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Extracellular vesicles (EVs) hold great promise for clinical application as new diagnostic and therapeutic modalities. This paper describes major GMP-based upstream and downstream manufacturing processes for EV large-scale production, also focusing on post-processing technologies such as surface bioengineering and uploading studies to yield novel EV-based diagnostics and advanced therapy medicinal products. This paper also focuses on the quality, safety, and efficacy issues of the bioengineered EV drug candidates before first-in-human studies. Because clinical trials involving extracellular vesicles are on the global rise, this paper encompasses different clinical studies registered on clinical-trial register platforms, with varying levels of advancement, highlighting the growing interest in EV-related clinical programs. Navigating the regulatory affairs of EVs poses real challenges, and obtaining marketing authorization for EV-based medicines remains complex due to the lack of specific regulatory guidelines for such novel products. This paper discusses the state-of-the-art regulatory knowledge to date on EV-based diagnostics and medicinal products, highlighting further research and global regulatory needs for the safe and reliable implementation of bioengineered EVs as diagnostic and therapeutic tools in clinical settings. Post-marketing pharmacovigilance for EV-based medicinal products is also presented, mainly addressing such topics as risk assessment and risk management. [ABSTRACT FROM AUTHOR]

Sarcopenia is a prevalent degenerative skeletal muscle condition in the elderly population, posing a tremendous burden on diseased individuals and healthcare systems worldwide. Conventionally, sarcopenia is currently managed through nutritional interventions, physical therapy, and lifestyle modification, with no pharmaceutical agents being approved for specific use in this disease. As the pathogenesis of sarcopenia is still poorly understood and there is no treatment recognized as universally effective, recent research efforts have been directed at better comprehending this illness and diversifying treatment strategies. In this respect, this paper overviews the new advances in sarcopenia treatment in correlation with its underlying mechanisms. Specifically, this review creates an updated framework for sarcopenia, describing its etiology, pathogenesis, risk factors, and conventional treatments, further discussing emerging therapeutic approaches like new drug formulations, drug delivery systems, stem cell therapies, and tissue-engineered scaffolds in more detail. [ABSTRACT FROM AUTHOR]

Achieving glycemic control and sustaining functional pancreatic β-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM). Glucokinase activators (GKAs) constitute a class of anti-diabetic drugs designed to regulate blood sugar levels and enhance β-cell function in patients with diabetes. A significant progression in GKA development is underway to address the limitations of earlier generations. Dorzagliatin, a dual-acting GKA, targets both the liver and pancreas and has successfully completed two phase III trials, demonstrating favorable results in diabetes treatment. The hepato-selective GKA, TTP399, emerges as a strong contender, displaying clinically noteworthy outcomes with minimal adverse effects. This paper seeks to review the current literature, delve into the mechanisms of action of these new-generation GKAs, and assess their efficacy and safety in treating T2DM based on published preclinical studies and recent clinical trials. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) hold great promise for clinical application as new diagnostic and therapeutic modalities. This paper describes major GMP-based upstream and downstream manufacturing processes for EV large-scale production, also focusing on post-processing technologies such as surface bioengineering and uploading studies to yield novel EV-based diagnostics and advanced therapy medicinal products. This paper also focuses on the quality, safety, and efficacy issues of the bioengineered EV drug candidates before first-in-human studies. Because clinical trials involving extracellular vesicles are on the global rise, this paper encompasses different clinical studies registered on clinical-trial register platforms, with varying levels of advancement, highlighting the growing interest in EV-related clinical programs. Navigating the regulatory affairs of EVs poses real challenges, and obtaining marketing authorization for EV-based medicines remains complex due to the lack of specific regulatory guidelines for such novel products. This paper discusses the state-of-the-art regulatory knowledge to date on EV-based diagnostics and medicinal products, highlighting further research and global regulatory needs for the safe and reliable implementation of bioengineered EVs as diagnostic and therapeutic tools in clinical settings. Post-marketing pharmacovigilance for EV-based medicinal products is also presented, mainly addressing such topics as risk assessment and risk management.

The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from "nonalcoholic fatty liver disease" (NAFLD) to "metabolic dysfunction-associated fatty liver disease" (MAFLD) and, finally, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut–liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH. [ABSTRACT FROM AUTHOR]

In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, DReAmocracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, DReAmocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease. [ABSTRACT FROM AUTHOR]

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments. [ABSTRACT FROM AUTHOR]

Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer's disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases. [ABSTRACT FROM AUTHOR]

Thyroid cancer, particularly undifferentiated tumors, poses a significant challenge due to its limited response to standard therapies. The incidence of thyroid cancer, predominantly differentiated carcinomas, is on the rise globally. Anaplastic thyroid carcinoma (ATC), though rare, is highly aggressive and challenging to treat. Therefore, this study aimed to collect data and explore alternative treatments, focusing on the efficacy of photodynamic therapy (PDT) combined with natural compounds as well as the potential role of phytochemicals, including quercetin, kaempferol, apigenin, genistein, daidzein, naringenin, hesperitin, anthocyanidins, epigallocatechin gallate (EGCG), resveratrol, ellagic acid, ferulic acid, caffeic acid, curcumin, saponins, ursolic acid, indole-3-carbinol (I3C), capsaicin, and piperine in thyroid cancer treatment. PDT, utilizing sensitizers activated by tumor-directed light, demonstrates promising specificity compared to traditional treatments. Combining PDT with natural photosensitizers, such as hypericin and genistein, enhances cytotoxicity against thyroid carcinoma cells. This literature review summarizes the current knowledge on phytochemicals and their anti-proliferative effects in in vitro and in vivo studies, emphasizing their effectiveness and mechanism of action as a novel therapeutic approach for thyroid cancers, especially those refractory to standard treatments. [ABSTRACT FROM AUTHOR]

Food allergy (FA) affects approximately 6–8% of children worldwide causing a significant impact on the quality of life of children and their families. In past years, the possible role of weaning in the development of FA has been studied. According to recent studies, this is still controversial and influenced by several factors, such as the type of food, the age at food introduction and family history. In this narrative review, we aimed to collect the most recent evidence about weaning and its role in FA development, organizing the gathered data based on both the type of study and the food. As shown in most of the studies included in this review, early food introduction did not show a potential protective role against FA development, and we conclude that further evidence is needed from future clinical trials. [ABSTRACT FROM AUTHOR]

The dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway can lead to uncontrolled cellular growth and tumorigenesis. Targeting PI3K and its downstream substrates has been shown to be effective in preclinical studies and phase III trials with the approval of several PI3K pathway inhibitors by the Food and Drug Administration (FDA) over the past decade. However, the limited clinical efficacy of these inhibitors, intolerable toxicities, and acquired resistances limit the clinical application of PI3K inhibitors. This review discusses the PI3K signaling pathway, alterations in the PI3K pathway causing carcinogenesis, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, challenging issues, and future directions of PI3K pathway inhibitors. [ABSTRACT FROM AUTHOR]

Tumorigenic assays are used during a clinical translation to detect the transformation potential of cell-based therapies. One of these in vivo assays is based on the separate injection of each cell type to be used in the clinical trial. However, the injection method requires many animals and several months to obtain useful results. In previous studies, we showed the potential of tissue-engineered skin substitutes (TESs) as a model for normal skin in which cancer cells can be included in vitro. Herein, we showed a new method to study tumorigenicity, using cancer spheroids that were embedded in TESs (cTES) and grafted onto athymic mice, and compared it with the commonly used cell injection assay. Tumors developed in both models, cancer cell injection and cTES grafting, but metastases were not detected at the time of sacrifice. Interestingly, the rate of tumor development was faster in cTESs than with the injection method. In conclusion, grafting TESs is a sensitive method to detect tumor cell growth with and could be developed as an alternative test for tumorigenicity. [ABSTRACT FROM AUTHOR]

Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current 'state-of-play' and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol's potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. In conclusion, over the last 20 years, the increasing weight of clinical evidence suggests resveratrol can benefit human health, but more large, high-quality clinical trials are required to transition this intriguing compound from health food shops to the clinic. [ABSTRACT FROM AUTHOR]

Achieving glycemic control and sustaining functional pancreatic β-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM). Glucokinase activators (GKAs) constitute a class of anti-diabetic drugs designed to regulate blood sugar levels and enhance β-cell function in patients with diabetes. A significant progression in GKA development is underway to address the limitations of earlier generations. Dorzagliatin, a dual-acting GKA, targets both the liver and pancreas and has successfully completed two phase III trials, demonstrating favorable results in diabetes treatment. The hepato-selective GKA, TTP399, emerges as a strong contender, displaying clinically noteworthy outcomes with minimal adverse effects. This paper seeks to review the current literature, delve into the mechanisms of action of these new-generation GKAs, and assess their efficacy and safety in treating T2DM based on published preclinical studies and recent clinical trials.