Secretases Related to Amyloid Precursor Protein Processing

Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce β-amyloid protein (Aβ), are a major pathological feature of AD. In recent years, a large number of studies have been conducted on the APP processing pathways and the role of secretion. This paper provides a summary of the involvement of secretases in the processing of APP and the potential drug targets that could provide new directions for AD therapy.

Proteomics

Proteomics is a branch of molecular biology that deals with the identification and quantification of proteins in living objects, as well as the analysis of protein functions and their interactions. Proteomics is studied by proteins that are expressed in a given cell, tissue or organism over a period of time (under certain conditions). It is known that information about the primary structure of a protein (the sequence of amino acid residues in a protein) is contained in a structural gene in the form of a codon sequence (genetic code). On the other hand, less than 10% of genes are functionally active (expressed) in the somatic cells of our body. Moreover, a distinct tissue-specific expression of genes is observed. This, in turn, leads to the peculiarities of the qualitative composition of the synthesized proteins in various tissues. No less important is the fact that the total amount of proteins synthesized by our tissues is much greater than the total number of structural genes containing information about their original structure. This phenomenon is explained by the activity of such mechanisms as alternative splicing and a wide variety of post-translational peptide processing pathways (covalent modification of a polypeptide synthesized on the ribosome) in health and disease. Thus, even a brief review of the semantic content of the term "proteomics" indicates an extremely complex system of protein molecules in our body, which plays a fundamental role in maintaining homeostasis and is involved in the formation of adaptive responses in response to adverse changes in the internal and external environment.

Manganese Stress Adaptation Mechanisms of Bacillus safensis Strain ST7 From Mine Soil

The mechanism of bacterial adaption to manganese-polluted environments was explored using 50 manganese-tolerant strains of bacteria isolated from soil of the largest manganese mine in China. Efficiency of manganese removal by the isolated strains was investigated using atomic absorption spectrophotometry. Bacillus safensis strain ST7 was the most effective manganese-oxidizing bacteria among the tested isolates, achieving up to 82% removal at a Mn(II) concentration of 2,200 mg/L. Bacteria-mediated manganese oxide precipitates and high motility were observed, and the growth of strain ST7 was inhibited while its biofilm formation was promoted by the presence of Mn(II). In addition, strain ST7 could grow in the presence of high concentrations of Al(III), Cr(VI), and Fe(III). Genome-wide analysis of the gene expression profile of strain ST7 using the RNA-seq method revealed that 2,580 genes were differently expressed under Mn(II) exposure, and there were more downregulated genes (n = 2,021) than upregulated genes (n = 559) induced by Mn stress. KAAS analysis indicated that these differently expressed genes were mainly enriched in material metabolisms, cellular processes, organism systems, and genetic and environmental information processing pathways. A total of twenty-six genes from the transcriptome of strain ST7 were involved in lignocellulosic degradation. Furthermore, after 15 genes were knocked out by homologous recombination technology, it was observed that the transporters, multicopper oxidase, and proteins involved in sporulation and flagellogenesis contributed to the removal of Mn(II) in strain ST7. In summary, B. safensis ST7 adapted to Mn exposure by changing its metabolism, upregulating cation transporters, inhibiting sporulation and flagellogenesis, and activating an alternative stress-related sigB pathway. This bacterial strain could potentially be used to restore soil polluted by multiple heavy metals and is a candidate to support the consolidated bioprocessing community.

The birth of piRNAs: how mammalian piRNAs are produced, originated, and evolved

PIWI-interacting RNAs (piRNAs), small noncoding RNAs 24–35 nucleotides long, are essential for animal fertility. They play critical roles in a range of functions, including transposable element suppression, gene expression regulation, imprinting, and viral defense. In mammals, piRNAs are the most abundant small RNAs in adult testes and the only small RNAs that direct epigenetic modification of chromatin in the nucleus. The production of piRNAs is a complex process from transcription to post-transcription, requiring unique machinery often distinct from the biogenesis of other RNAs. In mice, piRNA biogenesis occurs in specialized subcellular locations, involves dynamic developmental regulation, and displays sexual dimorphism. Furthermore, the genomic loci and sequences of piRNAs evolve much more rapidly than most of the genomic regions. Understanding piRNA biogenesis should reveal novel RNA regulations recognizing and processing piRNA precursors and the forces driving the gain and loss of piRNAs during animal evolution. Such findings may provide the basis for the development of engineered piRNAs capable of modulating epigenetic regulation, thereby offering possible single-dose RNA therapy without changing the genomic DNA. In this review, we focus on the biogenesis of piRNAs in mammalian adult testes that are derived from long non-coding RNAs. Although piRNA biogenesis is believed to be evolutionarily conserved from fruit flies to humans, recent studies argue for the existence of diverse, mammalian-specific RNA-processing pathways that convert precursor RNAs into piRNAs, perhaps associated with the unique features of mammalian piRNAs or germ cell development. We end with the discussion of major questions in the field, including substrate recognition and the birth of new piRNAs.

A comparative analysis of differentially expressed mRNAs, miRNAs and circRNAs provides insights into the key genes involved in the high-altitude adaptation of yaks

Background Yaks that inhabit the Tibetan Plateau exhibit striking phenotypic and physiological differences from cattle and have adapted well to the extreme conditions on the plateau. However, the mechanisms used by these animals for the regulation of gene expression at high altitude are not fully understood. Results Here, we sequenced nine lung transcriptomes of yaks at altitudes of 3400, 4200 and 5000 m, and low-altitude Zaosheng cattle, which is a closely related species, served as controls. The analysis identified 21,764 mRNAs, 1377 circRNAs and 1209 miRNAs. By comparing yaks and cattle, 4975 mRNAs, 252 circRNAs and 75 miRNAs were identified differentially expressed. By comparing yaks at different altitudes, we identified 756 mRNAs, 64 circRNAs and 83 miRNAs that were differentially expressed (fold change ≥2 and P-value < 0.05). The pathways enriched in the mRNAs, circRNAs and miRNAs identified from the comparison of yaks and cattle were mainly associated with metabolism, including ‘glycosaminoglycan degradation’, ‘pentose and glucuronate interconversions’ and ‘flavone and flavonol biosynthesis’, and the mRNAs, circRNAs and miRNAs identified from the comparison of yaks at different altitude gradients were significantly enriched in metabolic pathways and immune and genetic information processing pathways. The core RNAs were identified from the mRNA-miRNA-circRNA networks constructed using the predominant differentially expressed RNAs. The core genes specific to the difference between yaks and cattle were associated with the endoplasmic reticulum and fat deposition, but those identified from the comparison among yaks at different altitude gradients were associated with maintenance of the normal biological functions of cells. Conclusions This study enhances our understanding of the molecular mechanisms involved in hypoxic adaptation in yaks and might contribute to improvements in the understanding and prevention of hypoxia-related diseases.

Monoclonal Antibodies for Chronic Pain Treatment: Present and Future

Chronic pain remains a major problem worldwide, despite the availability of various non-pharmacological and pharmacological treatment options. Therefore, new analgesics with novel mechanisms of action are needed. Monoclonal antibodies (mAbs) are directed against specific, targeted molecules involved in pain signaling and processing pathways that look to be very effective and promising as a novel therapy in pain management. Thus, there are mAbs against tumor necrosis factor (TNF), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), or interleukin-6 (IL-6), among others, which are already recommended in the treatment of chronic pain conditions such as osteoarthritis, chronic lower back pain, migraine, or rheumatoid arthritis that are under preclinical research. This narrative review summarizes the preclinical and clinical evidence supporting the use of these agents in the treatment of chronic pain.

Cognitive and Central Vestibular Functions Correlate in People With Multiple Sclerosis

Background. Cognitive impairment is common, but poorly managed in people with multiple sclerosis (MS). Balance has been correlated with cognition in people with MS, potentially through shared utilization of central sensory integration pathways. Objective. This study characterized the relationship between central vestibular integration and cognition in people with MS through measurement of several clinical vestibular functions requiring central sensory integration and multiple cognitive domains. Methods. Forty people with MS and 20 controls completed a battery of vestibular and cognitive examinations targeting different central vestibular integration measures and different domains of cognition, respectively. Performance on these measures was compared between people with MS and controls, and then correlational analyses were undertaken between the vestibular and cognitive measures in the MS sample. Results. People with MS performed worse than controls on all vestibular and cognitive measures. There were consistent correlations between vestibular and cognitive measures in the MS sample. Factor analysis of vestibular functions yielded a single factor hypothesized to represent central vestibular integration that demonstrated a significant relationship with a composite cognitive measure in people with MS. Discussion. Our results suggest that vestibular and cognitive dysfunction may both arise from central sensory processing pathways in people with MS. This connection could be targeted through vestibular rehabilitation techniques that improve central sensory processing and both balance and cognition in people with MS.

The Antagonism of the Prokineticin System Counteracts Bortezomib Induced Side Effects: Focus on Mood Alterations

The development of neuropathy and of mood alterations is frequent after chemotherapy. These complications, independent from the antitumoral mechanism, are interconnected due to an overlapping in their processing pathways and a common neuroinflammatory condition. This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation. We also verify if the therapeutic treatment with the antagonist of the prokineticin (PK) system PC1, which is known to contrast pain and neuroinflammation, can prevent mood alterations. Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety (dark light and marble burying test), depression (sucrose preference and swimming test) and supraspinal neuroinflammation were checked at the end of the protocol. BTZ treated neuropathic mice develop anxiety and depression. The presence of mood alterations is related to the presence of neuroinflammation and PK system activation in prefrontal cortex, hippocampus and hypothalamus with high levels of PK2 and PKR2 receptor, IL-6 and TNF-α, TLR4 and an upregulation of glial markers. PC1 treatment, counteracting pain, prevented the development of supraspinal inflammation and depression-like behavior in BTZ mice.

Unilaterally Disrupted Structural and Functional Connectivity of The Fronto-Iimbic System In Idiopathic Hypogonadotropic Hypogonadism

Background: Idiopathic hypogonadotropic hypogonadism (IHH) is rare and can either be associated with normal or defective olfactory sensation, classified as normosmic IHH (nIHH) or Kallmann’s syndrome (KS), respectively. We do not yet understand the central processing pathways in the olfactory system, especially regarding these disorders. We aimed to compare the resting-state structural and functional connectivity (FC) of olfactory neural pathways in patients with nIHH and KS.Methods: A total of 50 males were studied: 13 nIHH patients, 12 KS patients, and 25 healthy controls (HCs). All subjects underwent diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) scans. Structural and functional connectivity data analyses were then performed.Results: The results indicated that fractional anisotropy (FA) was significantly decreased in the right uncinate fasciculus (UF) in the KS group. The olfactory cortex FC values of the right gyrus rectus and orbitofrontal cortex (OFC) in the KS group were decreased compared with those in the HC group and increased compared with those in the nIHH group (nIHH< KS <HC). Moreover, there were significant negative correlations between right UF FA and olfactory cortex FC to both the gyrus rectus and OFC within the nIHH and HC groups.Conclusion: We have reported significant structural and functional disruptions unilaterally at the right junction of the fronto-limbic system in KS patients. The results may indicate that a specific structural-functional asymmetry exists in the olfactory cortex pathways in KS patients.

Edible insect processing pathways and implementation of emerging technologies

The processing of insects is paramount to deliver safe and high quality raw materials, ingredients and products for large-scale food and feed applications. Depending upon the nature of the initial material and the desired end product, the processing pathways vary and may include several unit operations currently already used in food and feed processing. Insect processing pathways can involve harvesting, pre-processing, decontamination, further processing, packaging and storage. Several traditional and industrial decontamination methods have been proposed for edible insects, which include smoking, drying, blanching/boiling, marination, cooking, steaming, toasting and their combinations. Further processing steps are employed to produce insect meal, insect flour or extracted insect fractions. Each operation will have a different impact on the chemical and microbiological properties of the final product. Novel food processing technologies (e.g. high pressure processing, pulsed electric field, ultrasound and cold plasma) have shown potential to modify, complement or replace the conventional processing steps in insect processing. These technologies have been tested for microbial decontamination, enzyme inactivation, drying and extraction. Further, these are considered to be environmentally friendly and may be implemented for versatile applications to improve the processing efficiency, safety and quality of insect based products. Future research focuses in insect processing are development of efficient, environmentally friendly and low-cost processes; waste minimisation and incorporation of by-products/co-products.