Supramolecular Chitosan Micro-Platelets Synergistically Enhance Anti-<Emphasis Type="BoldItalic">Candida albicans</Emphasis> Activity of Amphotericin B Using an Immunocompetent Murine Model

Purpose

The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity.

Methods

Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic^® F127 20 wt% hydrogel.

Results

The formulation completely cured C. albicans vaginal infection in mice and had a superior activity in comparison with AmB-DOC without addition of chitosan micro-platelets. In vitro studies showed that the platelets significantly enhance AmB-DOC antifungal activity since the IC₅₀ and the MIC₉₀ decrease 4.5 and 4.8-times. Calculation of fractional inhibitory concentration index (FICI?=?0.198) showed that chitosan micro-platelets act in a synergistic way with AmB-DOC against C. albicans. No synergy is found between spherical nanoparticles composed poly(isobutylcyanoacrylate)/chitosan and AmB-DOC.

Conclusion

These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment.

     

Association between statin drug use and peripheral blood leukocyte telomere length in the National Health and Nutrition Examination Survey 1999–2002: a cross-sectional study

Purpose

To evaluate the association between statin drug use and peripheral blood leukocyte telomere length in a U.S. nationally representative sample of adults.

Animal Reservoir Hosts and Fish-borne Zoonotic Trematode Infections on Fish Farms, Vietnam

Fish-borne zoonotic trematodes (FZT) pose a risk to human food safety and health and may cause substantial economic losses in the aquaculture industry. In Nghe An Province, Vietnam, low prevalence of FZT for fish farmers but high prevalence for fish indicate that reservoir hosts other than humans may play a role in sustaining transmission. To determine whether domestic animals may be reservoir hosts, we assessed prevalence and species composition of FZT infections in dogs, cats, and pigs in a fish-farming community in Vietnam. Feces from 35 cats, 80 dogs, and 114 pigs contained small trematode eggs at 48.6%, 35.0%, and 14.4%, respectively; 7 species of adult FZT were recovered from these hosts. These results, combined with data from previous investigations in this community, imply that domestic animals serve as reservoir hosts for FZT and therefore must be included in any control programs to prevent FZT infection in humans.     

Acetylcholinesterase activity as a biomarker of exposure to antibiotics and pesticides in the black tiger shrimp (Penaeus monodon)

This study aimed to assess the potentiality to use cholinesterase activity (ChE) in black tiger shrimp (Penaeus monodon) as a biomarker of exposure to 2 antibiotics (enrofloxacin, furazolidone) and 2 pesticides (endosulfan, deltamethrin), commonly used in Vietnamese farms. ChE from muscle and gills was first characterised using three different substrates and specific inhibitors. Results showed that both tissues possess only one ChE which displays the typical properties of an acetylcholinesterase (AChE). In a second part, shrimp (average weight of 8.8–10 g) were fed with medicated-feed containing 4 g enrofloxacin (quinolone) or furazolidone (nitrofuran)/kg for 7 days, or exposed to 3 actual concentrations of endosulfan (0, 0.009, 0.09, 0.9 μg/L) or deltamethrin (0, 0.0007, 0.007, 0.07 μg/L) for 4 days. After treatment, animals were decontaminated during 7 days. We observed that AChE activity in muscle was not significantly affected in shrimp fed with enrofloxacin or furazolidone, while it significantly decreased (up to 28%) in gills of shrimp fed with furazolidone. Following endosulfan and deltamethrin exposure, no significant changes in AChE activity were observed in gills. However, a significant decrease occurred in muscle after 4 days exposure (inhibition of 30% and 49% at 0.9 μg/L endosulfan and 0.07 μg/L deltamethrin, respectively). While muscle AChE activity should be assessed to point out endosulfan or deltamethrin exposure, gill AChE activity impairment could indicate an exposure to furazolidone. The present study underlines the benefits to use AChE as a biomarker of chemotherapeutics as part of an integrated aquaculture management to reach industry sustainability.     

Cytotoxic saponins from the root ofDipsacus asper wall

Cytotoxic activitiy of seven hederagenin saponins isolated from the root of Dipsacus asper were investigated in vitro against L1210, HL-60 and SK-OV-3 tumor cell lines by the MTT method. 3-O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl hederagenin (2), 3-O-beta-D-xylopyranosyl-(1-->3)-alpha-L-Rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl hederagenin (6) and 3-O-beta-D-glucopyranosyl-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl hederagenin (7) exhibited the potent cytotoxicity against the three tumor cell lines with IC50 values ranging from 4.7 to 8.7 microg/mL, with the exception of compound 7, which exhibited weak cytotoxic activity against SK-OV-3 (IC50 22.5 microg/mL). Other compounds did not exhibit any cytotoxic activity (IC50 > 30 microg/mL).     

Inhibitory effects of oleanane-type triterpenes and saponins from the stem bark of Kalopanax pictus on LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells

Kalopanax pictus (Araliaceae) is a deciduous tree distributed in Korea, Japan, and China. The stem bark of K. pictus has been functionally used as a traditional crude drug for the treatment of various inflammatory diseases. In the present study, we describe the inhibitory effects of oleanane-type triterpenes and saponins isolated from the stem bark of K. pictus on production of pro-inflammatory cytokines in LPS-stimulated bone marrow-derived dendritic cells. Of the compounds tested, 16,23,29-trihydroxy-3-oxo-olean-12-en-28-oic acid (1), 4,23,29-trihydroxy-3,4-seco-olean-12-en-3-oate-28-oic acid (2), 3β,6β,23-trihydroxyolean-12-en-28-oic acid 28-O-β-D-glucopyranoside (3), nipponogenin E (6), 3β,6β,23-trihydroxyolean-12-en-28-oic acid (7), and caulophyllogenin (19) significantly inhibited the production of IL-12 p40 and IL-6 with IC₅₀ values ranging from 3.3 to 9.1 μM. Compounds 2, 3, 7, and 19 significantly suppressed the secretion of TNF-α with IC₅₀ ranging from 8.8 to 20.0 μM. These data provide scientific support for the use of K. pictus stem bark and its triterpene and saponin components in the inhibition of pro-inflammatory cytokine secretion, including IL-12 p40, IL-6, and TNF-α, and for prevention and treatment of inflammatory diseases.     

Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics

Hypoxia-inducible factors (HIFs) are master regulators of angiogenesis and cellular adaptation in hypoxic microenvironments. Accumulating evidence indicates that HIFs also regulate cell survival, glucose metabolism, microenvironmental remodeling, cancer metastasis, and tumor progression, and thus, HIFs are viewed as therapeutic targets in many diseases. Epigenetic changes are involved in the switching ‘on’ and ‘off’ of many genes, and it has been suggested that the DNA hypermethylation of specific gene promoters, histone modifications (acetylation, phosphorylation, and methylation) and small interfering or micro RNAs be regarded epigenetic gene targets for the regulation of disease-associated cellular changes. Furthermore, the hypoxic microenvironment is one of the most important cellular stress stimuli in terms of the regulation of cellular epigenetic status via histone modification. Therefore, drug development and therapeutic approaches to ischemic diseases or cancer for targeting HIFs by modulation of epigenetic status become an attractive area. Here, the authors provide a review of the literature regarding the targeting of HIF, a key modulator of hypoxic-cell response under various disease conditions, by modulating histone or DNA using endogenous small RNAs or exogenous chemicals.     

Anticancer properties of pomolic acid-induced AMP-activated protein kinase activation in MCF7 human breast cancer cells

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in tumor cells, which requires high rates of protein synthesis and de novo fatty acid synthesis for their rapid growth. Pomolic acid (PA) has been previously described as being active in inhibiting the growth of cancer cells. In this study, we investigated PA activated AMPK, and this activity was related to proliferation and apoptosis in MCF7 breast cancer cells. PA inhibited cell proliferation and induced sub-G(1) arrest, elevating the mRNA levels of the apoptotic genes p53 and p21. PA activated caspase-3, -9, and poly(ADP-ribose) polymerase, and this effect was inhibited by z-VAD-fmk. AMPK activation was increased by treating cells with PA, inactivated by treating cells with a compound C, and co-treatment consisting of PA and aminoimidazole carboxamide ribonucleotide (AICAR) synergistically activated AMPK. These anti-cancer potentials of PA were accompanied by effects on de novo fatty acid synthesis as shown by the decreased expression of fatty acid synthase, and decreased acetyl-CoA carboxylase activation and incorporation of [(3)H]acetyl-CoA into fatty acids. In addition, PA inhibited key enzymes involved in protein synthesis such as mammalian target of rapamycin (mTOR), 70?kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These results suggest that PA exerts anti-cancer properties through the modulation of AMPK pathways and its value as an anti-cancer agent in breast cancer therapy.     

Phenolic glycosides with antioxidant activity from the stem bark of Populus davidiana

Phytochemical study on the EtOAc-soluble fraction of the stem bark of Populus davidiana resulted in the isolation of 10 phenolic glycosides (1-10), which were identified on the basis of physicochemical and spectroscopic analyses. Among these, three new compounds, populosides A-C (1-3), were determined to be 2-coumaroylmethyl-4-hydroxyphenyl-beta-D-glucopyranoside, 2-coumaroylmethylphenyl-beta-D-glucopyranoside, and 2-feruoylmethylphenyl-beta-D-glucopyranoside, respectively. Compounds 1-10 were tested for their radical scavenging activity against an azo radical, ABTS*+. Of these, populosides A-C (1-3), populoside (4), grandidentatin (8), salireposide (9), and coumaroyl-beta-D-glucoside (10) exhibited antioxidant activity in this assay.     

Antioxidant activities of coumarins from Korean medicinal plants and their structure–activity relationships

The aim of this work was to study the structure–activity relationships of the antioxidant activity of natural coumarins isolated from four Korean medicinal plants (1–17) and four purchased coumarins (18–21). The free radical scavenging and lipid peroxidation assays revealed that five phenolic coumarins, scopoletin (1), aesculetin (2), fraxetin (3), umbelliferone (18) and daphnetin (19), possessed considerable antioxidant activities. The coumarins having a catechol group, 2, 3 and 19, showed significant free radical scavenging activity and inhibitory effects on lipid peroxidation, indicating that the catechol group significantly contributed to the antioxidant activities of coumarins. In contrast, the sugar moiety markedly reduced the activities of coumarin glycosides. The results also demonstrate that the α‐pyrone ring of coumarins significantly enhanced the capacity of inhibiting oxidative reactions of coumarins. Copyright © 2009 John Wiley & Sons, Ltd.