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Hearing loss is a widespread condition, affecting people from a range of demographics. Gene therapy is an emerging method for the amelioration of this condition. Challenges associated with the delivery of genes to various sites within the ear remain a significant challenge. In the present work, a novel polymer nanoparticle delivery system was developed, incorporating a bile acid excipient. Bile acids have previously been shown to improve drug delivery through their permeation enhancing properties; however, few studies report their use in gene delivery systems. Nanoparticles were developed with sodium alginate and poly-L-lysine through an ionotropic gelation method. Various surfactants including Tween-80 and poly-ethylene glycol 6000 were incorporated to both improve the solubility of the bile acid, ursodiol, and to modify nanoparticle properties. The evaluation of the nanoparticle's safety profiles was the primary outcome of this study. The secondary aims were to perform genetic studies, such as transfection efficiency. The nanoparticles generated in this study demonstrated formulation-dependent variability in particle size ranging from 30 to 300 nm. Several of the developed formulations demonstrated suitable safety profiles; further, the introduction of bile acid helped to reduce toxicity. Transfection efficiency for all formulations remained low, potentially due to poor plasmid release inside the cell. Poor transfection efficiency is one of the key pitfalls associated with polymer nanoparticles Overall the present study developed nanoparticles with suitable safety profiles but limited efficacy. The use of modified polymers, additional excipients, and cell-targeting peptides are potential methods that may be explored in future studies to help further improve gene delivery. [ABSTRACT FROM AUTHOR]

If the electrons in a plasma are suddenly heated, the resulting change in Debye shielding causes the ion kinetic energy to quickly increase. For the first time, this correlation heating , which is much faster than collisional energy exchange, is rigorously derived for a moderately coupled, electron–ion plasma. The electron–ion mass ratio is taken to be the smallest parameter in the Bogoliubov–Born–Green–Kirkwood–Yvon hierarchy, smaller even than the reciprocal of the plasma parameter. This ordering differs from conventional kinetic theory by making the electron collision rates faster than the ion plasma frequency, which allows stronger coupling and makes the ion heating a function only of the total energy supplied to the electrons. The calculation uses known formulae for correlations in a two-temperature plasma, for which a new, elementary derivation is presented. Suprathermal ions may be created more rapidly by this mechanism than by ion–electron Coulomb collisions. This means that the use of a femtosecond laser pulse could potentially help to achieve ignition in certain fast ignition approaches to inertial confinement fusion. [ABSTRACT FROM AUTHOR]

The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) provides benefits to low-income, nutritionally at-risk women, infants, and children. To administer WIC, officials and program managers at the federal and state levels want to understand who is eligible for the program, who among the eligible population chooses to participate, and who is not accessing the program despite their eligibility. Novel individual-level data linkages between restricted-use WIC Administrative Records and the American Community Survey provide WIC access rates estimated at the state and county levels, as well as estimates disaggregated by the demographic and socioeconomic characteristics of individuals and their households. These estimates are developed by the Census-FNS-ERS Joint Project, a research partnership among the US Census Bureau, the US Department of Agriculture's Food and Nutrition Service and Economic Research Service, and state WIC agencies that provide the requisite WIC administrative data to the Census Bureau. This article details and evaluates our current data linkage and estimation methods, reports results, and identifies areas for improvement and further research. [ABSTRACT FROM AUTHOR]

There is growing interest in understanding how ethanol use interacts with advancing age to influence the brain and cognition. Animal models are employed to investigate the cellular and molecular mechanisms of brain aging and age-related neurodegenerative diseases that underlie cognitive decline. However, all too often research on problems and diseases of the elderly are conducted in healthy young animals, providing little clinical relevance. The validity of animal models is discussed, and confounds due to age-related differences in anxiety, sensory-motor function, and procedural learning are highlighted in order to enhance the successful translation of preclinical results into clinical settings. The mechanism of action of ethanol on brain aging will depend on the dose, acute or chronic treatment, or withdrawal from treatment and the age examined. Due to the fact that humans experience alcohol use throughout life, important questions concern the effects of the dose and duration of ethanol treatment on the trajectory of cognitive function. Central to this research will be questions of the specificity of alcohol effects on cognitive functions and related brain regions that decline with age, as well as the interaction of alcohol with mechanisms or biomarkers of brain aging. Alternatively, moderate alcohol use may provide a source of reserve and resilience against brain aging. Longitudinal studies have the advantage of being sensitive to detecting the effects of treatment on the emergence of cognitive impairment in middle age and can minimize effects of stress/anxiety associated with the novelty of alcohol exposure and behavioral testing, which disproportionately influence aged animals. Finally, the effect of alcohol on senescent neurophysiology and biomarkers of brain aging are discussed. In particular, the interaction of age and effects of alcohol on inflammation, oxidative stress, N-methyl- d -aspartate receptor function, and the balance of excitatory and inhibitory synaptic transmission are highlighted. • An overview of validity of animal models for examining alcohol effects on brain aging is provided. • Advantages of longitudinal studies for minimizing confounds are discussed. • Specificity of effects on cognitive function and related brain regions are discussed. • Alcohol effects on senescent neurophysiology and biomarkers of brain aging are discussed. • Alcohol may affect susceptibility to brain aging or reserve and resilience. [ABSTRACT FROM AUTHOR]

• Cognitive reserve represents plastic properties to maintain cognition in the face of brain aging. • Statistical filtering across age identified brain aging genes. • Cognitive reserve genes predicted better-than-expected cognition for a given level of brainaging. Variability in cognitive decline is related to the environment, lifestyle factors, and individual differences in biological aging, including cognitive reserve, plastic properties of the brain, which account for better-than-expected cognition for a given level of brain aging or pathology. Cognitive reserve has not been thoroughly investigated in aged rodents. To address this gap, cognitive reserve was examined using Gene Expression Omnibus data for the CA1 region of the hippocampus of young and aged behaviorally characterized male rats. Statistical filtering identified brain aging and potential cognitive reserve genes, and multiple regression was employed to confirm cognitive reserve genes as genes that predicted better-than-expected cognition for a given level of brain aging. In general, cognitive reserve genes, in which increased expression was associated with better cognition, were not different with age or directly correlated with measures of cognition and appear to act as negative regulators of aging processes, including neuroinflammation and oxidative stress. The results suggest that, for some animals, resilience mechanisms are activated to counteract aging stressors that impair cognition. In contrast, cognitive reserve genes, in which decreased expression was associated with better cognition, were linked to nervous system development and cation transport, suggesting adaptive changes in the circuit to preserve cognition. [ABSTRACT FROM AUTHOR]

AbstractThe use of antioxidants could thus prove an effective medication to prevent or facilitate recovery from oxidative stress-induced sensorineural hearing loss (SNHL). One promising strategy to prevent SNHL is developing probucol (PB)-based nanoparticles using encapsulation technology and administering them to the inner ear via the established intratympanic route. The preclinical, clinical and epidemiological studies support that PB is a proven antioxidant that could effectively prevent oxidative stress in different study models. Such findings suggest its applicability in preventing oxidative stress within the inner ear and its associated neural cells. However, several hurdles, such as overcoming the blood-labyrinth barrier, ensuring sustained release, minimising systemic side effects and optimising targeted delivery in the intricate inner ear structures, must be overcome to efficiently deliver PB to the inner ear. This review explores the background and pathogenesis of hearing loss, the potential of PB in treating oxidative stress and its cellular mechanisms, and the obstacles linked to inner ear drug delivery for effectively introducing PB to the inner ear. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies in our laboratory have shown that some bile acids, such as chenodeoxycholic acid (CDCA), can exert cellular protective effects when encapsulated with viable β-cells via anti-inflammatory and anti-oxidative stress mechanisms. However, to explore their full potential, formulating such bile acids (that are intrinsically lipophilic) can be challenging, particularly if larger doses are required for optimal pharmacological effects. One promising approach is the development of nano gels. Accordingly, this study aimed to examine biological effects of various concentrations of CDCA using various solubilising nano gel systems on encapsulated β-cells. Methods: Using our established cellular encapsulation system, the Ionic Gelation Vibrational Jet Flow technology, a wide range of CDCA β-cell capsules were produced and examined for morphological, biological, and inflammatory profiles. Results and Conclusion: Capsules' morphology and topographic characteristics remained similar, regardless of CDCA or nano gel concentrations. The best pharmacological, anti-inflammatory, and cellular respiration, metabolism, and energy production effects were observed at high CDCA and nano gel concentrations, suggesting dose-dependent cellular protective and positive effects of CDCA when incorporated with high loading nano gel. [ABSTRACT FROM AUTHOR]

African swine fever (ASF) is a devastating disease of domestic pigs that has spread across the globe since its introduction into Georgia in 2007. The etiological agent is a large double-stranded DNA virus with a genome of 170 to 180 kb in length depending on the isolate. Much of the differences in genome length between isolates are due to variations in the copy number of five different multigene families that are encoded in repetitive regions that are towards the termini of the covalently closed ends of the genome. Molecular epidemiology of African swine fever virus (ASFV) is primarily based on Sanger sequencing of a few conserved and variable regions, but due to the stability of the dsDNA genome changes in the variable regions occur relatively slowly. Observations in Europe and Asia have shown that changes in other genetic loci can occur and that this could be useful in molecular tracking. ASFV has been circulating in Western Africa for at least forty years. It is therefore reasonable to assume that changes may have accumulated in regions of the genome other than the standard targets over the years. At present only one full genome sequence is available for an isolate from Western Africa, that of a highly virulent isolate collected from Benin during an outbreak in 1997. In Cameroon, ASFV was first reported in 1981 and outbreaks have been reported to the present day and is considered endemic. Here we report three full genome sequences from Cameroon isolates of 1982, 1994 and 2018 outbreaks and identify novel single nucleotide polymorphisms and insertion-deletions that may prove useful for molecular epidemiology studies in Western Africa and beyond. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy‐induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves the induction of peripheral cellular senescence and the release of senescence‐associated secretory phenotype (SASP) factors and these SASP factors can enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT‐263, which also has limited access to the brain. The results indicate that plasma SASP factors enter the brain, activating microglia, increasing oxidative stress, and altering gene transcription. In turn, the synaptic function required for memory was reduced in response to altered redox signaling. ABT‐263 prevented or limited most of the Dox‐induced effects. The results emphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate some differences as well as similarities between advanced age and Dox treatment. [ABSTRACT FROM AUTHOR]

Introduction: Despite worldwide consensus that coronary artery bypass graft computed tomography angiography (CABG CTA) confers benefit to patients when used for appropriate indications, the increased cancer risk due to radiation dose remains a concern. The aim of this study is the estimation of organ effective dose (ED) and lifetime attributable risk (LAR) of cancer incidence and mortality related to a single CABG CTA procedure. Methods and materials: This retrospective cross-sectional designed study included 102 CABG patients who, from January 2021 to June 2021, underwent a retrospective 64-slice ECG-gated CABG CTA covering the area of the grafts with optimal image quality. The estimation of ED was done using the imPACT CT Dosimetry spreadsheet. LAR of cancer incidence was estimated for CABG CTA using the website X-rayrisk.com. Results: The mean total ED of CABG procedure was 15.35 mSv. The highest organ doses were those to the lungs (5.04 mSv) and breast (4.49 mSv). The cancer risk is higher in female (1 in 1516) than in male patients (1 in 1762). The LAR of cancer is higher for the younger age group in both males and females. The total whole-body ED demonstrated that CABG CTA is equivalent to 154 chest radiographs or 37 screening mammography studies, which in turn correspond to approximately 4.3 or 5-years of natural background radiation, respectively. Conclusions: Despite many benefits of CABG CTA, it is associated with a non-negligible risk of malignancy, so a careful risk/benefit assessment is recommended in justifying CABG CTA procedures, especially for young female patients. [ABSTRACT FROM AUTHOR]

[Display omitted] Deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) are bile acids that may serve as permeation enhancers when incorporated within the nanogel matrix for drug delivery in the inner ear. In this study, thermoresponsive nanogels were formulated with DCA, LCA and UDCA and their rheological properties and biocompatibility were assessed. The impact of nanogel on cellular viability was evaluated via cell viability assay, the impact of nanogels on cellular bioenergetic parameters was estimated by Seahorse mito-stress test and glycolysis-stress test, while the presence of intracellular free radicals was assessed by reactive oxygen species assay. Nanogels showed a high level of biocompatibility after 24-hour exposure to auditory and macrophage cell lines, with minimal cytotoxicity compared to untreated control. Incubation with nanogels did not alter cellular respiration and glycolysis of the auditory cell line but showed possible mitochondrial dysfunction in macrophages, suggesting tissue-dependent effects of bile acids. Bile acid-nanogels had minimal impact on intracellular reactive oxygen species, with LCA demonstrating the most pro-oxidative behaviour. This study suggests that thermoresponsive nanogels with bile acid, particularly DCA and UDCA, may be promising candidates for inner ear drug delivery. [ABSTRACT FROM AUTHOR]

Sexual dimorphisms exist in multiple domains, from learning and memory to neurocognitive disease, and even in the immune system. Male sex has been associated with increased susceptibility to infection, as well as increased risk of adverse outcomes. Sepsis remains a major source of morbidity and mortality globally, and over half of septic patients admitted to intensive care are believed to suffer some degree of sepsis-associated encephalopathy (SAE). In the short term, SAE is associated with an increased risk of in-hospital mortality, and in the long term, has the potential for significant impairment of cognition, memory, and acceleration of neurocognitive disease. Despite increasing information regarding sexual dimorphism in neurologic and immunologic systems, research into these dimorphisms in sepsis-associated encephalopathy remains critically understudied. In this narrative review, we discuss how sex has been associated with brain morphology, chemistry, and disease, sexual dimorphism in immunity, and existing research into the effects of sex on SAE. [ABSTRACT FROM AUTHOR]

We examine similar and differential effects of two senolytic treatments, ABT‐263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT‐263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood–brain barrier (BBB) integrity, and prevented the age‐related decline in hippocampal N‐methyl‐D‐aspartate receptor (NMDAR) function associated with impaired cognition. Senolytic treatments decreased senescence‐associated secretory phenotype (SASP) and inflammatory cytokines/chemokines in the plasma (IL‐1β, IP‐10, and RANTES), with some markers more responsive to D + Q (TNFα) or ABT‐263 (IFNγ, leptin, EGF). ABT‐263 was more effective in decreasing senescence genes in the spleen. Both senolytic treatments decreased the expression of immune response and oxidative stress genes and increased the expression of synaptic genes in the dentate gyrus (DG). However, D + Q influenced twice as many genes as ABT‐263. Relative to D + Q, the ABT‐263 group exhibited increased expression of DG genes linked to cell death and negative regulation of apoptosis and microglial cell activation. Furthermore, D + Q was more effective at decreasing morphological markers of microglial activation. The results indicate that preserved cognition was associated with the removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, BBB breakdown, and impaired synaptic function. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential access. [ABSTRACT FROM AUTHOR]

Background: The outcome measure of neonatal hip screening is usually the radiographic acetabular index. Objective: To assess the feasibility of magnetic resonance imaging (MRI) without sedation and compare the utility of outcome parameters measured from MRI images. Materials and methods: The invitation for MRI scanning at 5 years of age was incorporated into follow-up for babies who had more than one ultrasound examination during treatment or surveillance. Results: Diagnostic images were obtained in 132 of 134 children. The mean osseous acetabular index (standard deviation [SD]) was 16.6 (3.3) degrees for the right hip and 17.8 (3.2) for the left; the values for the cartilaginous acetabular index were 3.1 (3) and 3.4 (3.2). The mean downslope of a tangent to the lateral bony acetabular roof was 10.4 (4.5) and 9.0 (4.3) with respect to Hilgenreiner's line and that of a line drawn through the apex to the margin of the acetabulum was 3.7 (4.6) and 3.9 (4.7). Intra- and interobserver variation was greater for measures specific to the lateral acetabular roof than for ossific and cartilaginous indices. There was significant negative correlation between the downslope of the tangent to the lateral roof index and the age at onset of treatment on both sides, but no significant correlation for ossific or cartilaginous acetabular indices or apex-marginal index. Conclusion: MRI without sedation at 5 years of age is feasible as an outcome measure for hip screening programmes. Parameters specific to the lateral acetabulum may better reflect acetabular sufficiency, despite having greater observer variation than cartilaginous and ossific acetabular indices. [ABSTRACT FROM AUTHOR]

Gerontological research reveals considerable interindividual variability in aging phenotypes, and emerging evidence suggests that high impact chronic pain may be associated with various accelerated biological aging processes. In particular, epigenetic aging is a robust predictor of health-span and disability compared to chronological age alone. The current study aimed to determine whether several epigenetic aging biomarkers were associated with high impact chronic pain in middle to older age adults (44–78 years old). Participants (n = 213) underwent a blood draw, demographic, psychosocial, pain and functional assessments. We estimated five epigenetic clocks and calculated the difference between epigenetic age and chronological age, which has been previously reported to predict overall mortality risk, as well as included additional derived variables of epigenetic age previously associated with pain. There were significant differences across Pain Impact groups in three out of the five epigenetic clocks examined (DNAmAge, DNAmPhenoAge and DNAmGrimAge), indicating that pain-related disability during the past 6 months was associated with markers of epigenetic aging. Only DNAmPhenoAge and DNAmGrimAge were associated with higher knee pain intensity during the past 48 h. Finally, pain catastrophizing, depressive symptomatology and more neuropathic pain symptoms were significantly associated with an older epigenome in only one of the five epigenetic clocks (i.e. DNAmGrimAge) after correcting for multiple comparisons (corrected p 's < 0.05). Given the scant literature in relation to epigenetic aging and the complex experience of pain, additional research is needed to understand whether epigenetic aging may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes. [ABSTRACT FROM AUTHOR]

Recent preclinical studies in our laboratory have shown that the bile acid profile is altered during diabetes development and such alteration has been linked to the diabetes-associated inflammatory profile. Hence, this study aimed to investigate if the first-line antidiabetic drug metformin will alter the bile acid profile and diabetes-associated inflammation in a murine model of pre-type 2 diabetes. C57 mice were randomly allocated into three equal groups of eight. Group One was given a low-fat diet (LFD), Group Two was given a high-fat diet (HFD), and Group Three was given an HFD and, upon prediabetes confirmation, daily oral metformin for one month. Blood glucose, glycated haemoglobin, drug concentrations in tissues and faeces, and the inflammatory and bile acid profiles were measured. Metformin showed wide tissue distribution and was also present in faeces. The bile acid profile showed significant alteration due to prediabetes, and although metformin did not completely normalize it, it did exert significant effects on both the bile acid and the inflammatory profiles, suggesting a direct and, to some extent, positive impact, particularly on the diabetes-associated inflammatory profile. [ABSTRACT FROM AUTHOR]

Background / Aim: Metformin is widely used in type 2 diabetes and exhibits many positive biological effects on pancreatic β-cells and muscle cells, such as supporting insulin release by β-cells and glucose uptake by muscle cells and reducing oxidative stress, particularly due to diabetes-associated hyperglycaemia. Interestingly, for type 1 diabetes, transplantation of healthy β-cells has been proposed as a novel way to replace insulin therapy. Recently, bile acid-formulations containing transplantable β-cells showed best stability. Hence, this study aimed to explore the effects of metformin-bile acid formulations in β-cell encapsulation and on the biological activities of β-cells and muscle-cells. Methods: Two sets of biological effects were examined, using metformin-bile acid formulations, on encapsulated β-cells and on muscle cells exposed to the formulations. Results: Various encapsulated β-cell formulations' cell viability, insulin levels, cellular oxidative stress, cellular inflammatory profile and bioenergetics at the normo- and hyper-glycaemic states showed differing results based upon the metformin concentration and the inclusion or absence of bile acid. Similar effects were observed with muscle cells. Low ratios of metformin and bile acids showed best biological effects, suggesting a formulation dependent result. The formulations' positive effects were more profound at the hyperglycaemic state suggesting efficient cell protective effects. Conclusion: Overall, metformin had positive impacts on the cells in a concentration-dependent manner, with the addition of chenodeoxycholic acid further improving results. [ABSTRACT FROM AUTHOR]

Bile acids (BA)s are known surfactants and well-documented to play a major role in food digestion and absorption. Recently, potential endocrinological and formulation-stabilisation effects of BAs have been explored and their pharmacological effects on supporting cell survival and functions have gained wide interest. Hence, this study aimed to explore the hyper-glycaemic dependent dose-effect of the BA chenodeoxycholic acid (CDCA) when encapsulated with pancreatic β-cells, allowing assessment of CDCA's impacts when encapsulated. Four different concentrations of the BA were prepared, and viable cells were encapsulated and incubated for 2 days. Multiple analyses were carried out including confocal imaging, glucose-induced cellular mitochondrial viability indices, insulin production, inflammatory biomarker analyses and cellular bioenergetics measurements. There was a significant dose-effect with different concentrations of the BA, affecting cellular viability and antioxidant activities, cell functions and insulin release, inflammatory biomarkers, and cellular-bioenergetics at different oxidative stress levels. The results demonstrate that, when encapsulated, the BA CDCA exerts positive pharmacological effects at the cellular level, and such effects are concentration dependent. [ABSTRACT FROM AUTHOR]

Due to the COVID-19 pandemic, several social modifications have been made in the United States to reduce the infection rate that resulted in changes to the workforce, education system, and general community interactions. This evolving new normal has caused distress in many individuals. The purpose of this article was to conceptualize these changes from a loss perspective and determine if any traumatic symptomology might emerge from the loss, thus producing traumatic loss due to the changing normal. Clinical recommendations are given to mental health professionals when working with individuals who report distress due to the changing normal. [ABSTRACT FROM AUTHOR]

An estimated 250 million people worldwide suffer from knee osteoarthritis (KOA), with older adults having greater risk. Like other age-related diseases, residents of high-deprivation neighborhoods experience worse KOA pain outcomes compared to their more affluent neighbors. The purpose of this study was to examine the relationship between neighborhood deprivation and pain severity in KOA and the influence of epigenetic age acceleration (EpAA) on that relationship. The sample of 128 participants was mostly female (60.9%), approximately half non-Hispanic Black (49.2%), and had a mean age of 58 years. Spearman bivariate correlations revealed that pain severity positively correlated with EpAA (ρ = 0.47, p ≤ 0.001) and neighborhood deprivation (ρ = 0.25, p = 0.004). We found a positive significant relationship between neighborhood deprivation and EpAA (ρ = 0.47, p ≤ 0.001). Results indicate a mediating relationship between neighborhood deprivation (predictor), EpAA (mediator), and pain severity (outcome variable). There was a significant indirect effect of neighborhood deprivation on pain severity through EpAA, as the mediator accounted for a moderate portion of the total effect, PM = 0.44. Epigenetic age acceleration may act as a mechanism through which neighborhood deprivation leads to worse KOA pain outcomes and may play a role in the well-documented relationship between the neighborhood of residence and age-related diseases. • Neighborhood deprivation is associated with worse knee osteoarthritis pain severity. • Epigenetic age acceleration shows a mediating relationship in this phenomenon. • Epigenetic aging may act as mechanism for socioeconomic - health outcomes link. [ABSTRACT FROM AUTHOR]

Knee pain is a leading cause of disability in the aging population and may indirectly accelerate biological aging processes. Chronological aging increases the risk of developing of knee pain and knee pain reduces physical function; however, limited data exist on how epigenetic aging, a known hallmark of biological aging shown to predict health span and mortality, may influence this relationship. The purpose of this study was to examine whether decreased physical performance associated with knee pain is mediated by markers of epigenetic aging. Participants (57.91 ± 8.04 years) with low impact knee pain (n = 95), high impact knee pain (n = 53) and pain-free controls (n = 26) completed self-reported pain, a blood draw and a short physical performance battery (SPPB) that included balance, walking, and sit to stand tasks. We employed an epigenetic clock previously associated with knee pain and shown to predict overall mortality risk (DNAmGrimAge). Bootstrapped-mediation analyses were used to determine associations of DNAmGrimAge and SPPB between pain groups. Those with high impact and low impact pain had a biologically older epigenetic age (5.14y ± 5.66 and 1.32y ± 5.41, respectively). However, while there were direct effects of pain on overall physical performance, these were not explained by epigenetic aging. Epigenetic aging only mediated the effect of pain on balance performance. Future work is needed to examine pain's impact on biological aging processes including epigenetic aging and its ultimate effect on physical function measures known to predict health span and mortality. • DNAmGrimAge is an epigenetic clock associated with pain and physical function. • An older epigenome is related to worse physical function, particularly balance. • Epigenetic aging mediated the effect of pain on balance performance. • Future work should examine pain's impact on biological aging and physical function. [ABSTRACT FROM AUTHOR]

The role of endogenous bile acids as lipid stabilizers aiding uptake of lipophilic nutrients via micelle formation and saponification effects is well documented and precedes their growing applications in pharmaceutical sciences. Their utility stems from their unique physico-chemical profile and ability to modulate immune cell signalling pathways. It has been shown that bile acids alter specific receptor-mediated pathways of cellular respiration and metabolism, providing potential clinical therapies for cardio-metabolic disorders such as diabetes mellitus, hypercholesterolemia, and heart disease. Additionally, some bile acids exert profound anti-oxidant, anti-inflammatory and immunosuppressant properties, and are effective at reducing blood pressure and alleviating hypertension. Their unique amphoteric properties and proven ability as permeability enhancers make them a desirable pharmaceutical excipient. When incorporated with various carbohydrates, polymers, hydrogels and/or polyelectrolytes to form micro- or nano-capsules, they provide enhanced thermodynamic, osmotic and structural stability, and cater for controlled delivery via specific tissue targeting, pH dependant release and temperature guided sol-gel complexation. Additionally, due to their immunosuppressant properties, they enhance the immunogenicity of encapsulated cells, increasing the feasibility of bioartificial organs as transplantable therapeutics. This review explores existing and future applications of bile acids and provides a synopsis of their role in advanced, novel therapeutic delivery systems. [ABSTRACT FROM AUTHOR]

Bile acids (BA)s are known surfactants and well-documented to play a major role in food digestion and absorption. Recently, potential endocrinological and formulation-stabilisation effects of BAs have been explored and their pharmacological effects on supporting cell survival and functions have gained wide interest. Hence, this study aimed to explore the hyper-glycaemic dependent dose-effect of the BA chenodeoxycholic acid (CDCA) when encapsulated with pancreatic β-cells, allowing assessment of CDCA's impacts when encapsulated. Four different concentrations of the BA were prepared, and viable cells were encapsulated and incubated for 2 days. Multiple analyses were carried out including confocal imaging, glucose-induced cellular mitochondrial viability indices, insulin production, inflammatory biomarker analyses and cellular bioenergetics measurements. There was a significant dose-effect with different concentrations of the BA, affecting cellular viability and antioxidant activities, cell functions and insulin release, inflammatory biomarkers, and cellular-bioenergetics at different oxidative stress levels. The results demonstrate that, when encapsulated, the BA CDCA exerts positive pharmacological effects at the cellular level, and such effects are concentration dependent. [ABSTRACT FROM AUTHOR]

Biguanides, particularly the widely prescribed drug metformin, have been marketed for many decades and have well-established absorption profiles. They are commonly administered via the oral route and, despite variation in oral uptake, remain commonly prescribed for diabetes mellitus, typically type 2. Studies over the last decade have focused on the design and development of advanced oral delivery dosage forms using bio nano technologies and novel drug carrier systems. Such studies have demonstrated significantly enhanced delivery and safety of biguanides using nanocapsules. Enhanced delivery and safety have widened the potential applications of biguanides not only in diabetes but also in other disorders. Hence, this review aimed to explore biguanides' pharmacokinetics, pharmacodynamics, and pharmaceutical applications in diabetes, as well as in other disorders. [ABSTRACT FROM AUTHOR]

Recent studies in our laboratories have shown promising effects of bile acids in ➀ drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D® and ➁ viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D® capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic β-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D® capsules, and capsules' images, viability, inflammation, and bioenergetics of encapsulated cells assessed. The capsules' thermal and chemical stability assays were also assessed to ascertain an association between capsules' stability and cellular biological activities. Bile acid-Eudragit NM30D® capsules showed improved cell viability (e.g., F1 < F2 & F8; p < 0.05), insulin, inflammatory profile, and bioenergetics as well as thermal and chemical stability, compared with control. These effects were formulation-dependent and suggest, overall, that changes in ratios of bile acids to Eudragit NM30D® can change the microenvironment of the capsules and subsequent cellular biological activities. [ABSTRACT FROM AUTHOR]

Introduction. Several studies have shown that different biomaterials and hydrogels comprising various bile acids such as chenodeoxycholic acid (CDCA), as well as excipients such as poly-(styrene)-sulphonate (PSS) and poly-(allyl)-amine (PAA), exhibited positive biological effects on encapsulated viable pancreatic β-cells. Hence, this study aimed to investigate whether incorporating CDCA with PSS and PAA will optimise the functions of encapsulated pancreatic islets post-transplantation in Type 1 diabetes (T1D). Methods. Mice were made T1D, divided into two equal groups, and transplanted with encapsulated islets in PSS-PAA (control) or with CDCA-PSS-PAA (treatment) microcapsules. The effects of transplanted microcapsules on blood glucose, inflammation and the bile acid profile were measured post-transplantation. Results and Conclusion. Compared with control, the treatment group showed better survival rate, improved glycaemic control, and lower inflammatory profile, illustrated by ↓ interleukin 1-β, interleukin-6, interleukin-12, and tumour-necrosis factor-α, and ↓ levels of the bile acid, as well as lithocholic acid in the plasma, liver, large intestine and faeces. The results suggest that CDCA incorporation with PSS-PAA microcapsules exerted beneficial effects on encapsulated islets and resulted in enhanced diabetes treatment, post-transplantation, at the local and systemic levels. [ABSTRACT FROM AUTHOR]

Introduction: Bile acid-based drug encapsulation for oral delivery has been recently explored in our laboratory and has shown to be beneficial in terms of drug-targeted delivery and release profile, but stability at various temperatures has not previously been examined; hence, this is the aim of this study. Methods: Various types of bile acid-based microcapsules containing the drug metformin were produced and tested for accelerated temperature-controlled profiles, as well as morphology, elemental composition, drug content, resilience, floatability, wettability and release profiles at various pH values. Results: Accelerated temperature-controlled analysis showed negligible effects on morphology, size, or shape at very low temperatures (below 0 °C), while higher temperatures (above 25 °C) caused alterations. Drug contents, morphology and elemental composition remained similar, while wettability and the release profiles showed formulation-dependent effects. Discussion and Conclusion: Results suggest that bile acid-based microcapsules containing metformin are affected by temperature; hence, their shelf life is likely to be affected by storage temperature, all of which have a direct impact on drug release and stability profiles. [ABSTRACT FROM AUTHOR]

Introduction. A major obstacle in islet transplantation and graft survival pre and post transplantation is islet apoptosis due to mainly inflammatory bio molecules released during islet harvesting and post graft transplantation and hence, subsequent graft fibrosis and failure. This study aimed to investigate if incorporation of the anti-inflammatory anti-hyperlipidaemic drug probucol (PB) would improve islet-graft survival and function, post transplantation in Type 1 diabetes (T1D). Methods. T1D was induced in mice, and biological profiles of the diabetic mice transplanted PB-microencapsulated islets harvested from healthy syngeneic mice were measured. Results and Conclusion. Compared with sham (no PB), the treated group showed significant reduction in serum levels of interleukin-1β, interleukin-6, interleukin-12, interleukin-17, and tumour necrosis factor-α, accompanied by a 3-fold increase in survival duration, which suggests PB islet-protective effects, post transplantation. [ABSTRACT FROM AUTHOR]

The utilisation of bioartificial organs is of significant interest to many due to their versatility in treating a wide range of disorders. Microencapsulation has a potentially significant role in such organs. In order to utilise microcapsules, accurate characterisation and analysis is required to assess their properties and suitability. Bioartificial organs or transplantable microdevices must also account for immunogenic considerations, which will be discussed in detail. One of the most characterized cases is the investigation into a bioartificial pancreas, including using microencapsulation of islets or other cells, and will be the focus subject of this review. Overall, this review will discuss the traditional and modern technologies which are necessary for the characterisation of properties for transplantable microdevices or organs, summarizing analysis of the microcapsule itself, cells and finally a working organ. Furthermore, immunogenic considerations of such organs are another important aspect which is addressed within this review. The various techniques, methodologies, advantages, and disadvantages will all be discussed. Hence, the purpose of this review is providing an updated examination of all processes for the analysis of a working, biocompatible artificial organ. [ABSTRACT FROM AUTHOR]