Mangiferin is a glycosylated xanthone widely distributed in nature, which exhibits wide pharmacological activities, highlighting its anti-cancer properties. Mangiferin interferes with inflammation, lipid, and calcium signaling, which selectively inhibits multiple NFkB target genes as interleukin-6, tumor necrosis factor, plasminogen, and matrix metalloproteinase, among others. In this work, the interactions of this polyphenol with MMP-9 and NF-κβ are characterized by using computational chemistry methods. The results show MMP-9 inhibition by mangiferina is characterized for the interact with the catalytic Zn atom through a penta-coordinate structure. It is also demonstrated through a strong charge transfer established between mangiferin and Zn in the QM/MM study. Concerning the mangiferin/NF-κβ system, the 92.3% of interactions between p50 sub-unity and DNA are maintained with a binding energy of - 8.04 kcal/mol. These findings indicate that mangiferin blocks the p50-p65/DNA interaction resulting in the loss of the functions of this hetero-dimeric member and suggesting inhibition of the cancer progression. Experimental results concerning the anti-cancer properties of mangiferin show that this natural compound can inhibit selectively MMP-9 and NF-ƙβ. Although the anti-tumor properties of mangiferin are well defined, its molecular mechanisms of actions are not described. In this work, a computational study is carried out to characterize the interactions of mangiferin with these molecular targets. The results obtained corroborate the anti-proliferative and anti-apoptotic activity of mangiferin and provide a depiction of its mechanisms of action.
Mangiferin is a kind of polyphenol chemical compound separated from these herbal medicines of Mangifera indica L., Anemarrhena asphodeloides Bge. and Belamcanda chinensis L., which has anti-inflammatory, anti-virus, and other physiological activities without toxic effects. Osteoarthritis (OA) is a chronic disease that is also a kind of arthritis disease in which articular cartilage or bones under the joint is damaged. In addition, artificial replacements are required in severe cases. At present, there are not too much researches on the potential biological activities of mangiferin that plays a protective role in the treatment of OA. In this study, we evaluated the protective effect of mangiferin on osteoarthritis (OA) in vitro and in vivo. First, the effect of different concentrations of mangiferin on rat chondrocytes was determined by MTT assay. Second, the effects of mangiferin on the expression levels of matrix metalloproteinase (MMP)-13, TNF alpha, Collagen II, Caspase-3, and cystatin-C in interleukin-1beta (IL-1beta)-induced rat chondrocytes were examined by the real-time polymerase chain reaction in vitro, meanwhile the effects of mangiferin on the nuclear factor kappa-B (NF-kappaB) signaling pathway were also investigated by Western Blot. Finally, the anti-osteoarthritic protective effect of mangiferin was evaluated in the rat model by anterior cruciate ligament transection (ACLT) combined with bilateral ovariectomy-induced OA in vivo. The results showed that the mangiferin was found to inhibit the expression of MMP-13, TNF-alpha, and Caspase-3 which also increased the expression of Collagen II and cystatin-C in IL 1beta induced rat chondrocytes. In addition, IL-1beta-induced activation of nuclear factor kappa-B (NF-kappaB) and the degradation of inhibitor of kappaB (IkappaB)-alpha were suppressed by mangiferin. For the in vivo study in a rat model of OA, 100 microl of mangiferin was administered by intra-articular injections for rats, the results showed that the cartilage degradation was suppressed by mangiferin through Micro CT and Histological Examination. According to both in vitro and in vivo results, mangiferin has a protective effect in the treatment of OA which may be a promising therapeutic agent for OA.
- MeSH
- chondrocyty MeSH
- interleukin-1beta MeSH
- kloubní chrupavka * metabolismus MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- NF-kappa B metabolismus MeSH
- osteoartróza * farmakoterapie metabolismus patologie MeSH
- xantony * metabolismus farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
During our investigation on the endophytic fungi of Azadirachta indica, the strain YM 311593 was obtained from the fruit of the plant. The culture extract of the strain showed antifungal activities against four phytopathogenic fungi. Based on the morphological features and phylogenetic definition, the strain YM 311593 was identified as Paraconiothyrium sp. Four xanthones and one anthraquinone were obtained from the extract of the fermentation broth of the strain. They were characterized to be globosuxanthone A (1), vertixanthone (2), hydroxyvertixanthone (3), 3,8-dihydroxy-1-methy1-9H- xanthen-9-one (4), and danthron (5), respectively, by spectroscopic elucidation. Furthermore, the absolute configuration of 1 was deduced by X-ray diffraction analysis. Besides, compound 4 was firstly found from natural sources. The antifungal activities of compounds 1-5 towards four phytopathogens were assayed using broth microdilution method. Among them, globosuxanthone A (1) showed obvious antifungal activity towards Fusarium graminearum, Fusarium solani, and Botrytis cinerea with MIC values of 4, 8, and 16 μg/mL, respectively.
- MeSH
- Ascomycota chemie izolace a purifikace MeSH
- Azadirachta mikrobiologie MeSH
- endofyty chemie izolace a purifikace MeSH
- fungicidy průmyslové izolace a purifikace farmakologie MeSH
- fylogeneze MeSH
- houby účinky léků MeSH
- kultivační média chemie MeSH
- ovoce mikrobiologie MeSH
- xantony izolace a purifikace farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
Seedling establishment following germination requires the fine tuning of plant hormone levels including that of auxin. Directional movement of auxin has a central role in the associated processes, among others, in hypocotyl hook development. Regulated auxin transport is ensured by several transporters (PINs, AUX1, ABCB) and their tight cooperation. Here we describe the regulatory role of the Arabidopsis thaliana CRK5 protein kinase during hypocotyl hook formation/opening influencing auxin transport and the auxin-ethylene-GA hormonal crosstalk. It was found that the Atcrk5-1 mutant exhibits an impaired hypocotyl hook establishment phenotype resulting only in limited bending in the dark. The Atcrk5-1 mutant proved to be deficient in the maintenance of local auxin accumulation at the concave side of the hypocotyl hook as demonstrated by decreased fluorescence of the auxin sensor DR5::GFP. Abundance of the polar auxin transport (PAT) proteins PIN3, PIN7, and AUX1 were also decreased in the Atcrk5-1 hypocotyl hook. The AtCRK5 protein kinase was reported to regulate PIN2 protein activity by phosphorylation during the root gravitropic response. Here it is shown that AtCRK5 can also phosphorylate in vitro the hydrophilic loops of PIN3. We propose that AtCRK5 may regulate hypocotyl hook formation in Arabidopsis thaliana through the phosphorylation of polar auxin transport (PAT) proteins, the fine tuning of auxin transport, and consequently the coordination of auxin-ethylene-GA levels.
- MeSH
- Arabidopsis účinky léků fyziologie MeSH
- biologické markery MeSH
- fenotyp MeSH
- fosforylace MeSH
- hypokotyl fyziologie MeSH
- klíčení MeSH
- morfogeneze * účinky léků genetika MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- proteiny huseníčku metabolismus MeSH
- receptory buněčného povrchu metabolismus MeSH
- regulace genové exprese u rostlin MeSH
- reportérové geny MeSH
- signální transdukce MeSH
- vývoj rostlin * účinky léků genetika MeSH
- xantony farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
Hypericum japonicum Thunb. ex Murray is traditionally used in Nepal to treat several diseases, among whom inflammation and acute pain. Although several secondary metabolites from the same Hypericum species have been already characterized and considered for their pharmacological use, an exhaustive phytochemical characterization of H. japonicum from Nepal is lacking, as well as the assessment of its potential pharmacological properties. Hence, the aims of this study were the characterization of a methanolic extract of H. japonicum (HJME) collected from the Northern region of Nepal by LC-MSn and UPLC-QTOF. The assessment of in vitro inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1) transcription factors and HJME's cytotoxic effect on human cell lines was performed to evaluate the potential use of this herb as a source of anti-inflammatory and cytotoxic lead compounds. Fifty-seven phytoconstituents were identified, being mainly flavonoids, phloroglucinols, phenolic acids and xanthones. Although compounds characteristic of H. japonicum were detected (quercetin, quercetin-7-O-α-l-rhamnoside, quercitrin and hyperoside), several others are here reported for the first time in this species. The results from bioassays indicated that HJME could significantly reduce the viability of human THP-1 cells (IC50 = 5.4 ± 1.1 μg mL-1), showing the promising potential of HJME as anti-tumor agent. Furthermore, HJME significantly decreased the activation of both NF-κB and AP-1 at the concentration of 2 μg mL-1. Overall, these data suggest that H. japonicum from Nepal could be used as a source of potential natural anti-inflammatory and anti-tumor lead compounds.
- MeSH
- antiflogistika farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- biotest MeSH
- buněčné linie MeSH
- chromatografie kapalinová MeSH
- flavonoidy farmakologie MeSH
- floroglucinol farmakologie MeSH
- hmotnostní spektrometrie MeSH
- hydroxybenzoáty farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- NF-kappa B - podjednotka p50 antagonisté a inhibitory MeSH
- rostlinné extrakty farmakologie MeSH
- THP-1 buňky MeSH
- transkripční faktor AP-1 antagonisté a inhibitory MeSH
- třezalka chemie MeSH
- viabilita buněk MeSH
- xantony farmakologie MeSH
- zánět MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Nepál MeSH
Beer, the most popular beverage containing hops, is also frequently consumed by cancer patients. Moreover, non-alcoholic beer, owing to its nutritional value and high content of biological active compounds, is sometimes recommended to patients by oncologists. However, the potential benefits and negatives have to date not been sufficiently evaluated. The present study was designed to examine the effects of four main hop-derived prenylflavonoids on the viability, reactive oxygen species (ROS) formation, activity of caspases, and efficiency of the chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (OxPt) and irinotecan (IRI) in colorectal cancer cell lines SW480, SW620 and CaCo-2. All the prenylflavonoids exerted substantial antiproliferative effects in all cell lines, with xanthohumol being the most effective (IC50 ranging from 3.6 to 7.3 μM). Isoxanthohumol increased ROS formation and the activity of caspases-3/7, but 6-prenylnaringenin and 8-prenylnaringenin exerted antioxidant properties. As 6-prenylnaringenin acted synergistically with IRI, its potential in combination therapy deserves further study. However, other prenylflavonoids acted antagonistically with all chemotherapeutics at least in one cell line. Therefore, consumption of beer during chemotherapy with 5-FU, OxPt and IRI should be avoided, as the prenylflavonoids in beer could decrease the efficacy of the treatment.
- MeSH
- antioxidancia MeSH
- antitumorózní látky fytogenní farmakologie terapeutické užití MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- Caco-2 buňky MeSH
- fixní kombinace léků MeSH
- flavanony farmakologie terapeutické užití MeSH
- flavonoidy farmakologie terapeutické užití MeSH
- fluorouracil terapeutické užití MeSH
- Humulus chemie MeSH
- irinotekan terapeutické užití MeSH
- kaspasy metabolismus MeSH
- kolorektální nádory farmakoterapie metabolismus MeSH
- lékové interakce * MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- oxaliplatin terapeutické užití MeSH
- pivo * škodlivé účinky MeSH
- propiofenony farmakologie terapeutické užití MeSH
- reaktivní formy kyslíku metabolismus MeSH
- rostlinné extrakty farmakologie terapeutické užití MeSH
- stravovací zvyklosti MeSH
- výsledek terapie MeSH
- xantony farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.
- MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků MeSH
- buňky HT-29 MeSH
- cisplatina farmakologie MeSH
- doxorubicin farmakologie MeSH
- HCT116 buňky MeSH
- kontrolní body buněčného cyklu účinky léků MeSH
- lidé MeSH
- mutace MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- neuroblastom farmakoterapie genetika metabolismus patologie MeSH
- protein p73 genetika metabolismus MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie MeSH
- protoonkogenní proteiny c-mdm2 genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- signální transdukce účinky léků MeSH
- synergismus léků MeSH
- xantony farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Currently, used oral antiplatelet drugs are both limited and associated with the risk of treatment failure/resistance. Research in this area is hence highly desired. A series of xanthene-3-ones derivatives, we had synthesized, showed us that these derivatives had antiplatelet activity. As far as we know, no research on the effects of xanthen-3-ones in this area has been done. OBJECTIVE: The aim was to study the antiplatelet potential of a series of synthesised 9-phenylxanthene- 3-ones and to find the ideal structural feature(s) for antiplatelet potential and determine the mechanism of action. METHODS: The compounds were synthesized from 1,2,4-triacetoxybenzene and various benzaldehydes. The reaction proceeded smoothly under acidic alcoholic conditions, furnishing the desired products in good yields. The compounds were first screened in whole human blood where platelet aggregation was induced by arachidonic acid. Further analysis was targeted at search of the mechanism of action. RESULTS: Initial screening showed that a majority of the synthesized derivatives had substantial antiplatelet potential. None of the compounds were able to block cyclooxygenase 1 or thromboxane synthase. The mechanism appeared to be based on antagonism of thromboxane effects. The most potent compound 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxy-xanthene-3-one had better potential to block collagen induced platelet aggregation than clinically used acetylsalicylic acid. CONCLUSION: The last mentioned derivative is promising for further in vivo testing.
- MeSH
- agregace trombocytů účinky léků MeSH
- inhibitory agregace trombocytů chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- thromboxan A2 antagonisté a inhibitory MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xantony chemická syntéza chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Neuropatická bolest je bolestivý syndrom způsobený lézí nebo dysfunkcí nervového systému nebo následkem lézí nebo chorob somato-senzorického systému. Neuropatická bolest je často spojována s nežádoucími účinky chemoterapie rakovinného onemocnění, s infiltrací rakovinných buněk do nervové tkáně, s neurodegenerací a s diabetes mellitus. Disbalance v produkci různých cytokinů hraje výraznou úlohu v patogenezi mnoha onemocnění spojovaných s neuropatiemi. Mezi takové cytokiny patří zejména interleukiny IL-1β, IL-15 a IL-6, tumor nekrotizující faktory nebo prostaglandiny. Produkce cytokinů je biochemicky podřízená jaderným faktorům ovlivňujícím expresi mRNA pro jednotlivé cytokiny nebo enzymy cytokiny metabolizující. Hlavním jaderným faktorem regulujícím expresi cytokinů je NF-κB. Vzhledem k nedostatečné efektivitě farmakologické léčby periferní neuropatie, nebo jejím nežádoucím účinkům, mnoho pacientů vyhledává podpůrnou a doplňkovou terapii. Přírodní sloučeniny modulující produkci zánětlivých cytokinů proto mohou redukovat symptomy neuropatií. Mezi látky ovlivňující aktivitu NF-κB a jím regulovaných cytokinů patří celá řada přírodních fenolů. Toto mini-review má za cíl zpracovat informace o třech přírodních fenolech potenciálně aplikovatelných v terapii neuropatií: kurkuminu, resveratrolu a mangiferinu a upozornit na jejich praktickou využitelnost. Kurkumin a mangiferin jsou obsahové látky považované za aktivní konstituenty rostlin používaných tradiční medicínou již po staletí. Biologické účinky resveratrolu jsou známé relativně krátkou dobu, pozornost je na resveratrol upřena zejména od doby popsání tzv. francouzského paradoxu. Do přehledu jsou zařazeny zejména údaje týkající se ovlivnění aktivity NF-κB, exprese prozánětlivých cytokinů a také antiradikálové aktivity, protože nerovnováha v tvorbě a degradaci volných radikálů hraje významnou roli v aktivaci NF-κB a v průběhu zánětlivých procesů. Stručně shrnuty jsou také základní informace o biodostupnosti, metabolismu, a praktické aplikaci těchto látek.
Neuropathic pain is a syndrome comprising pain caused by a lesion or dysfunction of the nervous system, or resulting from lesions or diseases of the somatosensory system. Neuropathic pain is often connected with adverse effects of chemotherapy administered because of cancer, infiltration of the nervous tissue with cancer cells, neurodegeneration and diabetes mellitus. Disbalance in the production of various cytokines plays an important role in the pathogenesis of many of the diseases connected with neuropathies. These cytokines comprise in particular interleukins IL-1β, IL-15, and IL-6, tumour necrosis factors, and prostaglandins. The biochemistry of the production of cytokines is directed by nuclear factors, which affect the expression of the mRNA for the respective cytokines or enzymes metabolizing the cytokines. The main nuclear factor which regulates the expression of cytokines is NF-κB. Because of insufficient effectiveness or adverse effects of the pharmacological treatment of peripheral neuropathy, many patients seek supportive or adjuvant therapy. Natural compounds which modulate the production of inflammatory cytokines may reduce the symptoms of neuropathies. Many natural phenolic compounds belong to substances affecting the activity of NF-κB and consequently the activity of cytokines which are regulated by this substance. The aim of this mini-review is to present information about three natural phenols which are potentially usable for the treatment of neuropathies: curcumin, resveratrol and mangiferin, and bring attention to the practical usability thereof. Curcumin and mangiferin are active constituents of plants; they have been used for centuries in traditional medicine. Biological effects of resveratrol have been known for a relatively short time; since the discovery of the so-called French paradox, attention has been focused on resveratrol. This summary includes particularly the information related to the influence on the activity of NF-κB, expression of anti-inflammatory cytokines, and antiradical activity, because imbalance between the creation and degradation of free radicals plays an important role in the activation of NF-κB and in inflammatory processes. It also briefly summarizes basic information concerning bioavailability, metabolism and practical application of the aforementioned substances.
- Klíčová slova
- mangiferin, periferní neuropatie,
- MeSH
- antiflogistika farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- antioxidancia farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- biologická dostupnost MeSH
- DNA vazebné proteiny účinky léků MeSH
- fenoly * farmakologie metabolismus terapeutické užití MeSH
- inhibitory enzymů farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- kurkumin * farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- lidé MeSH
- neuralgie * farmakoterapie MeSH
- NF-kappa B účinky léků MeSH
- oxidační stres účinky léků MeSH
- resveratrol MeSH
- ribonukleotidreduktasy antagonisté a inhibitory MeSH
- rostlinné extrakty MeSH
- scavengery volných radikálů MeSH
- stilbeny * farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- transkripční faktory účinky léků MeSH
- xantony farmakokinetika farmakologie metabolismus terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
A new xanthone derivative having axial chirality was isolated from Penicillium vinaceum. Owing to the axial chirality, its structure, including absolute configuration, was determined by means of extensive spectroscopic data, such as UV, IR, MS, and 1D and 2D NMR spectra, and computational chiroptical methods. The new compound, (a R)-2'-methoxyvinaxanthone, has a structure containing two aromatic moieties with substituents hindering rotation about the biaryl axis. The compound gave positive results in a sea urchin egg test ( Paracentrotus lividus) and a crown gall tumor on potato disks test (Agrobacterium tumefaciens).
- MeSH
- financování organizované MeSH
- ježovky růst a vývoj účinky léků MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- nádory rostlin MeSH
- nukleární magnetická rezonance biomolekulární MeSH
- ovum růst a vývoj účinky léků MeSH
- Penicillium chemie MeSH
- Solanum tuberosum chemie účinky léků MeSH
- xantony farmakologie chemie izolace a purifikace MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
