Fungistatic Intensity of Agricultural Soil Against Fungal Agents and Phylogenetic Analysis on the Actinobacteria Involved

A total of 287 agricultural soil samples collected from 26 provinces or autonomous regions of China were tested on their ability to suppress the conidial germination of nine biocontrol fungal agents. These soil samples showed great differences in the degree to inhibit the germination of conidia (22.8% < mean inhibition rate < 97.5%), but all exhibited fungistatic activities above the moderate levels (mean inhibition rate > 50%) to most of tested fungi. Ten soil samples that have stronger fungistatic intensity (germination inhibition rate > 68.3%) to the target fungi, Trichoderma viride and Paecilomyces lilacinus, were selected to evaluate their soil actinobacteria involved fungistasis in soil. Of the 1,000 isolates from those soil samples, 345 actinobacteria exhibited fungistatic activity to conidial germination of T. viride and P. lilacinus with germination inhibition rates higher than 10%. Sequences encoding 16S rRNA gene of the 345 actinobacteria were analyzed by ARDRA and resulted 44 different ARDRA types. Fifty-six isolates, at least one from each unique ARDRA type, were selected for 16S rDNA sequencing and phylogenetic analysis. Results indicated that the actinobacteria involved in the soil fungistasis had close phylogenetic relationship with the members of Sterptomycetaceae, Microbacteriaceae, Micrococcaceae, and Nocardiacea.     

Isoalantolactone protects against Staphylococcus aureus pneumonia

Staphylococcus aureus is a versatile pathogen that can cause life-threatening infections. The growing emergence of methicillin-resistant S.?aureus strains and a decrease in the discovery of new antibiotics warrant the search for new therapeutic targets to combat infections. Staphylococcus aureus produces many extracellular virulence factors that contribute to its pathogenicity. Therefore, targeting bacterial virulence as an alternative strategy to the development of new antimicrobials has gained great interest. α-Toxin is a 33.2-kDa, water-soluble, pore-forming toxin that is secreted by most S.?aureus strains. α-Toxin is essential for the pathogenesis of pneumonia, as strains lacking α-toxin display a profound defect in virulence. In this report, we demonstrate that isoalantolactone (IAL), a naturally occurring compound found in Inula helenium (Compositae), has no anti-S.?aureus activity as per MIC evaluation in vitro. However, IAL can markedly inhibit the expression of α-toxin in S.?aureus at very low concentrations. Furthermore, the in vivo data indicate that treatment with IAL protects mice from S.?aureus pneumonia.     

<Emphasis Type="Italic">BRAF</Emphasis> V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis

Epidemiologic studies have evaluated the association between BRAF mutations and resistance to the treatment of anti-EGFR monoclonal antibodies (MoAb) in patients with metastatic colorectal cancer (mCRC). However, the results are still inconclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. A total of 11 studies were included in the final meta-analysis. There were seven studies for unselected mCRC patients and four studies for patients with wild type KRAS mCRC. Among unselected mCRC patients, BRAF V600E mutation was detected in 48 of 546 primary tumors (8.8%). The objective response rate (ORR) of patients with mutant BRAF was 29.2% (14/48), whereas the ORR of patients with wild-type BRAF was 33.5% (158/472).The overall RR for ORR of mutant BRAF patients over wild-type BRAF patients was 0.86 (95% CI = 0.57–1.30; P = 0.48). For patients with KRAS wild-type mCRC, BRAF V600E mutation was detected in 40 of 376 primary tumors (10.6%). The ORR of patients with mutant BRAF was 0.0% (0/40), whereas the ORR of patients with wild-type BRAF was 36.3% (122/336). The pooled RR of mutant BRAF patients over wild-type BRAF patients was 0.14 (95% CI = 0.04–0.53; P = 0.004). In conclusion, this meta-analysis provides evidence that BRAF V600E mutation is associated with lack of response in wild-type KRAS mCRC treated with anti-EGFR MoAbs. BRAF mutation may be used as an additional biomarker for the selection of mCRC patients who might benefit from anti-EGFR MoAbs therapy.     

Protection by pyruvate against glutamate neurotoxicity is mediated by astrocytes through a glutathione-dependent mechanism

Pyruvate, an endogenous metabolite of glycolysis, is an anti-toxicity agent. Recent studies have suggested possible roles for pyruvate in protecting CNS neurons from excitotoxic and metabolic insults. Utilizing cultures derived from embryonic rat cortex, the studies presented in this paper indicate that an astroglia-mediated mechanism is involved in the neuroprotective effects of pyruvate against glutamate toxicity. Glutamate-induced toxicity could be reversed by pyruvate in a mixed culture of cortex cells. Importantly, in pure neuronal cultures from the same tissue, pyruvate failed to protect against glutamate toxicity. Addition of astroglia to the pure neuronal cultures restores the ability of pyruvate to protect neurons from glutamate-induced toxicity. Our results further suggest that pyruvate can induce glia to up-regulate the synthesis of glutathione (GSH), an antioxidant that protects cells from toxins such as free radicals. Taken together, our data suggest that astroglia in mixed cultures are essential for mediating the effects of pyruvate, revealing a novel mechanism by which pyruvate, an important intermediate of tricarboxylic acid cycle in the body, may act to protect neurons from damage during insults such as brain ischemia.     

Induction of cytotoxicity by photoexcitation of TiO<Subscript>2</Subscript> can prolong survival in glioma-bearing mice

We have investigated the possibility that photoexcited titanium dioxide (TiO₂) could inhibit the growth of malignant cells. We studied the anti-glioma effects of nano-TiO₂ excited with ultraviolet A (UVA) irradiation both in vitro and in vivo. Transmission electron microscopy demonstrated that glioma cells take up TiO₂ by phagocytosis, and vital staining revealed that TiO₂ alone has no effect on glioma cell proliferation. However, if TiO₂ was combined with UVA irradiation the proliferation rate was decreased significantly compared to controls (P < 0.05). RT–PCR suggested that TiO₂ induction of glioma cell apoptosis is associated with changes in the expression of genes encoding Bcl-2 family members. We then investigated the in vivo antitumor effects of combined TiO₂ plus UVA treatment of established glioma tumors. TiO₂ plus UVA led to pronounced areas of necrosis, elevated indices of apoptosis, delayed tumor growth, and increased survival compared with the TiO₂-alone control group (P < 0.001). Log-rank survival analysis showed that median survival duration was prolonged (P < 0.001). These findings suggest that nano-TiO₂ based photodynamic therapy has potential in the treatment of glioma.     

Inflammatory stress exacerbates lipid-mediated renal injury in ApoE/CD36/SRA triple knockout mice

Both lipids and inflammation play important roles in the progression of kidney disease. This study was designed to investigate whether inflammation exacerbates lipid accumulation via LDL receptors (LDLr), thereby causing renal injury in C57BL/6J mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE/CD36/scavenger receptor A triple KO mice. The mice were given a subcutaneous casein injection to induce inflammatory stress. After 14 wk, terminal blood samples were taken for renal function, lipid profiles, amyloid A (SAA), and IL-6 assays. Lipid accumulation in kidneys was visualized by oil red O staining. Fibrogenic molecule expression in kidneys was examined. There was a significant increase in serum SAA and IL-6 in the all casein-injected mice compared with respective controls. Casein injection reduced serum total cholesterol, LDL cholesterol, and HDL cholesterol and caused lipid accumulation in kidneys from three types of mice. The expression of LDLr and its regulatory proteins sterol-responsive element-binding protein (SREBP) 2 and SREBP cleavage-activating protein (SCAP) were upregulated in inflamed mice compared with controls. Casein injection induced renal fibrosis accompanied by increased expression of fibrogenic molecules in the triple KO mice. These data imply that inflammation exacerbates lipid accumulation in the kidney by diverting lipid from the plasma to the kidney via the SCAP-SREBP2-LDLr pathway and causing renal injury. Low blood cholesterol levels, resulting from inflammation, may be associated with high risk for chronic renal fibrosis.     

Scutellarin Blocks Sodium Current in Freshly Isolated Mouse Hippocampal CA1 Neurons

Scutellarin (Scu), the main bioactive component of Erilgeron breviscapus, protects the brain against ischemic damages. To explore the therapeutic mechanism of Scu, we investigated the impact of Scu on sodium current (I _Na) of freshly isolated mouse hippocampal CA1 neurons using the whole-cell patch clamp technique. Results showed that Scu inhibited I _Na in concentration- and holding potential-dependent manners. At 50 μM, Scu markedly shifted the steady state inactivation curve of I _Na towards a more negative potential, slowed down the recovery of I _Na from inactivation state, and elicited a frequency-dependent block of I _Na. The shape of the current–voltage (I–V) curve and the steady state activation curve of I _Na were unaffected by Scu treatment. These findings suggest that Scu is capable of inhibiting I _Na in neurons through predominantly affecting the inactivated state of I _Na. Inhibition of Na⁺ channels provides a novel pharmacological basis for the anti-ischemic application of Scu.     

Role of somatostatin receptor 1 and 5 on epidermal growth factor receptor mediated signaling

Epidermal growth factor (EGF) regulates normal and tumor cell proliferation via epidermal growth factor receptor (EGFR) phosphorylation, homo- or heterodimerization and activation of mitogen-activated protein kinases (MAPKs) and PI3K/AKT cell survival pathways. In contrast, SST via activation of five different receptor subtypes inhibits cell proliferation and has been potential target in tumor treatment. To gain further insight for the effect of SSTRs on EGFR activated signaling, we determine the role of SSTR1 and SSTR1/5 in human embryonic kidney (HEK) 293 cells. We here demonstrate that cells transfected with SSTR1 or SSTR1/5 negatively regulates EGF mediated effects attributed to the inhibition of EGFR phosphorylation, MAPKs as well as the cell survival signaling. Furthermore, SSTR effects were significantly enhanced in cells when EGFR was knock down using siRNA or treated with selective antagonist (AG1478). Most importantly, the presence of SSTR in addition to modulating signaling pathways leads to the dissociation of the constitutive and EGF induced heteromeric complex of EGFR/ErbB2. Furthermore, cells cotransfected with SSTR1/5 display pronounced effect of SST on the signaling and dissociation of the EGFR/ErbB2 heteromeric complex than the cells expressing SSTR1 alone. Taken together this study provides the first evidence that the presence of SSTR controls EGF mediated cell survival pathway via dissociation of ErbB heteromeric complex. We propose that the activation of SSTR and blockade of EGFR might serve novel therapeutic approach in inhibition of tumor proliferation.