Increased oxidative stress, inflammation, and glutamate: Potential preventive and therapeutic targets for hearing disorders.

Hearing disorders constitute one of the major health concerns in the USA. Decades of basic and clinical studies have identified numerous ototoxic agents and investigated their modes of action on the inner ear, utilizing tissue culture as well as animal and human models. Current preventive and therapeutic approaches are considered unsatisfactory. Therefore, additional modalities should be developed. Many studies suggest that increased levels of oxidative stress, chronic inflammation, and glutamate play an important role in the initiation and progression of damage to the inner ear leading to hearing impairments. To prevent these cellular deficits, antioxidants, anti-inflammatory agents, and antagonists of glutamate receptor have been used individually or in combination with limited success. It is essential, therefore, to simultaneously enhance the levels of antioxidant enzymes by activating the Nrf2 (a nuclear transcriptional factor) pathway, dietary and endogenous antioxidant compounds, and B12-vitamins in order to reduce the levels of oxidative stress, chronic inflammation, and glutamate at the same time. This review presents evidence to show that increased levels of these cellular metabolites, biochemical or factors are involved in the pathogenesis of cochlea leading to hearing impairments. It presents scientific rationale for the use of a mixture of micronutrients that may decrease the levels of oxidative damage, chronic inflammation, and glutamate at the same time. The benefits for using oral administration of proposed micronutrient mixture in humans are presented. Animal and limited human studies indirectly suggest that orally administered micronutrients can accumulate in the inner ear. Therefore, this route of administration may be useful in prevention, and in combination with standard care, in improved management of hearing problems following exposure to well-recognized and studied ototoxic agents, such as noise, cisplatin, aminoglycoside antibiotics, and advanced age

Early detection of capping risk in pharmaceutical compacts

Capping is a common mechanical defect in tablet manufacturing, exhibited during or after the compression process. Predicting tablet capping in terms of process variables (e.g. compaction pressure and speed) and formulation properties is essential in pharmaceutical industry. In current work, a non-destructive contact ultrasonic approach for detecting capping risk in the pharmaceutical compacts prepared under various compression forces and speeds is presented. It is shown that the extracted mechanical properties can be used as early indicators for invisible capping (prior to visible damage). Based on the analysis of X-ray cross-section images and a large set of waveform data, it is demonstrated that the mechanical properties and acoustic wave propagation characteristics is significantly modulated by the tablet’s internal cracks and capping at higher compaction speeds and pressures. In addition, the experimentally extracted properties were correlated to the directly-measured porosity and tensile strength of compacts of Pearlitol®, Anhydrous Mannitol and LubriTose® Mannitol, produced at two compaction speeds and at three pressure levels. The effect compaction speed and pressure on the porosity and tensile strength of the resulting compacts is quantified, and related to the compact acoustic characteristics and mechanical properties. The detailed experimental approach and reported wave propagation data could find key applications in determining the bounds of manufacturing design spaces in the development phase, predicting capping during (continuous) tablet manufacturing, as well as online monitoring of tablet mechanical integrity and reducing batch-to-batch end-product quality variations

Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?

Prion diseases are a group of incurable infectious terminal neurodegenerative diseases caused by the aggregated misfolded PrPsc in selected mammals including humans. The complex physical interaction between normal prion protein PrPc and infectious PrPsc causes conformational change from the α- helix structure of PrPc to the β-sheet structure of PrPsc, and this process is repeated. Increased oxidative stress is one of the factors that facilitate the conversion of PrPc to PrPsc. This overview presents evidence to show that increased oxidative stress and inflammation are involved in the progression of this disease. Evidence is given for the participation of redoxsensitive metals Cu and Fe with PrPsc inducing oxidative stress by disturbing the homeostasis of these metals. The fact that some antioxidants block the toxicity of misfolded PrPc peptide supports the role of oxidative stress in prion disease. After exogenous infection in mice, PrPsc enters the follicular dendritic cells where PrPsc replicates before neuroinvasion where they continue to replicate and cause inflammation leading to neurodegeneration. Therefore, reducing levels of oxidative stress and inflammation may decrease the rate of the progression of this disease. It may be an important order to reduce oxidative stress and inflammation at the same time. This may be achieved by increasing the levels of antioxidant enzymes by activating the Nrf2 pathway together with simultaneous administration of dietary and endogenous antioxidants. It is proposed that a mixture of micronutrients could enable these concurrent events thereby reducing the progression of human prion disease

Linker insertion mutagenesis of the human immunodeficiency virus reverse transcriptase expressed in bacteria: definition of the minimal polymerase domain

A plasmid construct expressing the p66 version of the human immunodeficiency virus reverse transcriptase as a bacterial fusion protein was subjected to in vitro mutagenesis, and the resulting variant proteins were assayed to define the locations of the two major enzymatic activities. The DNA polymerase activity was localized to the N-terminal portion of the protein; mutations altering or eliminating the C-terminal portion had little or no effect on that activity. The results suggest that, in contrast with previous reports, the p51 subunit found in virions should exhibit DNA polymerase activity. Mutations in many parts of the protein eliminated RNase H activity, suggesting that several areas are needed for proper folding and generation of that activity

Inhibition of Early Biochemical Defects in Prodromal Huntington's Disease by Simultaneous Activation of Nrf2 and Elevation of Multiple Micronutrients.

Huntington's disease (HD) is a progressive fatal dominant hereditary neurodegenerative disease of the brain, which primarily affects the cortex and the striatum. The disorder is typified by an expansion of more than 35 repeats of the nucleotide triplet cytosine- adenine-guanosine (CAG) which codes for the amino acid glutamine in the huntingtin gene. Despite studies of several decades, there are no effective means to block or postpone the appearance of symptoms of HD. Analysis of these studies led us to propose that increased oxidative stress and chronic inflammation are earliest events in the pathogenesis of HD, and together with excessive glutamate release, participate in the progression of the disease. This review briefly describes evidence for the involvement of oxidative stress, chronic inflammation and glutamate in the pathogenesis of HD. It is proposed that attenuation of these biochemical abnormalities together, may delay the appearance of symptoms of HD. In order to achieve this goal, the simultaneous activation of the nuclear transcriptional factor-2/antioxidant response elements (Nrf2/ARE) pathway that would enhance the transcription of target genes coding for antioxidant enzymes and phase-2-detoxifying enzymes, and an elevation of the levels of antioxidant compounds by supplementation may be needed. Normal mechanisms of activation of Nrf2 requiring reactive oxygen species (ROS) may be impaired in HD, but certain antioxidant compounds can activate Nrf2 without ROS. Use of a combination of micronutrients that can activate the Nrf2/ARE pathway and enhance the levels of antioxidant compounds is suggested

Dietary Fibers and Their Fermented Short-Chain Fatty Acids in Prevention of Human Diseases.

Many studies show that daily consumption of high-fiber diet is associated with a reduced risk of developing kidney stones, inflammatory disease, colon cancer and other malignancies, obesity, type II diabetes, and cardiovascular disease. Dietary fibers are non-digestible polysaccharides that are composed of complex carbohydrates. Based on their relative solubility in water, dietary fibers can be divided into insoluble and soluble forms. An important property of insoluble fibers is their ability to bind with carcinogens, mutagens, and other toxic chemicals that are formed during digestion of food and eliminate them through the feces. Soluble fibers can often be degraded to short-chain fatty acids, such as butyrate, propionate, and acetate by microbial fermentation. This review discusses mechanisms of action of fibers and their beneficial effects on the GI tract as well as on other organs. Among short-chain fatty acids, butyrate has been most extensively studied and the effects of sodium butyrate on cell culture and animal models are discussed in order to emphasize its potential value in prevention of certain diseases

Telomere shortening during aging: Attenuation by antioxidants and anti-inflammatory agents.

Telomeres are a repeated sequence -of bases found at the ends of chromosomes. In humans, this sequence is TTAGGG, which is repeated over 2000 times. Telomeres protect the ends chromosomes from fusion with nearby chromosomes, and allow effective replication of DNA. Each time a cell divides, 25-200 base pairs are lost from the terminal sequence of chromosomes. By becoming truncated during cell division, telomeres protect essential genes from being shortened and thus inactivated. In addition, telomeres are sensitive to inflammation and oxidative stress, which can further promote telomere shortening. Reduction in the length of telomeres leads to the cessation of cell division and thus cellular senescence and apoptosis. This review discusses evidence for the role of oxidative stress and inflammation in regulating the length of telomeres in mammalian cells during senescence. Evidence is presented suggesting that antioxidants and anti-inflammatories can reduce the pace of shortening of telomere length during aging. The distinctive properties of transformed cells suggest that treatment with such materials will have a deleterious rather than a protective effect on such abnormal cells

Total Hip Arthroplasty - over 100 years of operative history

Total hip arthroplasty (THA) has completely revolutionized the nature in which the arthritic hip is treated, and is considered to be one of the most successful orthopaedic interventions of its generation. With over 100 years of operative history, this review examines the progression of the operation from its origins, together with highlighting the materials and techniques that have contributed to its development. Knowledge of its history contributes to a greater understanding of THA, such as the reasons behind selection of prosthetic materials in certain patient groups, while demonstrating the importance of critically analyzing research to continually determine best operative practice. Finally, we describe current areas of research being undertaken to further advance techniques and improve outcomes

Retrosynthetic reaction prediction using neural sequence-to-sequence models

We describe a fully data driven model that learns to perform a retrosynthetic reaction prediction task, which is treated as a sequence-to-sequence mapping problem. The end-to-end trained model has an encoder-decoder architecture that consists of two recurrent neural networks, which has previously shown great success in solving other sequence-to-sequence prediction tasks such as machine translation. The model is trained on 50,000 experimental reaction examples from the United States patent literature, which span 10 broad reaction types that are commonly used by medicinal chemists. We find that our model performs comparably with a rule-based expert system baseline model, and also overcomes certain limitations associated with rule-based expert systems and with any machine learning approach that contains a rule-based expert system component. Our model provides an important first step towards solving the challenging problem of computational retrosynthetic analysis

Thin film diffusion barrier formation in PDMS microcavities

We describe a method to form glass like thin film barrier in polydimethylsiloxane (PDMS) microcavities. The reactive fragments for the surface reaction were created from O2 and hexamethyldisiloxane (HMDS) in RF plasma environment. The reaction is based on migration of the reactive fragments into the microcavities by diffusion, to form a glass like thin film barrier to conceal the naked surface of PDMS. The barrier successfully blocked penetration of a fluorescent dye rhodamine B (RhB) into PDMS. The thickness of the barrier could be controlled by the time of reaction and the pressure inside the reaction chamber. There is a wide range of applications of such a technique in various fields, e.g. for coating the covered surfaces of microfluidic channels, tubes, capillaries, medical devices, catheters, as well as chip-integrated capillary electrophoresis and advanced electronic and opto-fluidic packaging