Isolation and Identification of trans-2- and trans-3-Hydroxy-1,8-cineole Glucosides from Alpinia galanga

Three hydroxy-1,8-cineole glucopyranosides, (1R,2R,4S)- and (1S,2S,4R)-trans-2-hydroxy-1,8-cineole β-D-glucopyranosides, and (1R,3S,4S)-trans-3-hydroxy-1,8-cineole β-D-glucopyranoside, which are possible precursors of acetoxy-1,8-cineoles as unique aroma components, were isolated from the rhizomes of greater galangal (Alpinia galanga W.). Their structures were analyzed by FAB-MS and NMR spectrometry, and the absolute configulation of each aglycone was determined by using a GC-MS analysis with a capillary column coated with a chiral stationary phase. The composition of the diastereomers of (1R,2R,4S)- and (1S,2S,4R)- trans-2-hydroxy-1,8-cineole β-D-glucopyranosides in the rhizomes was determined as 3:7 by a GC-MS analysis after preparing the trifluoroacetate derivatives of the glucosides.     

Molecular basis of the Keap1–Nrf2 system

Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes, and Keap1 (Kelch-like ECH-associated protein 1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity. Keap1 also acts as a sensor for oxidative and electrophilic stresses. Keap1 retains multiple sensor cysteine residues that detect various stress stimuli. Increasing attention has been paid to the roles that Nrf2 plays in the protection of our bodies against drug toxicity and stress-induced diseases. On the other hand, Nrf2 is found to promote both oncogenesis and cancer cell resistance against chemotherapeutic drugs. Thus, although Nrf2 acts to protect our body from deleterious stresses, cancer cells hijack the Nrf2 activity to support their malignant growth. Nrf2 has emerged as a new therapeutic target, and both inducers and inhibitors of Nrf2 are awaited. Studies challenging the molecular basis of the Keap1–Nrf2 system functions are now critically important to improve translational studies of the system. Indeed, recent studies identified cross talk between Nrf2 and other signaling pathways, which provides new insights into the mechanisms by which the Keap1–Nrf2 system serves as a potent regulator of our health and disease.     

Tampering with cancer chemoresistance by targeting the TGM2-IL6-autophagy regulatory network

Macroautophagy/autophagy is a well-established process involved in maintaining cellular homeostasis, but its role in cancer is complex and even controversial. Many studies have reported a correlative relationship between increased autophagy and evolving cancer cells under stress conditions such as nutrient or oxygen deprivation; however, there has been a lack of a plausible mechanistic link to properly target the autophagy process in the context of this microenvironment. We recently unveiled a positive regulatory loop involving TGM2 (transglutaminase 2)-NFKB/NF-κB signaling, IL6 and autophagy in cancer using mantle cell lymphoma (MCL) as a model system. These pathways are functionally connected to each other, thereby promoting malignant B cell survival and leading to enhanced lymphoma progression both in mice and in patients. Disruption of this network could provide an opportunity to increase the efficacies of current therapies and to reduce MCL drug resistance.     

New pyranonaphthazarin and 2-naphthoic acid derivatives from the mangrove endophytic fungus Leptosphaerulina sp. SKS032

Two new compounds, named leptospyranonaphthazarin A (1) and leptosnaphthoic acid A (2), together with four known compounds (3–6) were isolated from an endophytic fungus Leptosphaerulina sp. SKS032. Their structures were assigned using spectroscopic methods, computational methods, and single-crystal X-ray diffraction analysis. In the antibiotic assay, compounds 1, 2, and 6 exhibited antibacterial activities against Staphylococcus aureus with minimal inhibitory concentration (MIC) values of 25.0, 50.0, and 50.0 μg/mL, respectively.     

A Survey Investigating the Infection of Fusarium langsethiae and Production of HT‐2 and T‐2 Mycotoxins in UK Oat Fields

Fusarium langsethiae is a toxigenic fungal species that has been reported in European small‐grain cereal crops such as oats, wheat and barley. Although its relative contribution to fusarium head blight (FHB) symptoms is not well understood, it is reported to contaminate these cereals with high levels of HT‐2 and T‐2 trichothecenes mycotoxins that are currently under consideration for legislation by the European Commission. Ten commercial oat fields in Shropshire and Staffordshire (two adjacent counties in the Midlands) in the UK were surveyed in the 2006/2007 growing season. Samples were taken from predetermined field locations at Zadoks growth stages 32/33, 69, 77‐85 and 90‐92 for F. langsethiae biomass and HT‐2 and T‐2 toxins quantification. The results from this study showed that oats can be heavily infected with F. langsethiae and have high concentrations of HT‐2 and T‐2 toxins with no apparent FHB symptoms. The regression of HT‐2 + T‐2 toxins on F. langsethiae DNA concentration was highly significant (P < 0.001, r² = 0.55). The results indicated that although F. langsethiae had no direct effect on crop yield, it may result in indirect economic losses where the grain can be rejected or downgraded as a result of intolerable levels of HT‐2 and T‐2 toxins, which are of human food and animal feed safety concern. The influence of cultural field practices on the infection and HT‐2 and T‐2 toxins accumulation in oats was not clear and warrants further studies to identify the sources of F. langsethiae inoculum and conditions favourable for infection and mycotoxin production.     

The Ca2+ channel β2 subunit is selectively targeted to the axon terminals of supraoptic neurons

The assembly of high voltage-activated Ca²⁺ channels with different β subunits influences channel properties and possibly subcellular targeting. We studied β subunit expression in the somata and axon terminals of the magnocellular neurosecretory cells, which are located in the supraoptic nucleus (SON) and neurohypophysis, respectively. Antibodies directed against the 4 Ca_Vβ subunits (Ca_Vβ₁-Ca_Vβ₄) were used for immunoblots and for immunostaining of slices of these two tissues. We found that all 4 β subunits are expressed in both locations, but that Ca_Vβ₂ had the highest relative expression in the neurohypophysis. These data suggest that the Ca_Vβ₂ subunit is selectively targeted to axon terminals and may play a role in targeting and/or regulating the properties of Ca²⁺ channels.     

UHRF2, a Ubiquitin E3 Ligase,Acts as a Small Ubiquitin-like Modifier E3 Ligase for Zinc Finger Protein 131

Small ubiquitin-like modifier (SUMO), a member of the ubiquitin-related protein family, is covalently conjugated to lysine residues of its substrates in a process referred to as SUMOylation. SUMOylation occurs through a series of enzymatic reactions analogous to that of the ubiquitination pathway, resulting in modification of the biochemical and functional properties of substrates. To date, four mammalian SUMO isoforms, a single heterodimeric SUMO-activating E1 enzyme SAE1/SAE2, a single SUMO-conjugating E2 enzyme ubiquitin-conjugating enzyme E2I (UBC9), and a few subgroups of SUMO E3 ligases have been identified. Several SUMO E3 ligases such as topoisomerase I binding, arginine/serine-rich (TOPORS), TNF receptor-associated factor 7 (TRAF7), and tripartite motif containing 27 (TRIM27) have dual functions as ubiquitin E3 ligases. Here, we demonstrate that the ubiquitin E3 ligase UHRF2 also acts as a SUMO E3 ligase. UHRF2 effectively enhances zinc finger protein 131 (ZNF131) SUMOylation but does not enhance ZNF131 ubiquitination. In addition, the SUMO E3 activity of UHRF2 on ZNF131 depends on the presence of SET and RING finger-associated and nuclear localization signal-containing region domains, whereas the critical ubiquitin E3 activity RING domain is dispensable. Our findings suggest that UHRF2 has independent functional domains and regulatory mechanisms for these two distinct enzymatic activities.     

Synthesis and anti-inflammatory activity of celecoxib like compounds

Nine novel 4-[3-(4-Dimethylamino-phenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamides (2a-i) were synthesized and evaluated for their anti-inflammatory and antiproliferative activities. These compounds (2a-i) showed moderate to strong anti-inflammatory activity in carrageenan rat paw oedema test. Compounds 2b, 2d and 2g showing comparable anti-inflammatory activity to that of reference drug celecoxib were evaluated for their ulcerogenic and analgesic activities. The effect of 2b, 2d and 2g on the content of NO, TNF-α and PGE₂ in exudates from rat paw stimulated by carrageenan was also evaluated. The compound 2c showed considerable antitumor activities against all 60 human tumor cell lines with effective GI₅₀ (MG-MID) value of 3.63 µM. It exhibited maximum activity against melanoma (LOX IMVI and SK-MEL-5) cancer cell lines with GI₅₀ value less than 2 μM.