P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators.

Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)-Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.

Design of nanosystems for melanoma treatment.

Melanoma is a prevalent and concerning form of skin cancer affecting millions of individuals worldwide. Unfortunately, traditional treatments can be invasive and painful, prompting the need for alternative therapies with improved efficacy and patient outcomes. Nanosystems offer a promising solution to these obstacles through the rational design of nanoparticles (NPs) which are structured into nanocomposite forms, offering efficient approaches to cancer treatment procedures. A range of NPs consisting of polymeric, metallic and metal oxide, carbon-based, and virus-like NPs have been studied for their potential in treating skin cancer. This review summarizes the latest developments in functional nanosystems aimed at enhancing melanoma treatment. The fundamentals of these nanosystems, including NPs and the creation of various functional nanosystem types, facilitating melanoma treatment are introduced. Then, the advances in the applications of functional nanosystems for melanoma treatment are summarized, outlining both their benefits and the challenges encountered in implementing nanosystem therapies.

Pharmaceuticals in the Environment: A hospital pharmacy's perspective. / El impacto ambiental de los medicamentos: una mirada desde la farmacia hospitalaria.

Drugs do not disappear once they have been excreted. In fact, 992 active principles have already been measured in the different environmental matrices. A recent study led by scientists from the University of York has studied the presence of drugs in the rivers of more than 100 different countries, showing that environmental contamination by pharmaceuticals is a global issue and that, concentrations found are frequently harmful to the environment. In this work, we have tried to briefly expose the problem of environmental contamination with medicines, but above all, we have tried to address the possible solutions, with a perspective from the field of hospital pharmacy. This is a very complex matter (a wicked problem), since it involves multiple stakeholders with different visions and interests regarding medicines. In order to find solutions, we will probably need to act at all steps of the drug's life cycle. Until now, health professionals have been part of the problem. It is time for us to be part of the solution.

[Translated article] Pharmaceuticals in the environment: A hospital pharmacy perspective.

Drugs do not disappear once they have been excreted. In fact, 992 active principles have already been measured in the different environmental matrices. A recent study led by scientists from the University of York has studied the presence of drugs in the rivers of more than 100 different countries, showing that environmental contamination by pharmaceuticals is a global issue and that, concentrations found are frequently harmful to the environment. In this work, we have tried to briefly expose the problem of environmental contamination with medicines, but above all, we have tried to address the possible solutions, with a perspective from the field of hospital pharmacy. This is a very complex matter (a wicked problem), since it involves multiple stakeholders with different visions and interests regarding medicines. In order to find solutions, we will probably need to act at all steps of the drug's life cycle. Until now, health professionals have been part of the problem. It is time for us to be part of the solution.

Regenerative cell therapy with 3D bioprinting.

In situ additive biomanufacturing of structures may boost regenerative medicine.

Latest progress of self-healing hydrogels in cardiac tissue engineering.

Cardiovascular diseases represent a significant public health challenge and are responsible for more than 4 million deaths annually in Europe alone (45% of all deaths). Among these, coronary-related heart diseases are a leading cause of mortality, accounting for 20% of all deaths. Cardiac tissue engineering has emerged as a promising strategy to address the limitations encountered after myocardial infarction. This approach aims to improve regulation of the inflammatory and cell proliferation phases, thereby reducing scar tissue formation and restoring cardiac function. In cardiac tissue engineering, biomaterials serve as hosts for cells and therapeutics, supporting cardiac restoration by mimicking the native cardiac environment. Various bioengineered systems, such as 3D scaffolds, injectable hydrogels, and patches play crucial roles in cardiac tissue repair. In this context, self-healing hydrogels are particularly suitable substitutes, as they can restore structural integrity when damaged. This structural healing represents a paradigm shift in therapeutic interventions, offering a more native-like environment compared to static, non-healable hydrogels. Herein, we sharply review the most recent advances in self-healing hydrogels in cardiac tissue engineering and their potential to transform cardiovascular healthcare.

A Cross-Sectional Study to Assess the Knowledge of Pharmacy Students About Drug Pollution in Spain.

The presence of pharmaceuticals in the environment is an issue of growing concern. The European Commission adopted the "European Union Strategic Approach to Pharmaceuticals in the Environment", which focuses on actions to reduce the risk of pharmaceuticals in the environment, including how environmental aspects can become part of medical training programs. OBJECTIVE: Obtain data from pharmacy students about pharmaceutical pollution to provide information about the training needs that may help develop new actions related to the training and dissemination of this issue. METHODS: A total of 1614 pharmacy students from 5 Schools of Pharmacy in Spain completed a self-administered questionnaire consisting of 24 questions: 13 about knowledge, 8 related to attitude, and 3 to opinion. RESULTS: Around 75% of students reported that they did not know "One Health" or "emerging pollutant" concepts and around 88% declared that they did not know that diclofenac caused a catastrophic vulture decline in Asia. The importance of this topic and their attitude to acquiring new knowledge was evaluated higher than 8 points out of 10, while received training during their studies was a score of 2.8 points out of 10. CONCLUSION: The knowledge about key concepts was relatively poor. In fact, they judged training about pharmaceuticals in the environment during their pharmacy studies was very scarce. However, students consider drug pollution to be a very important issue and have a very good attitude toward acquiring knowledge about it.

Wastewater-based epidemiology methodology to investigate human exposure to bisphenol A, bisphenol F and bisphenol S.

Wastewater-based epidemiology (WBE) has become an invaluable tool for tracking the evolution of use or exposure of/to numerous substances. Bisphenols, commonly utilized in manufacturing plastic goods, have been categorized as endocrine disrupting chemicals, underscoring the critical need for real-time data on their local-level exposure to safeguard public health. In this study, we have developed a novel analytical method and WBE framework for the assessment of population-level exposure to bisphenol A (BPA) and its most prominent substitutes, bisphenols F and S (BPF and BPS), through the determination their Phase II metabolites in wastewater by WBE. Stability and exclusivity tests denoted that glucuronides are not stable in sewage, whereas sulfate metabolites are good biomarkers. Therefore, a solid-phase extraction followed by liquid chromatography-tandem mass spectrometry method was developed for the bisphenols' monosulfates and BPA bissulfate. The analytical method was validated with three different wastewater matrices, providing trueness (as recovery) in the 79-112 % range with relative standard deviations < 12 %, and method quantification limits below 2 ng L-1 for monosulfates, but higher (35 ng L-1) for BPA bissulfate. Subsequently, the method was applied to 24h-composite raw wastewater samples collected over a week in 4 different locations in Spain and Portugal. BPA bissulfate was not detected, but the three monosulfate metabolites of each bisphenol were positively detected in the samples, being the metabolite of BPA the most prevalent, followed by those of BPF and BPS. Community-wide BPA intake was then estimated to be higher than the European Food Safety Agency (EFSA) tolerable daily intake (TDI) of 2 × 10-4 µg kg-1day-1 in all locations. In the case of BPF and BPS, there is not enough metabolism data or even established limit, but they would also surpass safe levels in several locations if a similar metabolism and TDI would be assumed. This innovative method could be used to a larger set of wastewater-treatment plants as an early-warning approach on human exposure to bisphenols.

Biopolymers Take Center Stage in Wound Healing Advancements.

The human body possesses a remarkable ability to heal itself from injuries [...].

Nanoliposomes as nonviral vectors in cancer gene therapy.

Nonviral vectors, such as liposomes, offer potential for targeted gene delivery in cancer therapy. Liposomes, composed of phospholipid vesicles, have demonstrated efficacy as nanocarriers for genetic tools, addressing the limitations of off-targeting and degradation commonly associated with traditional gene therapy approaches. Due to their biocompatibility, stability, and tunable physicochemical properties, they offer potential in overcoming the challenges associated with gene therapy, such as low transfection efficiency and poor stability in biological fluids. Despite these advancements, there remains a gap in understanding the optimal utilization of nanoliposomes for enhanced gene delivery in cancer treatment. This review delves into the present state of nanoliposomes as carriers for genetic tools in cancer therapy, sheds light on their potential to safeguard genetic payloads and facilitate cell internalization alongside the evolution of smart nanocarriers for targeted delivery. The challenges linked to their biocompatibility and the factors that restrict their effectiveness in gene delivery are also discussed along with exploring the potential of nanoliposomes in cancer gene therapy strategies by analyzing recent advancements and offering future directions.

Enhancing regenerative medicine with self-healing hydrogels: A solution for tissue repair and advanced cyborganic healthcare devices.

Considering the global burden related to tissue and organ injuries or failures, self-healing hydrogels may be an attractive therapeutic alternative for the future. Self-healing hydrogels are highly hydrated 3D structures with the ability to self-heal after breaking, this property is attributable to a variety of dynamic non-covalent and covalent bonds that are able to re-linking within the matrix. Self-healing ability specially benefits minimal invasive medical treatments with cell-delivery support. Moreover, those tissue-engineered self-healing hydrogels network have demonstrated effectiveness for myriad purposes; for instance, they could act as delivery-platforms for different cargos (drugs, growth factors, cells, among others) in tissues such as bone, cartilage, nerve or skin. Besides, self-healing hydrogels have currently found their way into new and novel applications; for example, with the development of the self-healing adhesive hydrogels, by merely aiding surgical closing processes and by providing biomaterial-tissue adhesion. Furthermore, conductive hydrogels permit the stimuli and monitoring of natural electrical signals, which facilitated a better fitting of hydrogels in native tissue or the diagnosis of various health diseases. Lastly, self-healing hydrogels could be part of cyborganics - a merge between biology and machinery - which can pave the way to a finer healthcare devices for diagnostics and precision therapies.

Progress in the Use of Hydrogels for Antioxidant Delivery in Skin Wounds.

The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved in delayed wound healing is oxidative injury, which is triggered by the overproduction of reactive oxygen species. Oxidative stress has been implicated in the pathogenesis of chronic wounds, where it is known to impair wound healing by causing damage to cellular components, delaying the inflammatory phase of healing, and inhibiting the formation of new blood vessels. Thereby, the treatment of chronic wounds requires a multidisciplinary approach that addresses the underlying causes of the wound, provides optimal wound care, and promotes wound healing. Among the promising approaches to taking care of chronic wounds, antioxidants are gaining interest since they offer multiple benefits related to skin health. Therefore, in this review, we will highlight the latest advances in the use of natural polymers with antioxidants to generate tissue regeneration microenvironments for skin wound healing.

A proposal to reduce the amount of permethrin entering wastewater resultant from topical use to treat scabies.

The incidence of scabies is rising in the last years. Subsequently, the use of pharmaceuticals to treat the disease has also increased. Treatment with topical permethrin is usually recommended as a first line agent. This substance is also an aquatic contaminant that is toxic for many non-target organisms, and has been included as a priority substance in the recently published proposal of the European Water Framework Directive. Current guidelines neglect the potential environmental impact of this drug, recommending that the cream should be applied head to toe and "washed off after 8-12 h". Recently, a wiping procedure before hand washing after application of the topical treatment resulted in a 66 % reduction of the amount of diclofenac released in wastewater. The authors suggested that this method could be explored for other topical treatments. In the case of scabiosis, a protocol implicating the whole body needs to be designed. The absorption of topical permethrin is low. Considering the growing incidence of scabies, the amount of the pyrethroid reaching the environment may also be increasing. Therefore, we believe that applying the wiping procedure to the case of topical permethrin deserves consideration. Other measures to minimize the amount of permethrin residues reaching wastewater by washing clothes and bed linen such as wearing single-use pijamas should also be explored. In conclusion, we need to apply a One Health approach in the treatment with scabies, without neglecting the environmental impact of pharmaceuticals. It is not rational to forget drugs once they go down the drain.

Advanced 3D imaging and organoid bioprinting for biomedical research and therapeutic applications.

Organoid cultures offer a valuable platform for studying organ-level biology, allowing for a closer mimicry of human physiology compared to traditional two-dimensional cell culture systems or non-primate animal models. While many organoid cultures use cell aggregates or decellularized extracellular matrices as scaffolds, they often lack precise biochemical and biophysical microenvironments. In contrast, three-dimensional (3D) bioprinting allows precise placement of organoids or spheroids, providing enhanced spatial control and facilitating the direct fusion for the formation of large-scale functional tissues in vitro. In addition, 3D bioprinting enables fine tuning of biochemical and biophysical cues to support organoid development and maturation. With advances in the organoid technology and its potential applications across diverse research fields such as cell biology, developmental biology, disease pathology, precision medicine, drug toxicology, and tissue engineering, organoid imaging has become a crucial aspect of physiological and pathological studies. This review highlights the recent advancements in imaging technologies that have significantly contributed to organoid research. Additionally, we discuss various bioprinting techniques, emphasizing their applications in organoid bioprinting. Integrating 3D imaging tools into a bioprinting platform allows real-time visualization while facilitating quality control, optimization, and comprehensive bioprinting assessment. Similarly, combining imaging technologies with organoid bioprinting can provide valuable insights into tissue formation, maturation, functions, and therapeutic responses. This approach not only improves the reproducibility of physiologically relevant tissues but also enhances understanding of complex biological processes. Thus, careful selection of bioprinting modalities, coupled with appropriate imaging techniques, holds the potential to create a versatile platform capable of addressing existing challenges and harnessing opportunities in these rapidly evolving fields.

Enhancing Diabetic Wound Healing Through Improved Angiogenesis: The Role of Emulsion-Based Core-Shell Micro/Nanofibrous Scaffold with Sustained CuO Nanoparticle Delivery.

Attempts are made to design a system for sustaining the delivery of copper ions into diabetic wounds and induce angiogenesis with minimal dose-dependent cytotoxicity. Here, a dual drug-delivery micro/nanofibrous core-shell system is engineered using polycaprolactone/sodium sulfated alginate-polyvinyl alcohol (PCL/SSA-PVA), as core/shell parts, by emulsion electrospinning technique to optimize sustained delivery of copper oxide nanoparticles (CuO NP). Herein, different concentrations of CuO NP (0.2, 0.4, 0.8, and 1.6%w/w) are loaded into the core part of the core-shell system. The morphological, biomechanical, and biocompatibility properties of the scaffolds are fully determined in vitro and in vivo. The 0.8%w/w CuO NP scaffold reveals the highest level of tube formation in HUVEC cells and also upregulates the pro-angiogenesis genes (VEGFA and bFGF) expression with no cytotoxicity effects. The presence of SSA and its interaction with CuO NP, and also core-shell structure sustain the release of the nanoparticles and provide a non-toxic microenvironment for cell adhesion and tube formation, with no sign of adverse immune response in vivo. The optimized scaffold significantly accelerates diabetic wound healing in a rat model. This study strongly suggests the 0.8%w/w CuO NP-loaded PCL/SSA-PVA as an excellent diabetic wound dressing with significantly improved angiogenesis and wound healing.

Chitosan-functionalized bioplatforms and hydrogels in breast cancer: immunotherapy, phototherapy and clinical perspectives.

Breast cancer is the most common and malignant tumor among women. Chitosan (CS)-based nanoparticles have been introduced into breast cancer therapy as a way to increase the targeted delivery of drugs and genes to the tumor site. CS nanostructures suppress tumorigenesis by enhancing both the targeted delivery of cargo (drug and gene) and its accumulation in tumor cells. The tumor cells internalize CS-based nanoparticles through endocytosis. Moreover, chitosan nanocarriers can also induce phototherapy-mediated tumor ablation. Smart and multifunctional types of CS nanoparticles, including pH-, light- and redox-responsive nanoparticles, can be used to improve the potential for breast cancer removal. In addition, the acceleration of immunotherapy by CS nanoparticles has also been achieved, and there is potential to develop CS-nanoparticle hydrogels that can be used to suppress tumorigenesis.

Pharmaceutical residues in stranded dolphins in the Bay of Biscay.

There is a growing concern about the presence of pharmaceuticals on the aquatic environment, while the marine environment has been much less investigated than in freshwater. Marine mammals are suitable sentinel species of the marine environment because they often feed at high trophic levels, have unique fat stores and long lifespan. Some small delphinids in particular serve as excellent sentinel species for contamination in the marine environment worldwide. To the best of our knowledge, no pharmaceuticals have been detected or reported in dolphins so far. In the present study, muscle, liver and blubber samples from three common dolphins (Delphinus delphis) and seven striped dolphins (Stenella coeruleoalba) stranded along the Basque Coast (northern Spain) were collected. A total of 95 pharmaceuticals based on detectability and predicted ability to bioaccumulate in fish were included in the liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. At least one pharmaceutical was found in 70 % of the individuals. Only three of the 95 monitored pharmaceuticals were detected in dolphin's tissues. Very low concentrations (<1 ng/g) of orphenadrine and pizotifen were found in liver and promethazine in blubber. Herein, the gap in the knowledge regarding the study organisms and marine environments with respect to pharmaceutical pollution, which demands further research to understand if pharmaceuticals are a threat for these apex predators, is highlighted and discussed.

4D Printing: The Development of Responsive Materials Using 3D-Printing Technology.

Additive manufacturing, widely known as 3D printing, has revolutionized the production of biomaterials. While conventional 3D-printed structures are perceived as static, 4D printing introduces the ability to fabricate materials capable of self-transforming their configuration or function over time in response to external stimuli such as temperature, light, or electric field. This transformative technology has garnered significant attention in the field of biomedical engineering due to its potential to address limitations associated with traditional therapies. Here, we delve into an in-depth review of 4D-printing systems, exploring their diverse biomedical applications and meticulously evaluating their advantages and disadvantages. We emphasize the novelty of this review paper by highlighting the latest advancements and emerging trends in 4D-printing technology, particularly in the context of biomedical applications.

Health financing policies during the COVID-19 pandemic and implications for universal health care: a case study of 15 countries.

BACKGROUND: The COVID-19 pandemic was a health emergency requiring rapid fiscal resource mobilisation to support national responses. The use of effective health financing mechanisms and policies, or lack thereof, affected the impact of the pandemic on the population, particularly vulnerable groups and individuals. We provide an overview and illustrative examples of health financing policies adopted in 15 countries during the pandemic, develop a framework for resilient health financing, and use this pandemic to argue a case to move towards universal health coverage (UHC). METHODS: In this case study, we examined the national health financing policy responses of 15 countries, which were purposefully selected countries to represent all WHO regions and have a range of income levels, UHC index scores, and health system typologies. We did a systematic literature review of peer-reviewed articles, policy documents, technical reports, and publicly available data on policy measures undertaken in response to the pandemic and complemented the data obtained with 61 in-depth interviews with health systems and health financing experts. We did a thematic analysis of our data and organised key themes into a conceptual framework for resilient health financing. FINDINGS: Resilient health financing for health emergencies is characterised by two main phases: (1) absorb and recover, where health systems are required to absorb the initial and subsequent shocks brought about by the pandemic and restabilise from them; and (2) sustain, where health systems need to expand and maintain fiscal space for health to move towards UHC while building on resilient health financing structures that can better prepare health systems for future health emergencies. We observed that five key financing policies were implemented across the countries-namely, use of extra-budgetary funds for a swift initial response, repurposing of existing funds, efficient fund disbursement mechanisms to ensure rapid channelisation to the intended personnel and general population, mobilisation of the private sector to mitigate the gaps in public settings, and expansion of service coverage to enhance the protection of vulnerable groups. Accountability and monitoring are needed at every stage to ensure efficient and accountable movement and use of funds, which can be achieved through strong governance and coordination, information technology, and community engagement. INTERPRETATION: Our findings suggest that health systems need to leverage the COVID-19 pandemic as a window of opportunity to make health financing policies robust and need to politically commit to public financing mechanisms that work to prepare for future emergencies and as a lever for UHC. FUNDING: Bill & Melinda Gates Foundation.