Munumbicins E-4 and E-5: novel broad-spectrum antibiotics from Streptomyces NRRL 3052

Streptomyces NRRL 30562 was originally isolated as an endophyte from Kennedia nigriscans, snakevine, in the Northern Territory of Australia. This plant has been used for centuries by Aboriginal peoples to treat open bleeding wounds to prevent sepsis. A solvent extract of the crude fluid from cultures of this endophyte possesses wide-spectrum antibiotic activity. Some of the bioactivity is associated with the appearance of actinomycins X2, D, and Xobeta, the first two of which had been previously designated munumbicins A and B, respectively. Other novel compounds bearing wide-spectrum antibiotic activity are also produced by Streptomyces NRRL 30562, and these are designated munumbicins E-4 and E-5. Mass spectrometric analyses of these peptide antibiotics show that they have identical masses (1445.00) but different retention times on HPLC. Both compounds showed activity against gram-positive and gram-negative bacteria. The plant pathogenic fungus, Pythium ultimum is sensitive to both munumbicins at 5.0 microg mL(-1) The malarial parasite, Plasmodium falciparum has IC50 values of 0.50+/-0.08 and 0.87+/-0.0.26 microg mL(-1) for E-4 and E-5, respectively. It appears that other bioactive compounds, related to E-4 and E-5, are also produced making it the most biologically active endophytic Streptomyces spp. on record.     

Involvement of 9-O-Acetyl GD3 Ganglioside in Mycobacterium leprae Infection of Schwann Cells

Mycobacterium leprae (ML), the etiologic agent of leprosy, mainly affects the skin and peripheral nerves, leading to demyelization and loss of axonal conductance. Schwann cells (SCs) are the main cell population infected by ML in the nerves, and infection triggers changes in the SC phenotype from a myelinated to a nonmyelinated state. In the present study, we show that expression of 9-O-acetyl GD3, a ganglioside involved in cellular anti-apoptotic signaling and nerve regeneration, increases in SCs following infection with ML. Observation by confocal microscopy together with coimmunoprecipitation suggested that this ganglioside participates in ML attachment and internalization by SC. Immunoblockage of 9-O-acetyl GD3 in vitro significantly reduced adhesion of ML to SC surfaces. Finally, we show that activation of the MAPK (ERK 1/2) pathway and SC proliferation, two known effects of ML on SCs that result in demyelization, are significantly reduced when the 9-O-acetyl GD3 ganglioside is immunoblocked. Taken together, these data suggest the involvement of 9-O-acetyl GD3 in ML infection on SCs.     

Sarcoglycan subcomplex expression in normal human smooth muscle.

The sarcoglycan complex (SGC) is a multimember transmembrane complex interacting with other members of the dystrophin-glycoprotein complex (DGC) to provide a mechanosignaling connection from the cytoskeleton to the extracellular matrix. The SGC consists of four proteins (alpha, beta, gamma, and delta). A fifth sarcoglycan subunit, epsilon-sarcoglycan, shows a wider tissue distribution. Recently, a novel sarcoglycan, the zeta-sarcoglycan, has been identified. All reports about the structure of SGC showed a common assumption of a tetrameric arrangement of sarcoglycans. Addressing this issue, our immunofluorescence and molecular results showed, for the first time, that all sarcoglycans are always detectable in all observed samples. Therefore, one intriguing possibility is the existence of a pentameric or hexameric complex considering zeta-sarcoglycan of SGC, which could present a higher or lower expression of a single sarcoglycan in conformity with muscle type--skeletal, cardiac, or smooth--or also in conformity with the origin of smooth muscle.     

Cellular stress response,sirtuins and UCP proteins in Alzheimer disease: role of vitagenes

Alzheimer’s Disease (AD) is a neurodegenerative disorder affecting up to one third of individuals reaching the age of 80. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed Vitagenes. Vitagenes encode for cytoprotective heat shock proteins (Hsp), as well as thioredoxin, sirtuins and uncouple proteins (UCPs). In the present study we evaluate stress response mechanisms in plasma and lymphocytes of AD patients, as compared to controls, in order to provide evidence of an imbalance of oxidant/antioxidant mechanisms and oxidative damage in AD patients and the possible protective role of vitagenes.We found that the levels of Sirt-1 and Sirt-2 in AD lymphocytes were significantly higher than in control subjects. Interestingly, analysis of plasma showed in AD patients increased expression of Trx, a finding associated with reduced expression of UCP1, as compared to control group.This finding can open up new neuroprotective strategies, as molecules inducing this defense mechanisms can represent a therapeutic target to minimize the deleterious consequences associated to oxidative stress, such as in brain aging and neurodegenerative disorders.     

Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: A causative mutation?

Cerebral cavernous malformations (CCMs; OMIM 116860) are vascular anomalies mostly located in the central nervous system (CNS) and occasionally within the skin and retina.     

Bone marrow-derived fibroblast growth factor-2 induces glial cell proliferation in the regenerating peripheral nervous system

Backgound

Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants.

Results

Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of caz in Drosophila led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death.

Conclusions

These data demonstrate that the overexpression of Fus/Caz causes in vivo toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different.     

Emergent macrophytes act selectively on ammonia-oxidizing bacteria and archaea

Ammonia-oxidizing bacteria (AOB) and archaea (AOA) were quantified in the sediments and roots of dominant macrophytes in eight neutral to alkaline coastal wetlands. The AOA dominated in most samples, but the bacterial-to-archaeal amoA gene ratios increased with increasing ammonium levels and pH in the sediments. For all plant species, the ratios increased on the root surface relative to the adjacent bulk sediment. This suggests that root surfaces in these environments provide conditions favoring enrichment of AOB.