Defensins: The Case for Their Use against Mycobacterial Infections

Human tuberculosis remains a huge global public health problem with an estimated 1/3rd of the population being infected. Defensins are antibacterial cationic peptides produced by a number of cell types, most notably neutrophil granulocytes and epithelial cells. All three defensin types (α-, β-, and θ-defensins) have antibacterial activities, mainly through bacterial membrane permeabilization. Defensins are effective against Gram-negative and Gram-positive bacteria including mycobacteria and are active both intra- and extracellularly. Mycobacterial resistance has never been demonstrated although the mprF gene encoding resistance in Staphylococcus aureus is present in the Mycobacterium tuberculosis genome. In addition to their antibacterial effect, defensins are chemoattractants for macrophages and neutrophils. There are many cases for their use for therapy or prophylaxis in tuberculosis as well. In conclusion, we propose that there is considerable scope and potential for exploring their use as therapeutic/prophylactic agents and more comprehensive survey of defensins from different species and their bioactivity is timely

CNN-based ranking for biomedical entity normalization

Abstract Background Most state-of-the-art biomedical entity normalization systems, such as rule-based systems, merely rely on morphological information of entity mentions, but rarely consider their semantic information. In this paper, we introduce a novel convolutional neural network (CNN) architecture that regards biomedical entity normalization as a ranking problem and benefits from semantic information of biomedical entities. Results The CNN-based ranking method first generates candidates using handcrafted rules, and then ranks the candidates according to their semantic information modeled by CNN as well as their morphological information. Experiments on two benchmark datasets for biomedical entity normalization show that our proposed CNN-based ranking method outperforms traditional rule-based method with state-of-the-art performance. Conclusions We propose a CNN architecture that regards biomedical entity normalization as a ranking problem. Comparison results show that semantic information is beneficial to biomedical entity normalization and can be well combined with morphological information in our CNN architecture for further improvement

Downregulation of the Repressor Element 1-Silencing Transcription Factor (REST) Is Associated with Akt-mTOR and Wnt-β-Catenin Signaling in Prion Diseases Models

Prion diseases are a group of infectious diseases characterized by multiple neuropathological changes, yet the mechanisms that preserve function and protect against prion-associated neurodegeneration are still unclear. We previously reported that the repressor element 1-silencing transcription factor (REST) alleviates neurotoxic prion peptide (PrP106-126)-induced toxicity in primary neurons. Here we confirmed the findings of the in vitro model in 263K infected hamsters, an in vivo model of prion diseases and further showed the relationships between REST and related signaling pathways. REST was depleted from the nucleus in prion infected brains and taken up by autophagosomes in the cytoplasm, co-localizing with LC3-II. Importantly, downregulation of the Akt–mTOR and at least partially inactivation of LRP6-Wnt-β-catenin signaling pathways correlated with the decreased levels of REST in vivo in the brain of 263K-infected hamsters and in vitro in PrP106-126-treated primary neurons. Overexpression of REST in primary cortical neurons alleviated PrP106-126 peptide-induced neuronal oxidative stress, mitochondrial damage and partly inhibition of the LRP6-Wnt-β-catenin and Akt–mTOR signaling. Based on our findings, a model of REST-mediated neuroprotection in prion infected animals is proposed, with Akt–mTOR and Wnt-β-catenin signaling as the key pathways. REST-mediated neuronal survival signaling could be explored as a viable therapeutic target for prion diseases and related neurodegenerative diseases

Expression of cytokines from cells infected with different bacterial isolates.

<p>RAW264.7 were infected with different bacterial isolates for 10 MOI and the cell culture supernatants were collected at 6h, 12h, 24h post-infection. Cytokines shown are IFN-β (A), IFN-γ (B) and TNF-α(C). Interleukins related to the Th1, Th2 and Th17 immune pathways such as IL-1β (D), IL-10 (E), IL-12 (F) and IL-17 (G) were analyzed. Results from each group was averaged with the individual results from three experiments and shown as mean±SD. Statistical analysis was performed using one-way ANOVA. ***P<0.0001 were considered significantly different.</p

Representative anatomic morphology of the lungs from mice infected with different strains of <i>Mycobacterium</i>.

<p>The lungs were aseptically removed from the mice either at the end of the clinical observation (80 dpi) or at 18 dpi before death. Pictures of the lungs of mice infected with strains MBO (panel A to D), MTB (panel E to H) and MAV (panel I to L) are shown individually. M shows the lungs of the mice inoculated with PBS. The dosages of inoculums are indicated above.</p

PP2Ac Modulates AMPK-Mediated Induction of Autophagy in Mycobacterium bovis-Infected Macrophages

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis in cattle population across the world. Human beings are at equal risk of developing tuberculosis beside a wide range of M. bovis infections in animal species. Autophagic sequestration and degradation of intracellular pathogens is a major innate immune defense mechanism adopted by host cells for the control of intracellular infections. It has been reported previously that the catalytic subunit of protein phosphatase 2A (PP2Ac) is crucial for regulating AMP-activated protein kinase (AMPK)-mediated autophagic signaling pathways, yet its role in tuberculosis is still unclear. Here, we demonstrated that M. bovis infection increased PP2Ac expression in murine macrophages, while nilotinib a tyrosine kinase inhibitor (TKI) significantly suppressed PP2Ac expression. In addition, we observed that TKI-induced AMPK activation was dependent on PP2Ac regulation, indicating the contributory role of PP2Ac towards autophagy induction. Furthermore, we found that the activation of AMPK signaling is vital for the regulating autophagy during M. bovis infection. Finally, the transient inhibition of PP2Ac expression enhanced the inhibitory effect of TKI-nilotinib on intracellular survival and multiplication of M. bovis in macrophages by regulating the host&rsquo;s immune responses. Based on these observations, we suggest that PP2Ac should be exploited as a promising molecular target to intervene in host&ndash;pathogen interactions for the development of new therapeutic strategies towards the control of M. bovis infections in humans and animals