We previously demonstrated that flavonoid metabolites inhibit cancer cell proliferation through both CDK-dependent and -independent mechanisms. The existing evidence suggests that gut microbiota is ...capable of flavonoid biotransformation to generate bioactive metabolites including 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA), 3,4,5-trihyroxybenzoic acid (3,4,5-THBA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In this study, we screened 94 human gut bacterial species for their ability to biotransform flavonoid quercetin into different metabolites. We demonstrated that five of these species were able to degrade quercetin including Bacillus glycinifermentans, Flavonifractor plautii, Bacteroides eggerthii, Olsenella scatoligenes and Eubacterium eligens. Additional studies showed that B. glycinifermentans could generate 2,4,6-THBA and 3,4-DHBA from quercetin while F. plautii generates DOPAC. In addition to the differences in the metabolites produced, we also observed that the kinetics of quercetin degradation was different between B. glycinifermentans and F. plautii, suggesting that the pathways of degradation are likely different between these strains. Similar to the antiproliferative effects of 2,4,6-THBA and 3,4-DHBA demonstrated previously, DOPAC also inhibited colony formation ex vivo in the HCT-116 colon cancer cell line. Consistent with this, the bacterial culture supernatant of F. plautii also inhibited colony formation in this cell line. Thus, as F. plautii and B. glycinifermentans generate metabolites possessing antiproliferative activity, we suggest that these strains have the potential to be developed into probiotics to improve human gut health.
Species with relatively small, membraneous, black ascomata, with or without long necks, unitunicate, cylindrical asci with apical rings and fusiform, hyaline ascospores with or without mucilaginous ...sheaths are common in freshwater habitats in tropical and temperate regions. Many of these taxa have originally been recorded as
Annulatascaceae
-like taxa. Twenty genera have been included in the family
Annulatascaceae
, mostly based on morphological characters, while molecular work and phylogenetic analyses are lacking for many genera. In this study, nine new
Annulatascaceae
-like taxa collected from Thailand were morphologically examined. Pure cultures obtained from single ascospores were used in molecular studies. The nine new strains and several other strains of Annulatascaceae-like Sordariomycetes species were used to establish phylogenetic and evolution relationships among the taxa, based on combined LSU, SSU, ITS and RPB2 sequence data. Phylogenetic analyses provide evidence to introduce one new order and six new families, to accommodate taxa excluded from
Annulatascaceae
sensu stricto. A new order
Atractosporales
is established based on the molecular study, including three new introduced families
Conlariaceae
,
Pseudoproboscisporaceae
and
Atractosporaceae
.
Conlariaceae
is introduced for the genus
Conlarium
which comprises two species,
Conlarium duplumascosporun
and a new Hyphomycetous asexual morph taxon
Conlarium aquaticum
which has subglobose or irregular, brown, clathrate, muriform conidia.
Pseudoproboscisporaceae
includes
Pseudoproboscispora
and
Diluviicola
, while
Atractosporaceae
includes the genera
Rubellisphaeria
and
Atractospora. Barbatosphaeria
,
Xylomelasma
and
Ceratostomella
form a distinct stable lineage which is introduced as a new family
Barbatosphaeriaceae
in Diaporthomycetidae families
incertae sedis.
A new family
Lentomitellaceae
is introduced in Diaporthomycetidae families
incertae sedis
, to accommodate the genus
Lentomitella. Woswasiaceae
is introduced to accommodate
Woswasia
,
Xylochrysis
and
Cyanoannulus
in Diaporthomycetidae families
incertae sedis
. Three new species of
Fluminicola
viz.
F. saprophytica
,
F. thailandensis
and
F. aquatica
are introduced. A new sexual morph,
Dictyosporella thailandensis,
is reported and
Dictyosporella
is excluded from
Annulatascaceae
and placed in Diaporthomycetidae genera
incertae sedis
. The first sexual morph of
Sporidesmium
,
S. thailandense
is also described. The new species
Atractospora thailandensis
,
Diluviicola aquatica
and
Pseudoproboscispora thailandensis
are also introduced.
Platytrachelon
is added to
Papulosaceae
based on phylogenetic analysis and morphological characters.
Aquaticola
,
Fusoidispora
and
Pseudoannulatascus
are excluded from
Annulatascaceae
and placed in Diaporthomycetidae genera
incertae sedis
.
Mirannulata
is accommodated in Sordariomycetes, genera
incertae sedis
.
Inflammatory Bowel Diseases (IBD) is a debilitating condition that affects ~70,000 new people every year and has been described as “an expensive disease with no known cure”. In addition, IBD ...increases the risk of developing colon cancer. The current therapeutics for IBD focus on the established disease where the immune dysfunction and bowel damage have already occurred but do not prevent or delay the progression. The current work describes a polymer-based anti-inflammatory technology (Ora-Curcumin-S) specifically targeted to the luminal side of the colon for preventing and/or treating IBD. Ora-Curcumin-S was prepared by molecular complexation of curcumin with a hydrophilic polymer Eudragit® S100 using co-precipitation method. Curcumin interacted with the polymer non-covalently and existed in an amorphous state as demonstrated by various physicochemical techniques. Ora-Curcumin-S is a polymer-drug complex, which is different than solid dispersions in that the interactions are retained even after dissolving in aqueous buffers. Ora-Curcumin-S was >1000 times water soluble than curcumin and importantly, the enhanced solubility was pH-dependent, which was observed only at pHs above 6.8. In addition, around 90% of Ora-Curcumin-S was stable in phosphate buffer, pH 7.4 and simulated intestinal fluid after 24 h, in contrast to 10–20% unformulated curcumin. Ora-Curcumin-S inhibited Monophosphoryl Lipid-A and E. coli induced inflammatory responses in dendritic cells and cells over expressing Toll-Like Receptor-4 (TLR-4) suggesting that Ora-Curcumin-S is a novel polymer-based TLR-4 antagonist. Preliminary pharmacokinetics in mice showed targeted delivery of soluble curcumin to the colon lumen without exposing to the systemic circulation. Furthermore, Ora-Curcumin-S significantly prevented colitis and associated injury in a mouse model of ulcerative colitis estimated using multiple preclinical parameters: colonoscopy pictures, body weight, colon length, colon edema, spleen weight, pro-inflammatory signaling and independent pathological scoring. Overall, the outcome of this innovative proof-of-concept study provides an exciting and locally-targeted pathway for a dietary therapeutic option for IBD patients to help limit colonic inflammation and thus susceptibility to colitis-associated colorectal cancer.
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Curcumin is a natural dietary compound with demonstrated potential in preventing/treating several chronic diseases in animal models. However, this success is yet to be translated to humans mainly ...because of its poor oral bioavailability caused by extremely low water solubility. This manuscript demonstrates that water insoluble curcumin (~1μg/ml) forms highly aqueous soluble complexes (>2mg/ml) with a safe pH sensitive polymer, poly(butyl-methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl-methacrylate) when precipitated together in water. The complexation process was optimized to enhance curcumin loading by varying several formulation factors. Acetone as a solvent and polyvinyl alcohol as a stabilizer with 1:2 ratio of drug to polymer yielded complexes with relatively high loading (~280μg/ml) and enhanced solubility (>2mg/ml). The complexes were amorphous in solid and were soluble only in buffers with pHs less than 5.0. Hydrogen bond formation and hydrophobic interactions between curcumin and the polymer were recorded by infrared spectroscopy and nuclear magnetic resonance spectroscopy, respectively. Molecular complexes of curcumin were more stable at various pHs compared to unformulated curcumin. In mice, these complexes increased peak plasma concentration of curcumin by 6 times and oral bioavailability by ~20 times. This is a simple, economic and safer strategy of enhancing the oral bioavailability of curcumin.
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Aspirin, synthesized and marketed in 1897 by Bayer, is one of the most widely used drugs in the world. It has a well-recognized role in decreasing inflammation, pain and fever, and in the prevention ...of thrombotic cardiovascular diseases. Its anti-inflammatory and cardio-protective actions have been well studied and occur through inhibition of cyclooxygenases (COX). Interestingly, a vast amount of epidemiological, preclinical and clinical studies have revealed aspirin as a promising chemopreventive agent, particularly against colorectal cancers (CRC); however, the primary mechanism by which it decreases the occurrences of CRC has still not been established. Numerous mechanisms have been proposed for aspirin's chemopreventive properties among which the inhibition of COX enzymes has been widely discussed. Despite the wide attention COX-inhibition has received as the most probable mechanism of cancer prevention by aspirin, it is clear that aspirin targets many other proteins and pathways, suggesting that these extra-COX targets may also be equally important in preventing CRC. In this review, we discuss the COX-dependent and -independent pathways described in literature for aspirin's anti-cancer effects and highlight the strengths and limitations of the proposed mechanisms. Additionally, we emphasize the potential role of the metabolites of aspirin and salicylic acid (generated in the gut through microbial biotransformation) in contributing to aspirin's chemopreventive actions. We suggest that the preferential chemopreventive effect of aspirin against CRC may be related to direct exposure of aspirin/salicylic acid or its metabolites to the colorectal tissues. Future investigations should shed light on the role of aspirin, its metabolites and the role of the gut microbiota in cancer prevention against CRC.
A survey of bambusicolous fungi in Bijiashan Mountain Park, Shenzhen, Guangdong Province, China, revealed several
-like taxa from dead sheaths, twigs, and clumps of
species. Phylogenetic ...relationships were investigated based on morphology and combined analyses of the internal transcribed spacer region (ITS), large subunit nuclear ribosomal DNA (LSU), beta tubulin (β-tubulin), and translation elongation factor 1-alpha (tef 1-α) gene sequences. Based on morphological characteristics and phylogenetic data,
sp. nov. and
sp. nov. are introduced herein with descriptions and illustrations. Additionally, two new locality records of
and
are described and illustrated.
To date there is virtually no information available concerning the fungi associated with
Tectona grandis
(teak) (
Lamiaceae
) in Thailand. In this study, samples of microfungi were collected from ...both asymptomatic stems and dead wood, and symptomatic branches, stem and leaves of
T. grandis
from 27 sites in six provinces (Chiang Mai, Chiang Rai, Phayao, Phitsanulok, Phrae and Uttaradit Provinces). Morphology and combined multi-gene phylogeny (CAL, GAPDH, ITS, LSU, RPB2, SSU, TEF1 and TUB) were used to identify taxa. A total of 270 collections, representing 28 fungal species residing in 12 families, 7 orders and 21 genera, with three species of uncertain taxonomic placement were identified. Of these, one family, three genera and 14 species are new to science. The new family,
Pseudocoleodictyosporaceae
is introduced based on its distinct lineage in the Dothideomycetes and its unique morphology as compared to
Roussoellaceae
and
Torulaceae
. The new genera are
Neooccultibambusa
,
Pseudocoleodictyospora
and
Subglobosporium
. The newly described species are
Diaporthe neoraonikayaporum
,
D. tectonendophytica
,
D. tectonae
,
D. tectonigena
,
Hermatomyces tectonae
,
H. thailandica
,
Manoharachariella tectonae
,
Neooccultibambusa chiangraiensis
,
Pseudocoleodictyospora sukhothaiensis
,
Ps. tectonae
,
Ps. thailandica
,
Rhytidhysteron tectonae
,
Subglobosporium tectonae
and
Tubeufia tectonae
. Fourteen species are known published taxa including
Alternaria tillandsiae
,
Berkleasmium talaumae
,
Boerlagiomyces macrospora
,
Ceratocladium purpureogriseum
,
Fusarium solani
,
Helicoma siamense
,
Lasiodiplodia theobromae
,
Macrovalsaria megalospora
,
Paradictyoarthrinium diffractum
,
Phaeoacremonium italicum
,
Sphaeropsis eucalypticola
,
Stachybotrys levispora
,
St. renispora
and
Thaxteriellopsis lignicola
. Epitypifications or reference specimens are designated for
Boerlagiomyces macrospora
and
Macrovalsaria megalospora. Macrovalsaria megalospora
is transferred from
Botryosphaeriaceae
to Dothideomycetes genus,
incertae sedis
based on taxonomy and phylogenetic analysis, which indicate it is distinct from
Botryosphaeriaceae
. All fungal species represent first reports on
T. grandis
in Thailand. New taxa and taxa
incertae sedis
, as well as known taxa which are established as reference specimens or epitypes, are presented with phylogenetic tree analyses, habitat, known distribution, material examined, full descriptions, notes and figures. Information is also provided for known taxa to add to the body of knowledge and to assist those wishing to study fungi occurring on
T. grandis
in future.
Despite decades of research to elucidate the cancer preventive mechanisms of aspirin and flavonoids, a consensus has not been reached on their specific modes of action. This inability to accurately ...pinpoint the mechanism involved is due to the failure to differentiate the primary targets from its associated downstream responses. This review is written in the context of the recent findings on the potential pathways involved in the prevention of colorectal cancers (CRC) by aspirin and flavonoids. Recent reports have demonstrated that the aspirin metabolites 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,5-dihydroxybenzoic acid (2,5-DHBA) and the flavonoid metabolites 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA) and 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) were effective in inhibiting cancer cell growth in vitro. Limited in vivo studies also provide evidence that some of these hydroxybenzoic acids (HBAs) inhibit tumor growth in animal models. This raises the possibility that a common pathway involving HBAs may be responsible for the observed cancer preventive actions of aspirin and flavonoids. Since substantial amounts of aspirin and flavonoids are left unabsorbed in the intestinal lumen upon oral consumption, they may be subjected to degradation by the host and bacterial enzymes, generating simpler phenolic acids contributing to the prevention of CRC. Interestingly, these HBAs are also abundantly present in fruits and vegetables. Therefore, we suggest that the HBAs produced through microbial degradation of aspirin and flavonoids or those consumed through the diet may be common mediators of CRC prevention.
Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin as a chemopreventive agent; however, the mechanisms leading to its anticancer effects are ...still being elucidated. We hypothesized that aspirin's chemopreventive actions may involve cell-cycle regulation through modulation of the levels or activity of cyclin A2/cyclin-dependent kinase-2 (CDK2). In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The downregulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. First, inclusion of salicylic acid in naïve cell lysates, or in recombinant CDK2 preparations, increased the ability of the anti-CDK2 antibody to immunoprecipitate CDK2, suggesting that salicylic acid may directly bind and alter its conformation. Second, in 8-anilino-1-naphthalene-sulfonate (ANS)-CDK2 fluorescence assays, preincubation of CDK2 with salicylic acid dose-dependently quenched the fluorescence due to ANS. Third, computational analysis using molecular docking studies identified Asp145 and Lys33 as the potential sites of salicylic acid interactions with CDK2. These results demonstrate that aspirin and salicylic acid downregulate cyclin A2/CDK2 proteins in multiple cancer cell lines, suggesting a novel target and mechanism of action in chemoprevention.
Biochemical and structural studies indicate that the antiproliferative actions of aspirin are mediated through cyclin A2/CDK2.
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