant leukemia cells

In our continuous search for cytotoxic compounds from the genus Zanthoxylum, chromatographic separation of the MeOH/CH2Cl2 (1:1) extract of Z. chalybeum yielded one new alkamide; 4-(isoprenyloxy)-3-methoxy-3,4-deoxymethylenedioxyfagaramide (1) and a known one; fagaramide (2). Similarly, from the MeOH/CH2Cl2 (1:1) extract of the stem bark of Z. parachanthum four known compounds; canthin-6-one (3), dihydrochelerythrine (4), lupeol (5) and sesamin (6) were isolated. Characterization of the structures of these compounds was achieved using spectroscopic techniques (NMR and MS). Using resazurin reduction assay 1, 3 and 6 displayed moderate cytotoxicity with IC50 values below 50 μM against the dru…

Differentially Tolerized Mouse Antigen Presenting Cells Share a Common miRNA Signature Including Enhanced mmu-miR-223-3p Expression Which Is Sufficient to Imprint a Protolerogenic State

Dendritic cells (DCs) are pivotal for the induction and maintenance of antigen-specific tolerance and immunity. miRNAs mediate post-transcriptional gene regulation and control in part the differentiation and stimulation-induced immunogenic function of DCs. However, the relevance of miRNAs for the induction and maintenance of a tolerogenic state of DCs has scarcely been highlighted yet. We differentiated mouse bone marrow cells to conventional/myeloid DCs or to tolerogenic antigen presenting cells (APCs) by using a glucocorticoid (dexamethasone) or interleukin-10, and assessed the miRNA expression patterns of unstimulated and LPS-stimulated cell populations by array analysis and QPCR. Differ…

Prevention from radiation damage by natural products

Abstract Background Radiotherapy is a mainstay of cancer treatment since decades. Ionizing radiation (IR) is used for destruction of cancer cells and shrinkage of tumors. However, the increase of radioresistance in cancer cells and radiation toxicity to normal tissues are severe concerns. The exposure to radiation generates intracellular reactive oxygen species (ROS), which leads to DNA damage by lipid peroxidation, removal of thiol groups from cellular and membrane proteins, strand breaks and base alterations. Hypothesis Plants have to deal with radiation-induced damage (UV-light of sun, other natural radiation sources). Therefore, it is worth speculating that radioprotective mechanisms ha…

Cytotoxic Bufadienolides from the Leaves of Melianthus major

Melianthus major is a medicinal plant endemic to South Africa. Its leaf extract led to the isolation of five new bufadienolides, 2β-acetoxy-3,5-di-O-acetylhellebrigenin (1), 2β-acetoxy-3-O-acetylhellebrigenin (2), 2β-acetoxy-14-deoxy-15β,16β-epoxymelianthugenin (4), 2β-acetoxy-14-deoxy-15β,16β-epoxymelianthusigenin (5), and 2β-hydroxymelianthusigenin (6), and four known analogues. The structures of the compounds were elucidated using NMR and HRESIMS data analyses. The relative configurations were defined by single-crystal X-ray crystallography and NOESY correlations. The isolated compounds exhibited strong cytotoxicity against MCF-7 breast cancer cells and sensitive CCRF-CEM and multidrug-r…

Biopiracy of natural products and good bioprospecting practice

Made available in DSpace on 2018-11-26T16:27:45Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-02-15 Deutsche Forschungsgemeinschaft Background: Biopiracy mainly focuses on the use of biological resources and/or knowledge of indigenous tribes or communities without allowing them to share the revenues generated out of economic exploitation or other non-monetary incentives associated with the resource/knowledge. Methods: Based on collaborations of scientists from five continents, we have created a communication platform to discuss not only scientific topics, but also more general issues with social relevance. This platform was termed 'PhytCancer -Phytotherapy to Fight Cancer' (www.phy…

Cryptotanshinone deregulates unfolded protein response and eukaryotic initiation factor signaling in acute lymphoblastic leukemia cells.

Abstract Background: Unfolded protein responses (UPR) determine cell fate and are recognized as anticancer targets. In a previous research, we reported that cryptotanshinone (CPT) exerted cytotoxic effects toward acute lymphoblastic leukemia cells through mitochondria-mediated apoptosis. Purpose: In the present study, we further investigated the role of UPR in CPT-induced cytotoxicity on acute lymphoblastic leukemia cells by applying tools of pharmacogenomics and bioinformatics. Methods: Gene expression profiling was performed by mRNA microarray hybridization. Potential transcription factor binding motifs were identified in the promoter regions of the deregulated genes by Cistrome software.…

Acceptor Specificity of Amylosucrase from Deinococcus radiopugnans and Its Application for Synthesis of Rutin Derivatives

The transglycosylation activity of amylosucrase (ASase) has received significant attention owing to its use of an inexpensive donor, sucrose, and broad acceptor specificity, including glycone and aglycone compounds. The transglycosylation reaction of recombinant ASase from Deinococcus radiopugnans (DRpAS) was investigated using various phenolic compounds, and quercetin-3-O-rutinoside (rutin) was found to be the most suitable acceptor molecule used by DRpAS. Two amino acid residues in DRpAS variants (DRpAS Q299K and DRpAS Q299R), assumed to be involved in acceptor binding, were constructed by site-directed mutagenesis. Intriguingly, DRpAS Q299K and DRpAS Q299R produced 10-fold and 4-fold hig…

Ancistrolikokine I and further 5,8'-coupled naphthylisoquinoline alkaloids from the Congolese liana Ancistrocladus likoko and their cytotoxic activities against drug-sensitive and multidrug resistant human leukemia cells.

Abstract The Congolese liana Ancistrocladus likoko (Ancistrocladaceae) produces naphthylisoquinoline alkaloids that are, chemotaxonomically remarkable, all based on the same coupling type, with the biaryl axis located between C-5 and C-8′. About 20 alkaloids, belonging to the subclass of 5,8′-linked naphthylisoquinolines, have so far been discovered in this plant species. Here, we report on the isolation and structure elucidation of six further such 5,8′-coupled monomeric alkaloids, named ancistrolikokines I (9), C3 (10), F2 (11), J (12), J2 (13), and J3 (14). They were identified in the twigs of A. likoko, along with the two new atropo-diastereomeric dimers michellamines A8 (15a) and B8 (1…

Novel molecular mechanisms for the adaptogenic effects of herbal extracts on isolated brain cells using systems biology.

Abstract Introduction Adaptogens are natural compounds or plant extracts that increase adaptability and survival of organisms under stress. Adaptogens stimulate cellular and organismal defense systems by activating intracellular and extracellular signaling pathways and expression of stress-activated proteins and neuropeptides. The effects adaptogens on mediators of adaptive stress response and longevity signaling pathways have been reported, but their stress-protective mechanisms are still not fully understood. Aim of the study The aim of this study was to identify key molecular mechanisms of adaptogenic plants traditionally used to treat stress and aging-related disorders, i.e., Rhodiola r…

Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells.

Abstract Background Resistance of cancer cells towards chemotherapeutics represents a major cause of therapy failure. The objective of our study was to evaluate cellular defense strategies in response to the novel vacuolar H+-ATPase inhibitor, archazolid B. Experimental approach: The effects of archazolid B on T24 bladder carcinoma cells were investigated by combining “omics” technologies (transcriptomics (mRNA and miRNA) and proteomics). Free cholesterol distribution was determined by filipin staining using flow cytometry and fluorescence microscopy. Flow cytometry was performed for LDLR surface expression studies. Uptake of LDL cholesterol was visualized by confocal microscopy. SREBP acti…

Dioncophyllines C2, D2, and F and related naphthylisoquinoline alkaloids from the Congolese liana Ancistrocladus ileboensis with potent activities against Plasmodium falciparum and against multiple myeloma and leukemia cell lines

Dioncophylline F (1), the first 5,8'-coupled dioncophyllaceous alkaloid (i.e., lacking an oxygen function at C-6 and possessing an R-configuration at C-3), was isolated from the recently described Congolese liana Ancistrocladus ileboensis. Two further, likewise Dioncophyllaceae-type, alkaloids, the dioncophyllines C2 (2) and D2 (3), were identified, along with the Ancistrocladaceae-type compound ancistrocladisine B (4), which is oxygenated at C-6 and S-configured at C-3. The structures of the new compounds were determined by spectroscopic, chemical, and chiroptical methods. The stereostructure of 1 was further confirmed by total synthesis. As a consequence of the lack of a methyl group orth…

Collateral sensitivity of natural products in drug-resistant cancer cells

Cancer chemotherapy is frequently hampered by drug resistance. Concepts to combine anticancer drugs with different modes of action to avoid the development of resistance did not provide the expected success in the past, because tumors can be simultaneously non-responsive to many drugs (e.g. the multidrug resistance phenotype). However, tumors may be specifically hypersensitive to other drugs - a phenomenon also termed collateral sensitivity. This seems to be a general biological mechanism, since it also occurs in drug-resistant Escherichia coli and Saccharomyces cerevisiae. Here, we give a timely and comprehensive overview on hypersensitivity in resistant cancer cells towards natural produc…

Biopiracy versus One-World Medicine-From colonial relicts to global collaborative concepts.

Abstract Background Practices of biopiracy to use genetic resources and indigenous knowledge by Western companies without benefit-sharing of those, who generated the traditional knowledge, can be understood as form of neocolonialism. Hypothesis The One-World Medicine concept attempts to merge the best of traditional medicine from developing countries and conventional Western medicine for the sake of patients around the globe. Study design Based on literature searches in several databases, a concept paper has been written. Legislative initiatives of the United Nations culminated in the Nagoya protocol aim to protect traditional knowledge and regulate benefit-sharing with indigenous communiti…

Targeting Angiogenesis by Therapeutic Antibodies

Ruthenium(II) and platinum(II) homo- and heterobimetallic complexes: Synthesis, crystal structures, theoretical calculations and biological studies

Four Ru-Pd heterobimetallic complexes, each one in two different coordination modes (NNSS and NS) having metals connected by a binucleating dialkyldithiooxamidate [N(R)SC-CS(R)N] [R = methyl, ethyl, n-butyl and isopropyl], were prepared by reacting the monochelate [(trinpropyl-phosphine)ClPd(HR2C2N2S2κ-S,S-Pd)] with [(η6-p-cymene)RuCl2]2. Furthermore, two palladium homobimetallic complexes having two (trinpropyl-phosphine)ClPd moieties joined by a diethyldithiooxamidate in both κ-N,S Pd, κ-N',S' Pd' and κ-N,N' Pd, κ-S,S' Pd' coordination modes were synthesized. For both kinds of complexes, homo- and heterobimetallic, at room temperature and in chloroform solution, the NNSS coordination mode…

Effects of anti-inflammatory and adaptogenic herbal extracts on gene expression of eicosanoids signaling pathways in isolated brain cells.

Abstract Introduction The adaptogens modulate expression of genes playing key roles in development of aging-related disorders, which are considered as low-grade systemic inflammatory conditions characterized by an imbalance between pro-and anti-inflammatory eicosanoids. Aim of the Study We compared the effects of anti-inflammatory and adaptogenic plant extracts on the expression of genes involved in biosynthesis of eicosanoids with the purpose to find those plants, which selectively upregulated the expression of anti-inflammatory lipoxins signaling pathways and inhibited pro-inflammatory signaling pathways associated with biosynthesis of leukotrienes, prostaglandins and thromboxanes. Materi…

Cytotoxicity of natural products and derivatives toward MCF-7 cell monolayers and cancer stem-like mammospheres

Abstract Although cancer stem-like cells (CSCs) are rare, they can enter a non-proliferative or dormant state and resist therapy. Furthermore, quiescent CSCs are responsible for metastases that can appear after curative surgical treatment of a primary tumor. Because of drug resistance of CSCs, the development of novel therapies is urgently required that specifically target CSCs. Purpose The aim of the present study was to investigate the potential of a panel of natural products and derivatives to inhibit CSC-enriched mammospheres of MCF-7 breast cancer cells. Methods CD44high/CD24low cells were identified by flow cytometry and maintained as mammospheres. As a control, we used two clinically…

CCDC 1816140: Experimental Crystal Structure Determination

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CCDC 1920565: Experimental Crystal Structure Determination

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CCDC 1981430: Experimental Crystal Structure Determination

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CCDC 1816139: Experimental Crystal Structure Determination

Related Article: Aysun Çapcı Karagöz, Christoph Reiter, Ean-Jeong Seo, Lisa Gruber, Friedrich Hahn, Maria Leidenberger, Volker Klein, Frank Hampel, Oliver Friedrich, Manfred Marschall, Barbara Kappes, Thomas Efferth, Svetlana B. Tsogoeva|2018|Bioorg.Med.Chem.|26|3610|doi:10.1016/j.bmc.2018.05.041

CCDC 1961566: Experimental Crystal Structure Determination

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CCDC 1961567: Experimental Crystal Structure Determination

Related Article: Kibrom Gebreheiwot Bedane, Lukas Brieger, Carsten Strohmann, Ean-Jeong Seo, Thomas Efferth, Michael Spiteller|2020|J.Nat.Prod.|83|2122|doi:10.1021/acs.jnatprod.0c00060

CCDC 1920566: Experimental Crystal Structure Determination

Related Article: Banafshe Askari, Hadi Amiri Rudbari, Nicola Micale, Tanja Schirmeister, Thomas Efferth, Ean-Jeong Seo, Giuseppe Bruno, Kevin Schwickert|2019|Dalton Trans.|48|15869|doi:10.1039/C9DT02353D

CCDC 1981431: Experimental Crystal Structure Determination

Related Article: Kibrom Gebreheiwot Bedane, Lukas Brieger, Carsten Strohmann, Ean-Jeong Seo, Thomas Efferth, Michael Spiteller|2020|Bioorg.Chem.|102|104102|doi:10.1016/j.bioorg.2020.104102