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The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.

Small extracellular vesicles (sEVs) possess many advantageous characteristics which highlight their potential as nanocarriers for biomedical applications, including the ability to cross the blood brain barrier, improved biocompatibility and exhibit tissue tropism. Despite this potential, the clinical translation of sEVs has been hindered by a variety of factors and lipid nanoparticles (LNPs) remain as the gold standard for nanocarriers, indicating a knowledge gap which could unlock the potential of sEVs. A growing body of research suggests that the lipid profile, rather than the proteome, of sEVs may be contributing to these beneficial characteristics much more than previously thought. This review highlights and discusses the current state of the field in terms of lipid composition between sEVs originating from various cell sources and the roles which the different lipids play in the function of sEVs as natural nanocarriers within the body. We also discuss the potential of various EV‐mimetics and synthetic EVs (synEVs) in terms of clinical translation which may provide a means to allow wider therapeutic adoption of EVs.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily characterized by dopaminergic neuronal loss in the substantia nigra and intracellular accumulation of misfolded α-synuclein aggregates. Despite being extensively studied, current pharmacological and surgical interventions remain mostly symptomatic, leaving limited efficacy in halting or reversing disease progression. The complicated pathogenesis of PD involves oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, and proteostasis imbalance, altogether contributing to neuronal vulnerability. In addition to established drugs such as levodopa, other medications affecting dopamine pathways and incretin mimetics, numerous studies have highlighted the therapeutic potential of phytomolecules to target these processes. This includes resveratrol, curcumin, quercetin, baicalein, berberine and epigallocatechin gallate (EGCG), which have demonstrated pleiotropic neuroprotective effects by mitigating oxidative and inflammatory cascades, improving mitochondrial biogenesis, preventing proteostasis imbalance, and/or blocking α-synuclein aggregation. Some phytomolecules may also act through the sirtuin and PI3K/Akt signaling pathways, linking neuroprotection with metabolic regulation. Some phytomolecules may additionally alleviate insulin resistance and stimulate incretin (GLP-1/GIP) secretion, potentially enhancing their neuroprotective. The exact relationship between αS, sirtuins, insulin signaling and phytomolecules is not yet fully understood. Nevertheless, increasing evidence suggests that phytomolecules can modulate brain insulin resistance and enhance incretin signaling, which contribute to their neuroprotective effects in PD. This review highlights the interconnected metabolic and neuronal mechanisms in Parkinson’s disease encompassing α-synuclein pathology, sirtuin imbalance, and disrupted insulin signaling role in PD and explores incretin and phytomolecules molecule based therapies, often utilized for type 2 diabetes management as complementary multi-target neuroprotective strategies.

Extracellular vesicles (EVs) are small membrane-based nanovesicles naturally released from cells. Extracellular vesicles mimetics (EVMs) are artificial vesicles engineered from cells or in combination with lipid materials, and they mimic certain characteristics of EVs. As such, EVs facilitate intracellular communication by carrying and delivering biological materials, such as proteins, lipids, and nucleic acids, and they have been found to find organ tropism in preclinical studies. Because of their native structure and characteristics, they are considered promising drug carriers for future clinical use. This review outlines the origin and composition of natural EVs and EVM engineering and internalization. It then details different loading approaches, with examples of the drug delivery of therapeutic molecules. In addition, the advantages and disadvantages of loading drugs into EVs or EVMs as a drug delivery system are discussed. Finally, the advantages of EVMs over EVs and the future clinical translation of EVM-based drug delivery platforms are outlined.

Cerium oxide nanoparticles (CeNPs) exhibit antioxidant properties both in vitro and in vivo. This is due to the self-regeneration of their surface, which is based on redox-cycling between 3+ and 4+ states for cerium, in response to their immediate environment. Additionally, oxygen vacancies in the lattice structure allow for alternating between CeO2 and CeO2−x during redox reactions. Research to identify and characterize the biomedical applications of CeNPs has been heavily focused on investigating their use in treating diseases that are characterized by higher levels of reactive oxygen species (ROS). Although the bio-mimetic activities of CeNPs have been extensively studied in vitro, in vivo interactions and associated protein corona formation are not well understood. This review describes: (1) the methods of synthesis for CeNPs, including the recent green synthesis methods that offer enhanced biocompatibility and a need for establishing a reference CeNP material for consistency across studies; (2) their enzyme-mimetic activities, with a focus on their antioxidant activities; and, (3) recent experimental evidence that demonstrates their ROS scavenging abilities and their potential use in personalized medicine.

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide “drugs” initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the body’s antioxidant defence, compromising redox homeostasis and increasing oxidative stress, leading to the development of several diseases. Manganese superoxide dismutase (MnSOD) is a principal antioxidant enzyme that protects cells from oxidative damage by converting superoxide anion radicals to hydrogen peroxide and oxygen in mitochondria. Systematic studies have demonstrated that MnSOD plays an indispensable role in multiple diseases. This review focuses on preclinical evidence that describes the mechanisms of MnSOD in diseases accompanied with an imbalanced redox status, including fibrotic diseases, inflammation, diabetes, vascular diseases, neurodegenerative diseases, and cancer. The potential therapeutic effects of MnSOD activators and MnSOD mimetics are also discussed. Targeting this specific superoxide anion radical scavenger may be a clinically beneficial strategy, and understanding the therapeutic role of MnSOD may provide a positive insight into preventing and treating related diseases.

Glycosaminoglycans (GAGs) are a class of biomolecules expressed virtually on all mammalian cells and usually covalently attached to proteins, forming proteoglycans. They are present not only on the cell surface, but also in the intracellular milieu and extracellular matrix. GAGs interact with multiple ligands, both soluble and insoluble, and modulate an important role in various physiological and pathological processes including cancer, bacterial and viral infections, inflammation, Alzheimer’s disease, and many more. Considering their involvement in multiple diseases, their use in the development of drugs has been of significant interest in both academia and industry. Many GAG-based drugs are being developed with encouraging results in animal models and clinical trials, showcasing their potential for development as therapeutics. In this review, the role GAGs play in both the development and inhibition of cancer and inflammation is presented. Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed.

Extracellular vesicles (EVs) hold great promise as therapeutic modalities due to their endogenous characteristics, however, further bioengineering refinement is required to address clinical and commercial limitations. Clinical applications of EV-based therapeutics are being trialed in immunomodulation, tissue regeneration and recovery, and as delivery vectors for combination therapies. Native/biological EVs possess diverse endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype. Moreover, EVs are important components of paracrine signaling in stem/progenitor cell-based therapies, are employed as standalone therapies, and can be used as a drug delivery system. Despite remarkable utility of native/biological EVs, they can be improved using bio/engineering approaches to further therapeutic potential. EVs can be engineered to harbor specific pharmaceutical content, enhance their stability, and modify surface epitopes for improved tropism and targeting to cells and tissues in vivo . Limitations currently challenging the full realization of their therapeutic utility include scalability and standardization of generation, molecular characterization for design and regulation, therapeutic potency assessment, and targeted delivery. The fields’ utilization of advanced technologies (imaging, quantitative analyses, multi-omics, labeling/live-cell reporters), and utility of biocompatible natural sources for producing EVs (plants, bacteria, milk) will play an important role in overcoming these limitations. Advancements in EV engineering methodologies and design will facilitate the development of EV-based therapeutics, revolutionizing the current pharmaceutical landscape.

Apoptosis is a form of programmed cell death that is essential for tissue homeostasis. De-regulation of the balance between proliferation and apoptosis contributes to tumor initiation. Particularly in the colon where apoptosis is a crucial process in intestinal turnover, inhibition of apoptosis facilitates transformation and tumor progression. The BCL-2 family of proteins are key regulators of apoptosis and have been implicated in colorectal cancer (CRC) initiation, progression and resistance to therapy. In this review we outline the current knowledge on the BCL-2 family-regulated intrinsic apoptosis pathway and mechanisms by which it is de-regulated in CRC. We further review BH3 mimetics as a therapeutic opportunity to target this pathway and evaluate their potential for CRC treatment.