A study of Titanium and Magnesium particle-induced oxidative stress and toxicity to human osteoblasts.

Hybrid implants combine both Titanium (Ti) and Magnesium (Mg) are prevalent nowadays. The long-term implications of Ti and Mg implants within the human body are not yet fully understood. Many implant failure cases due to inflammation, allergic responses, and aspect loosening have been reported frequently. Particles generated through daily wear and tear of implants may worsen the situation by causing acute complications. An in-depth understanding of the behavior of metal particles with human osteoblasts is necessary. In this study, a novel and systematic attempt was made to understand the effects of different concentrations of Ti and Mg particles to the osteoblastic SAOS2 cell: toxicity, alterations to mitochondria, and changes to the specific gene and protein expression. Ti particles were found toxic to SAOS2 cells at different dosages, while Mg particles at lower concentrations could improve cell viability. To understand this phenomenon better, we have measured cellular reactive oxygen species (ROS) production and cell apoptosis & necrosis percentage. We also have checked the mitochondrial structure with transmission electron microscope (TEM), and mitochondrial function using Tetramethyl rhodamine, ethyl ester staining (TMRE). NDUFB6, SDHC, and ATP5F1 were the essential mitochondrial genes involved in the ROS production and ATP production. Immunocytochemistry (ICC) and real-time polymerase chain reaction (qPCR) were implemented to check the regulations of these related genes.

Reactive oxygen/nitrogen species (ROS/RNS) and oxidative stress in arthroplasty.

The interplay between implant design, biomaterial characteristics, and the local microenvironment adjacent to the implant is of utmost importance for implant performance and success of the joint replacement surgery. Reactive oxygen and nitrogen species (ROS/RNS) are among the various factors affecting the host as well as the implant components. Excessive formation of ROS and RNS can lead to oxidative stress, a condition that is known to damage cells and tissues and also to affect signaling pathways. It may further compromise implant longevity by accelerating implant degradation, primarily through activation of inflammatory cells. In addition, wear products of metallic, ceramic, polyethylene, or bone cement origin may also generate oxidative stress themselves. This review outlines the generation of free radicals and oxidative stress in arthroplasty and provides a conceptual framework on its implications for soft tissue remodeling and bone resorption (osteolysis) as well as implant longevity. Key findings derived from cell culture studies, animal models, and patients' samples are presented. Strategies to control oxidative stress by implant design and antioxidants are explored and areas of controversy and challenges are highlighted. Finally, directions for future research are identified. A better understanding of the host-implant interplay and the role of free radicals and oxidative stress will help to evaluate therapeutic approaches and will ultimately improve implant performance in arthroplasty.

Fabrication of Ti + Mg composites by three-dimensional printing of porous Ti and subsequent pressureless infiltration of biodegradable Mg.

A semi-degradable Ti + Mg composite with superior compression and cytotoxicity properties have been successfully fabricated using ink jet 3D printing followed by capillary mediated pressureless infiltration technique targeting orthopaedic implant applications. The composite exhibited low modulus (~5.2 GPa) and high ultimate compressive strength (~418 MPa) properties matching that of the human cortical bone. Ti + Mg composites with stronger 3D interconnected open-porous Ti networks are possible to be fabricated via 3D printing. Corrosion rate of samples measured through immersion testing using 0.9%NaCl solution at 37 °C indicate almost negligible corrosion rate for porous Ti (~1.14 µm/year) and <1 mm/year for Ti + Mg composites for 5 days of immersion, respectively. The composite significantly increased the SAOS-2 osteoblastic bone cell proliferation rate when compared to the 3D printed porous Ti samples and the increase is attributed to the exogenous Mg2+ ions originating from the Ti + Mg samples. The cell viability results indicated absent to mild cytotoxicity. An attempt is made to discuss the key considerations for net-shape fabrication of Ti + Mg implants using ink jet 3D printing followed by infiltration approach.

MicroRNA-134-5p inhibition rescues long-term plasticity and synaptic tagging/capture in an Aß(1-42)-induced model of Alzheimer's disease.

Progressive memory loss is one of the most common characteristics of Alzheimer's disease (AD), which has been shown to be caused by several factors including accumulation of amyloid ß peptide (Aß) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD. Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long-term potentiation (late LTP) and its associative mechanisms such as synaptic tagging and capture (STC) were impaired in Aß (1-42)-induced AD condition. This study demonstrates that expression of miR-134-5p, a brain-specific miRNA is upregulated in Aß (1-42)-treated AD hippocampus. Interestingly, the loss of function of miR-134-5p restored late LTP and STC in AD. In AD brains, inhibition of miR-134-5p elevated the expression of plasticity-related proteins (PRPs), cAMP-response-element binding protein (CREB-1) and brain-derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition. The results provide the first evidence that the miR-134-mediated post-transcriptional regulation of CREB-1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR-134-5p as a potential therapeutic target for restoring plasticity in AD condition.

Role of MicroRNAs in Parkinson's Disease.

Parkinson's disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood-brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.

Epigenetic mechanisms in nanomaterial-induced toxicity.

With the growing advent of nanotechnology in medicine (therapeutic, diagnostic and imaging applications), cosmetics, electronics, clothing and food industries, exposure to nanomaterials (NMs) is on the rise and therefore exploring their toxic biological effects have gained great significance. In vitro and in vivo studies over the last decade have revealed that NMs have the potential to cause cytotoxicity and genotoxicity although some contradictory reports exist. However, there are only few studies which have explored the epigenetic mechanisms (changes to DNA methylation, histone modification and miRNA expression) of NM-induced toxicity, and there is a scarcity of information and many questions in this area remain unexplored and unaddressed. This review comprehensively describes the epigenetic mechanisms involved in the induction of toxicity of engineered NMs, and provides comparisons between similar effects observed upon exposure to small or nanometer-sized particles. Lastly, gaps in existing literature and scope for future studies that improve our understanding of NM-induced epigenetic toxicity are discussed.