Charareh Pourzand

Understanding how synthetic molecular probes interact with biological carbohydrates is essential for theranostics design and discovery. We report new supramolecular polysaccharide complexes, comprising simultaneously functionalised boronic acids conjugated to xanthate‐based fluorescent tags bound to saccharides such as glucose or β‐D‐glucan (a natural product from Hordeum Vulgare ). These hybrids were investigated in solution and in the cellular milieu using advanced biophysical methods, including multiphoton fluorescence lifetime imaging microscopy (MP‐FLIM). A new type of fluorescent hybrid nanoparticle was also generated by conjugating boronic acids to ─Si(OH) ₂ functionalities on the surface of core–shell Fe ₃ O ₄ @SiO ₂ nanoparticles. Cellular uptake and distribution were probed using correlated confocal and multiphoton fluorescence microscopy using 2‐photon excitation at 910 nm, whereby TCSPC and FLIM provided insight into probe environments, interactions with β‐D‐glucan, and cellular context. Colocalization studies with a range of standard dyes were carried out to assess the potential of the probes for cellular penetration and targeting cellular organelles, and the nature of the lipophilic linker involved greatly influences the cytoplasmic distribution and facilitates zebrafish uptake. Complementary in vivo investigations using fluorescence stereomicroscopy of zebrafish showed differential uptake and quenching of these complexes throughout the digestive system, dependent on exogenous and endogenous concentrations of carbohydrates, glucose, or β‐ d ‐glucan.

Background/Objective: Ferroptosis is an iron-dependent form of programmed cell death characterized by lipid peroxidation products (LPOs). A chemotherapeutic drug, 5–fluorouracil (5–FU), can induce epithelial mucositis and favor drug synergism with erastin in ferroptosis. Camellia tea saponin extract (TS) is known to exert antioxidative properties. This study aims to delineate the protective role of TS in mitigating 5–FU-induced ferroptosis and inflammation in human keratinocytes. Methods: HaCaT cells were induced by 5–FU and erastin, treated with different TS doses, and their viability was then determined. Levels of cellular reactive oxygen species (ROS), LPOs, labile iron pool (LIP), glutathione (GSH), glutathione peroxidase 4 (GPX–4) activity, as well as IL–6, IL–1β, and TNF–α levels, and their wound healing properties were assessed. Results: TS per se (at up to 25 µg/mL) was not toxic to HaCaT cells but was unable to restore the viability of 5–FU-induced cells up to the baseline levels. The compound significantly diminished increases in cellular ROS, LPOs, and LIP, while restoring GSH content and GPX–4 activity. Additionally, it suppressed the cytokine production of 5–FU-induced cells in a concentration–dependent manner. Moreover, TS exerted wound-healing effects against skin injuries and 5–FU damage significantly and dose dependently. Conclusions: The insights of this work have identified biochemical mechanisms using tea saponin extract to protect against 5–FU-induced keratinocyte ferroptosis and inflammation. This study highlights the promising adjunctive potential of tea saponin in the mitigation and management of chemotherapy-induced mucositis.

The chemical nature of intracellular labile iron pools (LIPs) is described. By virtue of the kinetic lability of these pools, it is suggested that the isolation of such species by chromatography methods will not be possible, but rather mass spectrometric techniques should be adopted. Iron-sensitive fluorescent probes, which have been developed for the detection and quantification of LIP, are described, including those specifically designed to monitor cytosolic, mitochondrial, and lysosomal LIPs. The potential of near-infrared (NIR) probes for in vivo monitoring of LIP is discussed.

Editorial: Targeted drug discovery in ectopic calcification: mechanism, prospect, and clinical application

5-Aminolevulinic acid-based photodynamic therapy (ALA-PDT) was first implemented over three decades ago and has since been mainly part of clinical practice for the management of pre-cancerous and cancerous skin lesions. Photodynamic therapy relies on the combination of a photosensitizer, light and oxygen to cause photo-oxidative damage of cellular components. 5-Aminolevulinic acid (ALA) is a natural precursor of the heme biosynthetic pathway, which when exogenously administered leads to the accumulation of the photoactivatable protoporphyrin IX. Although, effective and providing excellent cosmetic outcomes, its use has been restricted by the burning, stinging, and prickling sensation associated with treatment, as well as cutaneous adverse reactions that may be induced. Despite intense research in the realm of drug delivery, pain moderation, and light delivery, a novel protocol design using sunlight has led to some of the best results in terms of treatment response and patient satisfaction. Daylight PDT is the protocol of choice for the management of treatment of multiple or confluent actinic keratoses (AK) skin lesions. This review aims to revisit the photophysical, physicochemical and biological characteristics of ALA-PDT, and the underlying mechanisms resulting in daylight PDT efficiency and limitations.

Reactive oxygen species (ROS) are necessary for normal cell signaling and the antimicrobial defense of the skin. However excess production of ROS can disrupt the cellular redox balance and overwhelm the cellular antioxidant (AO) capacity, leading to oxidative stress. In the skin, oxidative stress plays a key role in driving both extrinsic and intrinsic aging. Sunlight exposure has also been a major contributor to extrinsic photoaging of the skin as its oxidising components disrupt both redox- and iron-homeostasis, promoting oxidative damage to skin cells and tissue constituents. Upon oxidative insults, the interplay between excess accumulation of ROS and redox-active labile iron (LI) and its detrimental consequences to the skin are often overlooked. In this review we have revisited the oxidative mechanisms underlying skin damage and aging by focussing on the concerted action of ROS and redox-active LI in the initiation and progression of intrinsic and extrinsic skin aging processes. Based on these, we propose to redefine the selection criteria for skin antiaging and photoprotective ingredients to include natural antioxidants (AOs) exhibiting robust redox–balancing and/or iron-chelating properties. This would promote the concept of natural-based or bio-inspired bifunctional anti-aging and photoprotective ingredients for skincare and sunscreen formulations with both AO and iron-chelating properties.

Light has attracted special attention as a stimulus for triggered drug delivery systems (DDS) due to its intrinsic features of being spatially and temporally tunable. Ultraviolet A (UVA) radiation has recently been used as a source of external light stimuli to control the release of drugs using a “switch on- switch off” procedure. This review discusses the promising potential of UVA radiation as the light source of choice for photo-controlled drug release from a range of photo-responsive and photolabile nanostructures via photo-isomerization, photo-cleavage, photo-crosslinking, and photo-induced rearrangement. In addition to its clinical use, we will also provide here an overview of the recent UVA-responsive drug release approaches that are developed for phototherapy and skin photoprotection.

Mitochondrial labile iron (LI) is a major contributor to the susceptibility of skin fibroblasts to ultraviolet A (UVA)-induced oxidative damage leading to necrotic cell death via ATP depletion. Mitochondria iron overload is a key feature of the neurodegenerative disease Friedreich's ataxia (FRDA). Here we show that cultured primary skin fibroblasts from FRDA patients are 4 to 10-fold more sensitive to UVA-induced death than their healthy counterparts. We demonstrate that FRDA cells display higher levels of mitochondrial LI (up to 6-fold on average compared to healthy counterparts) and show higher increase in mitochondrial reactive oxygen species (ROS) generation after UVA irradiation (up to 2-fold on average), consistent with their differential sensitivity to UVA. Pre-treatment of the FRDA cells with a bespoke mitochondrial iron chelator fully abrogates the UVA-mediated cell death and reduces UVA-induced damage to mitochondrial membrane and the resulting ATP depletion by a factor of 2. Our results reveal a link between FRDA as a disease of mitochondrial iron overload and sensitivity to UVA of skin fibroblasts. Our findings suggest that the high levels of mitochondrial LI in FRDA cells which contribute to high levels of mitochondrial ROS production after UVA irradiation are likely to play a crucial role in the marked sensitivity of these cells to UVA-induced oxidative damage. This study may have implications not only for FRDA but also for other diseases of mitochondrial iron overload, with the view to develop topical mitochondria-targeted iron chelators as skin photoprotective agents.

Mitochondrial labile iron (LI) plays a crucial role in oxidative injuries and pathologies. At present, there is no organelle-specific sensitive iron sensor which can reside exclusively in the mitochondria and reliably monitor levels of LI in this organelle. In the present study, we describe the development of novel fluorescent and highly specific mitochondria iron sensors, using the family of mitochondria-homing 'SS-peptides' (short cell-permeant signal peptides mimicking mitochondrial import sequence) as carriers of highly specific iron chelators for sensitive evaluation of the mitochondrial LI. Microscopic analysis of subcellular localization of a small library of fluorescently labelled SS-like peptides identified dansyl (DNS) as the lead fluorophore for the subsequent synthesis of chimaeric iron chelator-peptides of either catechol (compounds 10 and 11) or hydroxypyridinone (compounds 13 and 14) type. The iron-sensing ability of these chimaeric compounds was confirmed by fluorescent quenching and dequenching studies both in solution and in cells, with compound 13 exhibiting the highest sensitivity towards iron modulation. The intramolecular fluorophore-chelator distance and the iron affinity both influence probe sensitivity towards iron. These probes represent the first example of highly sensitive mitochondria-directed fluorescent iron chelators with potential to monitor mitochondrial LI levels.