Overexpression of Human Syndecan-1 Protects against the Diethylnitrosamine-Induced Hepatocarcinogenesis in Mice

Although syndecan-1 (SDC1) is known to be dysregulated in various cancer types, its implication in tumorigenesis is poorly understood. Its effect may be detrimental or protective depending on the type of cancer. Our previous data suggest that SDC1 is protective against hepatocarcinogenesis. To further verify this notion, human SDC1 transgenic (hSDC1+/+) mice were generated that expressed hSDC1 specifically in the liver under the control of the albumin promoter. Hepatocarcinogenesis was induced by a single dose of diethylnitrosamine (DEN) at an age of 15 days after birth, which resulted in tumors without cirrhosis in wild-type and hSDC1+/+ mice. At the experimental endpoint, livers were examined macroscopically and histologically, as well as by immunohistochemistry, Western blot, receptor tyrosine kinase array, phosphoprotein array, and proteomic analysis. Liver-specific overexpression of hSDC1 resulted in an approximately six month delay in tumor formation via the promotion of SDC1 shedding, downregulation of lipid metabolism, inhibition of the mTOR and the β-catenin pathways, and activation of the Foxo1 and p53 transcription factors that lead to the upregulation of the cell cycle inhibitors p21 and p27. Furthermore, both of them are implicated in the regulation of intermediary metabolism. Proteomic analysis showed enhanced lipid metabolism, activation of motor proteins, and loss of mitochondrial electron transport proteins as promoters of cancer in wild-type tumors, inhibited in the hSDC1+/+ livers. These complex mechanisms mimic the characteristics of nonalcoholic steatohepatitis (NASH) induced human liver cancer successfully delayed by syndecan-1.

Strain specific differences in muscle Ca2+ transport and mitochondrial electron transport proteins between FVB/N and C57BL/6J mice

Genetically engineered mouse models have been used to determine the role of sarcolipin (SLN) in muscle. However, few studies had difficulty in detecting SLN in FBV/N mice and questioned its relevance to muscle metabolism. It is known that genetic alteration of proteins in different inbred mice strains produce dissimilar functional outcome. Therefore, here we compared the expression of SLN and key proteins involved in Ca2+-handling and mitochondrial metabolism between FVB/N and C57BL/6J mouse strains. Data suggests that, SLN expression is less abundant in the skeletal muscles of FVB/N mice compared to C57BL/6J strain. The expression of Ca2+-transporters in the mitochondrial membranes, were also lower in FVB/N compared to C57BL/6J. Similarly the electron transport proteins in the mitochondria were less abundant in FVB/N mice which may contribute to differences in energy metabolism. Future studies using different mouse strains should take these differences into account while interpreting their data.

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

Potentially neurotoxic systems involved in traumatic and degenerative diseases of the brain were assessed in acute psychosis. Astrocyte-derived exosomes (ADEs) and neuron-derived exosomes (NDEs) were immunoprecipitated from plasma of ten untreated first-episode psychotics (FPs) and ten matched normal controls (Cs). Neural mitochondrial electron transport and complement proteins were extracted, quantified by ELISAs and normalized with levels of CD81 exosome marker. Levels of subunits 1 and 6 of NADH-ubiquinone oxidoreductase (complex I) and subunit 10 of cytochrome b-c1 oxidase (complex III), but not of subunit 1 of cytochrome C oxidase (complex IV) or superoxide dismutase 1 (SOD1) were significantly lower in ADEs and NDEs of FPs than Cs. This dysregulated pattern of electron transport proteins is associated with increased generation of reactive oxygen species. ADE glial fibrillary acidic protein levels were significantly higher in FPs than Cs, indicating a higher percentage of inflammatory astrocytes in FPs. ADE levels of C3b opsonin were significantly higher and those of C5b-9 attack complex was marginally higher in FPs than Cs. A significantly lower ADE level of the C3 convertase inhibitor CD55 may explain the higher levels of C3 convertase-generated C3b. ADE levels of the neuroprotective protein leukemia inhibitory factor (LIF) were significantly lower in FPs than Cs, whereas levels of IL-6 were no different. Plasma neural exosome levels of electron transport and complement proteins may be useful in predicting FP and guiding therapy. SOD mimetics, C3 convertase inhibitors and LIF receptor agonists also may have therapeutic benefits in FP.

Skin Bacteria Mediate Glycerol Fermentation to Produce Electricity and Resist UV-B

Bacteria that use electron transport proteins in the membrane to produce electricity in the gut microbiome have been identified recently. However, the identification of electrogenic bacteria in the skin microbiome is almost completely unexplored. Using a ferric iron-based ferrozine assay, we have identified the skin Staphylococcus epidermidis (S. epidermidis) as an electrogenic bacterial strain. Glycerol fermentation was essential for the electricity production of S. epidermidis since the inhibition of fermentation by 5-methyl furfural (5-MF) significantly diminished the bacterial electricity measured by voltage changes in a microbial fuel cell (MFC). A small-scale chamber with both anode and cathode was fabricated in order to study the effect of ultraviolet-B (UV-B) on electricity production and bacterial resistance to UV-B. Although UV-B lowered bacterial electricity, a prolonged incubation of S. epidermidis in the presence of glycerol promoted fermentation and elicited higher electricity to suppress the effect of UV-B. Furthermore, the addition of glycerol into S. epidermidis enhanced bacterial resistance to UV-B. Electricity produced by human skin commensal bacteria may be used as a dynamic biomarker to reflect the UV radiation in real-time.

Unravelling lactate-acetate conversion to butyrate by intestinal Anaerobutyricum and Anaerostipes species

SummaryThe D-and L-forms of lactate are important fermentation metabolites produced by intestinal bacteria but have been found to negatively affect mucosal barrier function and human health. Of interest, both enantiomers of lactate can be converted with acetate into the presumed beneficial butyrate by a phylogenetically related group of anaerobes, including Anaerobutyricum and Anaerostipes spp. This is a low energy yielding process with a partially unknown pathway in Anaerobutyricum and Anaerostipes spp. and hence, we sought to address this via a comparative genomics, proteomics and physiology approach. We focused on Anaerobutyricum soehngenii and compared its growth on lactate with that on sucrose and sorbitol. Comparative proteomics revealed a unique active gene cluster that was abundantly expressed when grown on lactate. This active gene cluster, lctABCDEF, encodes a lactate dehydrogenase (lctD), electron transport proteins A and B (lctCB), along with a nickel-dependent racemase (lctE) and a lactate permease (lctF). Extensive search of available genomes of intestinal bacteria revealed this gene cluster to be highly conserved in only Anaerobutyricum and Anaerostipes spp. The present study demonstrates that A. soehngenii and several related Anaerobutyricum and Anaerostipes spp. are highly adapted for a lifestyle involving lactate plus acetate utilization in the human intestinal tract.

Role of the Nitric Oxide (NO) in the Regulation of Steroidogenesis in Placenta During Physiological Pregnancy and Preeclampsia (Experimental Study)

The aim of the study was to establish the role of nitric oxide (NO) in the regulation of steroidogenesis in the placenta during physiological pregnancy and experimental preeclampsia (PE) in rats. EPR centers of the placenta, free NO and its metabolites were determined by the Electron Paramagnetic Resonance (EPR) method. At the last stage of pregnancy in the EPR spectra of the rats’ placenta with PE alterations of the signals intensity of mitochondrial steroidogenic electron transport proteins were detected: the FeS-centers of adrenodoxin decreased, the ferricytochrome P-450 increased, the free NO content decreased, and the complexes of NO with heme (HbNO) and non-heme iron (FeSNO) were detected. These data indicate the violation of placental steroidogenesis, which is confirmed by a decrease in the level of progesterone in blood. Therefore, the nitrosylation of mitochondrial proteins is an important redox-dependent mechanism of regulation of the intensity of steroidogenesis.

CoQ10 and Aging

The aging process includes impairment in mitochondrial function, a reduction in anti-oxidant activity, and an increase in oxidative stress, marked by an increase in reactive oxygen species (ROS) production. Oxidative damage to macromolecules including DNA and electron transport proteins likely increases ROS production resulting in further damage. This oxidative theory of cell aging is supported by the fact that diseases associated with the aging process are marked by increased oxidative stress. Coenzyme Q10 (CoQ10) levels fall with aging in the human but this is not seen in all species or all tissues. It is unknown whether lower CoQ10 levels have a part to play in aging and disease or whether it is an inconsequential cellular response to aging. Despite the current lay public interest in supplementing with CoQ10, there is currently not enough evidence to recommend CoQ10 supplementation as an anti-aging anti-oxidant therapy.