Cancer is one of the compelling and pegged diseases battled by clinicians and researchers worldwide. Among different types of cancer, oral cancer holds the sixth position globally. With an escalating ...prevalence in Asian countries, India, China, and Pakistan constitute a large proportion of total incidents of oral cancer patients in terms of new cases or deaths. This mounting prevalence is ascribed to poor oral hygiene and rampant use of substances earmarked as potential risk factors for the disease. Risk factors (dietary/lifestyle habits/occupational/environmental) trigger the activation of oncogenes, dysregulation of lncRNA and miRNA, and silence the tumor suppressor genes, which robustly contributes to the onset and progression of tumorigenesis in oral squamous cell carcinoma. Evidence suggests that specific carcinogens identified in tobacco and related products alter many cellular pathways predisposing to advanced stages of oral cancer. Long non-coding RNAs represent a broad group of heterogenous transcripts longer than 200 nucleotides which do not translate to form functional proteins. They regulate various cellular pathways by specifically interacting with other RNAs, DNA, and proteins. Their role in the pathogenesis of OSCC and other cancer is still being debated. In this review, we discuss the molecular insights of significant lncRNAs involved in some crucial deregulated pathways of tobacco-associated OSCC. The implications and challenges to harnessing the potential of lncRNAs as biomarkers in early diagnosis and targeted treatment have also been analyzed.
Diabetic retinopathy, a progressive disease, is the major cause of acquired blindness in the developed countries. Despite cutting-edge research in the field, the exact mechanism of this ...multifactorial disease remains elusive. Matrix metalloproteinases (MMPs) degrade extracellular matrix and play significant role in regulating intracellular homeostasis. In the pathogenesis of diabetic retinopathy, activation of gelatinase MMPs (MMP-2 and MMP-9) in the retina is an early event, and activated MMPs damage the mitochondria and augment retinal capillary cell apoptosis, a phenomenon which is observed before histopathology characteristic of diabetic retinopathy can be seen. MMPs are regulated by a number of different mechanisms including cleavage of their zymogens, regulation of their tissue inhibitors, and their gene expressions by transcriptional factors and epigenetic modifications. This chapter reviews the current literature about the role of MMPs in the development of diabetic retinopathy, and describes different mechanisms to regulate their activation. With evolving research implicating MMPs in both preneovascularization and neovascularization stages of diabetic retinopathy, they could be an attractive target to inhibit the development/progression of diabetic retinopathy, a disease which has potential to rob vision during the most productive years of a diabetic patient's life.
We report here the first pharmaceutical twistable hydrogen-bonded two-dimensional plastic hydrate crystal of a well-known psychoactive drug, caffeine (CAH). The availability of two pairs of ...plastically bendable faces in orthogonal directions allows for twisting of the CAH crystals to obtain the helical morphology. We further demonstrate the first pharmaceutical application of such twistable crystals, i.e., exceptional tabletability. The plasticity of CAH is comparable to a commonly used highly plastic tablet diluent, microcrystalline cellulose. This example suggests that the strategies for designing twistable crystals, among other potential applications, can be used to effectively overcome compression problems of certain drugs and enable the development of high-quality drug tablets.
Abstract
There is a close relationship between arterial stiffness and blood pressure. The studies suggest that the advanced glycation end products (AGEs) and its cell receptor (RAGE) are involved in ...the arterial stiffness in two ways: changes in arterial structure and vascular function. Plasma levels of AGEs and expression of RAGE are elevated, while the levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are lowered in patients with hypertension (HTN). There is a positive correlation between plasma levels of AGEs and arterial stiffness, and an inverse association between arterial stiffness/HTN, and serum levels of sRAGE and esRAGE. Various measures can reduce the levels of AGEs and expression of RAGE, and elevate sRAGE. Arterial stiffness and blood pressure could be reduced by lowering the serum levels of AGEs, and increasing the levels of sRAGE. Levels of AGEs can be lowered by reducing the consumption of AGE-rich diet, short duration of cooking in moist heat at low temperature, and cessation of cigarette smoking. Drugs such as aminoguanidine, vitamins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, statins, and metformin inhibit AGE formation. Alagebrium, an AGE breakers reduces levels of AGEs. Clinical trials with some drugs tend to reduce stiffness. Systemic administration of sRAGE has beneficial effect in animal studies. In conclusion, AGE–RAGE axis is involved in arterial stiffness and HTN. The studies suggest that inhibition of AGEs formation, reduction of AGE consumption, blockade of AGE–RAGE interaction, suppression of RAGE expression, and exogenous administration of sRAGE may be novel therapeutic strategies for treatment of arterial stiffness and HTN.
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•To our knowledge, this is the first report which uses liquid penetration as a tool to compare the wettability.•Results emphasize the importance functional group attached to cationic ...moiety in controlling clay surface properties.•Two techniques are utilized viz., contact angle and liquid penetration to exhibit the behavior of the modified clays.•This report reveals that longer chain on cationic moiety is not the most effective way to hydrophobize the clay.
The montmorillonite clays were modified with quaternary ammonium salts (QASs) having different alkyl chain lengths and a benzyl substitute group. The modified organoclays were characterized by different analytical techniques. The wettability and hydrophilicity/hydrophobicity of the modified clays was evaluated using water or oil penetration (adsorption) and contact angle measurements. The loading of QASs was in the range of 0.60–0.75mmol/g per clay, irrespective of the type of QAS used for the modification of the clay. From the analytical investigations, it was elucidated that the modification of clay with QAS affected the structural, textural, and surface properties. Moreover, it should be noted that the modification with QAS having benzyl substitute group resulted in water-non-wettable and superhydrophobic surface, whereas clays modified with QAS without benzyl substitute group became more water-wettable and hydrophilic than the pristine clay. The presence of benzyl groups on the clay prevents water from penetration into the inter-clay or interlayer spacing, which yields the hydrophobic surface. These behaviors can arise from molecular arrangement of QAS on clay but not be attributable to the amount of QASs, and the surface area, size, and zeta potential of particles.
Diabetes activates matrix metalloproteinase-9 (MMP-9), and MMP-9 via damaging retinal mitochondria, activates capillary cell apoptosis. MMP-9 promoter has binding sites for many transcription ...factors, and in diabetes its promoter undergoes epigenetic modifications, including histone modifications and DNA methylation. Enhancer of Zeste homolog 2 (Ezh2), which catalyzes dimethylation/trimethylation of histone 3 lysine 27 (H3K27me2 and me3), is also associated with DNA methylation. Our aim was to investigate link(s) between histone and DNA modifications in the regulation of MMP-9.
Using human retinal endothelial cells, and also retinal microvessels from diabetic rats, effect of hyperglycemia on H3K27me3, and recruitment of Ezh2 at the MMP-9 promoter were quantified by chromatin-immunoprecipitation technique. Role of H3K27 trimethylation in regulating DNA methylation-transcription of MMP-9 was determined by regulating Ezh2 by its specific siRNA and also a pharmacologic inhibitor.
Hyperglycemia elevated H3K27me3 levels and the recruitment of Ezh2 at the MMP-9 promoter, and increased the enzyme activity of Ezh2. Inhibition of Ezh2 attenuated recruitment of both DNA methylating (Dnmt1) and hydroxymethylating (Tet2) enzymes and 5 hydroxymethyl cytosine at the same region of the MMP-9 promoter, and prevented increase in MMP-9 transcription and mitochondrial damage.
Activation of Ezh2 in diabetes, via trimethylation of H3K27, facilitates recruitment of the enzymes responsible for regulation of DNA methylation of the MMP-9 promoter, resulting in its transcriptional activation. Thus, a close crosstalk between H3K27 trimethylation and DNA methylation in diabetes plays a critical role in the maintenance of cellular epigenetic integrity of MMP-9.
Hospital-acquired pressure injuries are localised skin injuries that cause significant mortality and are costly. Nursing best practices prevent pressure injuries, including time-consuming, complex ...tasks that lack payment incentives. The Braden Scale is an evidence-based stratification tool nurses use daily to assess pressure-injury risk. Our objective was to analyse the cost-utility of performing repeated risk-assessment for pressure-injury prevention in all patients or high-risk groups.
Cost-utility analysis using Markov modelling from US societal and healthcare sector perspectives within a 1-year time horizon.
Patient-level longitudinal data on 34 787 encounters from an academic hospital electronic health record (EHR) between 2011 and 2014, including daily Braden scores. Supervised machine learning simulated age-adjusted transition probabilities between risk levels and pressure injuries.
Hospitalised adults with Braden scores classified into five risk levels: very high risk (6-9), high risk (10-11), moderate risk (12-14), at-risk (15-18), minimal risk (19-23).
Standard care, repeated risk assessment in all risk levels or only repeated risk assessment in high-risk strata based on machine-learning simulations.
Costs (2016 $US) of pressure-injury treatment and prevention, and quality-adjusted life years (QALYs) related to pressure injuries were weighted by transition probabilities to calculate the incremental cost-effectiveness ratio (ICER) at $100 000/QALY willingness-to-pay. Univariate and probabilistic sensitivity analyses tested model uncertainty.
Simulating prevention for all patients yielded greater QALYs at higher cost from societal and healthcare sector perspectives, equating to ICERs of $2000/QALY and $2142/QALY, respectively. Risk-stratified follow-up in patients with Braden scores <15 dominated standard care. Prevention for all patients was cost-effective in >99% of probabilistic simulations.
Our analysis using EHR data maintains that pressure-injury prevention for all inpatients is cost-effective. Hospitals should invest in nursing compliance with international prevention guidelines.
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