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The 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]

Background / Aim: Metformin is widely used in type 2 diabetes and exhibits many positive biological effects on pancreatic b-cells and muscle cells, such as supporting insulin release by b-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 b-cells has been proposed as a novel way to replace insulin therapy. Recently, bile acid-formulations containing transplantable b-cells showed best stability. Hence, this study aimed to explore the effects of metformin-bile acid formulations in b-cell encapsulation and on the biological activities of b-cells and muscle-cells. Methods: Two sets of biological effects were examined, using metformin-bile acid formulations, on encapsulated b-cells and on muscle cells exposed to the formulations. Results: Various encapsulated b-cell formulations' cell viability, insulin levels, cellular oxidative stress, cellular inflammatory profile and bioenergetics at the normoand hyperglycaemic 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.

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]

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]

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]

A recent study showed an association between diabetes development and the bile acid lithocholic acid (LCA), while another study demonstrated positive biological effects of the conjugated bile acid, taurocholic acid (TCA), on pancreatic cells. Thus, this study aimed to encapsulate TCA with primary islets (graft) and study the biological effects of the graft, post-transplantation, in diabetic mice, including effects on LCA concentrations. Sixteen mature adult mice were made diabetic and randomly divided into two equal groups, control and test (transplanted encapsulated islets without or with TCA). Graft pharmaceutical features pre-transplantation, and biological effects including on LCA concentrations post-transplantation, were measured. TCA-microcapsules had an oval shape and similar size compared with the control. The treatment group survived longer, showed improved glucose and interleukin-6 concentrations, and lower LCA concentrations in plasma, large intestine, faeces, liver and spleen, compared with control. Results suggest that TCA incorporation with islets encapsulated graft exerted beneficial effects, but there was no direct and significant dependency between concentrations of interleukin-6 and LCA. [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]

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]