Dexrazoxane prevents vascular toxicity in doxorubicin-treated mice.

BACKGROUND: Doxorubicin (DOX) is used for breast cancer and lymphoma, but can cause cardiotoxicity, arterial stiffness, and endothelial dysfunction. We recently reported SERPINA3N as biomarker of cardiovascular toxicity in patients and mice. Dexrazoxane (DEXRA) is an FDA-approved drug that prevents DOX-induced cardiac toxicity in high-risk patients. However, the effect of DEXRA on vascular dysfunction during DOX treatment has not been documented. Therefore, here we investigated whether DEXRA protects against DOX-induced arterial stiffness, endothelial dysfunction, and SERPINA3N upregulation in tissue and plasma from mice. METHODS: Male C57BL6/J mice were treated with DOX (4 mg/kg), DEXRA (40 mg/kg), a combination (DEXRA + DOX), or VEHICLE (0.9% NaCl) weekly i.p. for 6 weeks (n = 8 per group). Cardiovascular function was measured in vivo by ultrasound imaging at baseline, weeks 2 and 6. Vascular reactivity was analyzed ex vivo in the thoracic aorta at week 6 and molecular analysis was performed. RESULTS: DEXRA prevented left ventricular ejection fraction decline by DOX (DEXRA + DOX: 62 ± 2% vs DOX: 51 ± 2%). Moreover, DEXRA prevented the increase in pulse wave velocity by DOX (DEXRA + DOX: 2.1 ± 0.2 m/s vs DOX: 4.5 ± 0.3 m/s) and preserved endothelium-dependent relaxation (DEXRA + DOX: 82 ± 3% vs DOX: 62 ± 3%). In contrast to DOX-treated mice, SERPINA3N did not increase in the DEXRA + DOX group. CONCLUSION: Our results not only confirm the cardioprotective effects of DEXRA against DOX-induced cardiotoxicity but also add preservation of vascular endothelial cell function as an important mechanism. Moreover, the study demonstrates the potential of SERPINA3N as a biomarker for monitoring cardiovascular complications of DOX in high-risk patients.

Calciprotein particles induce arterial stiffening ex vivo and impair vascular cell function.

Calciprotein particles (CPPs) are an endogenous buffering system, clearing excessive amounts of Ca2+ and PO43- from the circulation and thereby preventing ectopic mineralization. CPPs circulate as primary CPPs (CPP1), which are small spherical colloidal particles, and can aggregate to form large, crystalline, secondary CPPs (CPP2). Even though it has been reported that CPPs are toxic to vascular smooth muscle cells (VSMC) in vitro, their effect(s) on the vasculature remain unclear. Here we have shown that CPP1, but not CPP2, increased arterial stiffness ex vivo. Interestingly, the effects were more pronounced in the abdominal infrarenal aorta compared to the thoracic descending aorta. Further, we demonstrated that CPP1 affected both endothelial and VSMC function, impairing vasorelaxation and contraction respectively. Concomitantly, arterial glycosaminoglycan accumulation was observed as well, which is indicative of an increased extracellular matrix stiffness. However, these effects were not observed in vivo. Hence, we concluded that CPP1 can induce vascular dysfunction.

Use of the BRANT-MERQS scoring table for the quality assessment of type 3 medication review in patients with rheumatoid arthritis and those with type 2 diabetes mellitus.

Background: A type 3 medication review (MR3) is a patient-centred medication service primarily provided by pharmacists and is presently employed routinely in several countries. In this process, pharmacists interview patients and collaborate with the treating physician to optimize the patient's pharmacotherapy, taking into account the patient's medication history and other medical data including laboratory values. The need to maintain the quality of such interventions during and after their initial implementation cannot be overstated. Aim: The objective of this study was to refine and assess a scoring table to evaluate the quality of MR3 conducted in Belgian community pharmacies. Methods: The comprehensive quality of MR3s was assessed by scoring its various components using a previously developed scoring table, called BRANT-MERQS, Brussels Antwerp Medication Review Quality Score. MR3s were analysed from an implementation study with patients suffering from rheumatoid arthritis (RA, subproject 1) and type 2 diabetes mellitus (T2DM, subproject 2). Additional information was obtained during a telephone call with a subset of participating pharmacists of subproject 1 who finalized their first MR3. Results: In subproject 1, a total of 21 MR3s of patients with RA were examined. The assessment showed favourable scores for elements such as a well-organized medication schedule, treatment adherence, and the elaboration of specific interventions. However, certain other quality criteria posed challenges in the evaluation, for example, the use of simple and understandable language. Pharmacists faced time constraints, and elderly general practitioners (GPs) displayed limited enthusiasm, which were notable barriers observed for this subproject. In the context of subproject 2 that investigated 41 MR3s in patients with T2DM, the quality criteria of interaction between pharmacist and GP, and used sources and tools received high scores. However, there was still room for improvement, especially in areas such as accurate dosing, handling kidney function, QT prolongation, correctly associating laboratory values with relevant drugs and medical conditions, and optimisation of medication schedules for patients. Conclusion: This study demonstrated the feasibility of MR3 quality assessment through a scoring system. However, it also unveiled the tool's current imperfections and highlighted the ongoing need for refinement, something expected of a new service in an implementation phase.

NR0B2 Is a Key Factor for Gastric Diseases: A GEO Database Analysis Combined with Drug-Target Mendelian Randomization.

Small Heterodimer Partner (SHP; NR0B2) is an orphan receptor that acts as a transcriptional regulator, controlling various metabolic processes, and is a potential therapeutic target for cancer. Examining the correlation between the expression of NR0B2 and the risk of gastric diseases could open a new path for treatment and drug development. The Gene Expression Omnibus (GEO) database was utilized to explore NR0B2 gene expression profiles in gastric diseases. Co-expressed genes were identified through Weighted Correlation Network Analysis (WGCNA), and GO enrichment was performed to identify potential pathways. The Xcell method was employed to analyze immune infiltration relationships. To determine the potential causal relationship between NR0B2 expression and gastric diseases, we identified six single-nucleotide polymorphisms (SNPs) as a proxy for NR0B2 expression located within 100 kilobases of NR0B2 and which are associated with triglyceride homeostasis and performed drug-target Mendelian randomization (MR). Bioinformatics analysis revealed that NR0B2 expression levels were reduced in gastric cancer and increased in gastritis. GO analysis and Gene Set Enrichment Analysis (GSEA) showed that NR0B2 is widely involved in oxidation-related processes. Immune infiltration analyses found that NR0B2 was associated with Treg. Prognostic analyses showed that a low expression of NR0B2 is a risk factor for the poor prognoses of gastric cancer. MR analyses revealed that NR0B2 expression is associated with a risk of gastric diseases (NR0B2 vs. gastric cancer, p = 0.006, OR: 0.073, 95%CI: 0.011-0.478; NR0B2 vs. gastric ulcer, p = 0.03, OR: 0.991, 95%CI: 0.984-0.999; NR0B2 vs. other gastritis, p = 0.006, OR:3.82, 95%CI: 1.468-9.942). Our study confirms the causal relationship between the expression of NR0B2 and the risk of gastric diseases, and highlights its role in the progression of gastric cancer. The present study opens new avenues for exploring the potential of drugs that either activate or inhibit the NR0B2 receptor in the treatment of gastric diseases.

Carbon emissions from the 2023 Canadian wildfires.

The 2023 Canadian forest fires have been extreme in scale and intensity with more than seven times the average annual area burned compared to the previous four decades1. Here, we quantify the carbon emissions from these fires from May to September 2023 on the basis of inverse modelling of satellite carbon monoxide observations. We find that the magnitude of the carbon emissions is 647 TgC (570-727 TgC), comparable to the annual fossil fuel emissions of large nations, with only India, China and the USA releasing more carbon per year2. We find that widespread hot-dry weather was a principal driver of fire spread, with 2023 being the warmest and driest year since at least 19803. Although temperatures were extreme relative to the historical record, climate projections indicate that these temperatures are likely to be typical during the 2050s, even under a moderate climate mitigation scenario (shared socioeconomic pathway, SSP 2-4.5)4. Such conditions are likely to drive increased fire activity and suppress carbon uptake by Canadian forests, adding to concerns about the long-term durability of these forests as a carbon sink5-8.

Unravelling the impact of active and passive contributors to arterial stiffness in male mice and their role in vascular aging.

Arterial stiffness, a key indicator of vascular health, encompassing active (vascular tone) and passive (extracellular matrix) components. This study aims to address how these different components affect arterial stiffness along the aorta and the influence of aging. Aortic segments of 12 week and 24 month old (both n = 6) male C57BL/6J mice were mounted in a Rodent Oscillatory Set-up to study Arterial Compliance, in order to measure arterial stiffness and vascular reactivity. Regional variations in arterial stiffness were evident, with abdominal infrarenal aorta (AIA) exhibiting highest stiffness and smallest diameters. AIA displayed both the highest amount of collagen and collagen:elastin ratio. Regional ex vivo vascular reactivity revealed heightened AIA contractions and lowered NO availability. Aging is a significant factor contributing towards vessel remodelling and arterial stiffness. Aging increased arterial stiffness, aortic diameters, collagen content, and reduced VSMC contraction. The results of this study could identify specific regions or mechanisms to target in the development of innovative therapeutic interventions aimed at enhancing overall vascular health.

Use of Magnetic Resonance Direct Thrombus Imaging for the Diagnostic Management of Suspected Thrombosis in Routine Clinical Practice.

Background The noninvasive magnetic resonance direct thrombus imaging (MRDTI) technique can be used to diagnose acute deep vein thrombosis (DVT), without the use of intravenous contrast. MRDTI holds the potential to differentiate between acute and chronic DVT and could be helpful when diagnosing thrombosis is challenging. Objectives Our objective was to evaluate the application of MRDTI in clinical practice, including the frequency and indications of MRDTI scans performed in practice-based conditions, results, impact on treatment decisions, and associated patient outcomes. Methods A retrospective study was performed at the Leiden University Medical Center, the Netherlands. MRDTI scans performed since its implementation in patients aged ≥18 years as part of clinical practice for the diagnostic management of suspected thrombosis were evaluated. Results Between October 2015 and September 2023, 36 patients had undergone MRDTI for the diagnostic evaluation of thrombosis. MRDTI application increased since 2019 (five-eight scans per year). The most common indication was to differentiate between acute and chronic thrombosis, mainly for suspected recurrent ipsilateral DVT after inconclusive compression ultrasonography. In over a third of patients, acute thrombosis was confirmed by MRDTI. MRDTI results determined treatment decisions in all except two patients. One patient had symptomatic thrombosis of the lower extremity within 3 months after an MRDTI of the upper extremity without signs of acute thrombosis (1/23; 4.3%, 95% confidence interval: 0.77-21). Conclusion Over the past 4 years, MRDTI has been used increasingly in our hospital. MRDTI results guided treatment decisions, which confirms the clinical impact and feasibility of its application in daily practice.

The study of galactomannans with different molecular weights and their ability to form microparticles suitable for pulmonary delivery.

The influence of locust bean gum (LBG) galactomannans (GMs) molecular weight (Mw) to assemble microparticulate systems was evaluated, and carriers for deep lung delivery were developed. A commercial batch of LBG with a mannose/galactose (M/G) ratio of 2.4 (batch 1) was used to study the influence of different microwave partial acid hydrolysis conditions on carbohydrate composition, glycosidic linkages, and aqueous solutions viscosity. The microwave treatment did not affect the composition, presenting 4-Man (36-42 %), 4,6-Man (27-35 %), and T-Gal (24-25 %) as the main glycosidic linkages. Depolymerization led to a viscosity reduction (≤0.005 Pa·s) with no major impact on polysaccharide debranching. The structural composition of the LBG galactomannans were further elucidated with sequence-specific proteins using carbohydrate microarray technologies. A second batch of LBG (M/G 3.3) was used to study the impact of GMs with different Mw on microparticle assembling, characteristics, and insulin release kinetics. The low-Mw GMs microparticles led to a faster release (20 min) than the higher-Mw (40 min) ones, impacting the release kinetics. All microparticles exhibited a safety profile to cells of the respiratory tract. However, only the higher-Mw GMs allowed the assembly of microparticles with sizes suitable for this type of administration.

Characterization of systolic and diastolic function, alongside proteomic profiling, in doxorubicin-induced cardiovascular toxicity in mice.

BACKGROUND: The anthracycline doxorubicin (DOX) is a highly effective anticancer agent, especially in breast cancer and lymphoma. However, DOX can cause cancer therapy-related cardiovascular toxicity (CTR-CVT) in patients during treatment and in survivors. Current diagnostic criteria for CTR-CVT focus mainly on left ventricular systolic dysfunction, but a certain level of damage is required before it can be detected. As diastolic dysfunction often precedes systolic dysfunction, the current study aimed to identify functional and molecular markers of DOX-induced CTR-CVT with a focus on diastolic dysfunction. METHODS: Male C57BL/6J mice were treated with saline or DOX (4 mg/kg, weekly i.p. injection) for 2 and 6 weeks (respectively cumulative dose of 8 and 24 mg/kg) (n = 8 per group at each time point). Cardiovascular function was longitudinally investigated using echocardiography and invasive left ventricular pressure measurements. Subsequently, at both timepoints, myocardial tissue was obtained for proteomics (liquid-chromatography with mass-spectrometry). A cohort of patients with CTR-CVT was used to complement the pre-clinical findings. RESULTS: DOX-induced a reduction in left ventricular ejection fraction from 72 ± 2% to 55 ± 1% after 2 weeks (cumulative 8 mg/kg DOX). Diastolic dysfunction was demonstrated as prolonged relaxation (increased tau) and heart failure was evident from pulmonary edema after 6 weeks (cumulative 24 mg/kg DOX). Myocardial proteomic analysis revealed an increased expression of 12 proteins at week 6, with notable upregulation of SERPINA3N in the DOX-treated animals. The human ortholog SERPINA3 has previously been suggested as a marker in CTR-CVT. Upregulation of SERPINA3N was confirmed by western blot, immunohistochemistry, and qPCR in murine hearts. Thereby, SERPINA3N was most abundant in the endothelial cells. In patients, circulating SERPINA3 was increased in plasma of CTR-CVT patients but not in cardiac biopsies. CONCLUSION: We showed that mice develop heart failure with impaired systolic and diastolic function as result of DOX treatment. Additionally, we could identify increased SERPINA3 levels in the mice as well as patients with DOX-induced CVT and demonstrated expression of SERPINA3 in the heart itself, suggesting that SERPINA3 could serve as a novel biomarker.

α-Tocopherol inhibits atherogenesis and improves cardiac function in mice independently of its antioxidant properties.

The impact of α-tocopherol on atherosclerosis is unclear and controversial. While some studies suggest potential benefits, such as antioxidant properties that may reduce oxidative stress, other studies indicate no significant preventive effects. The intricate interplay of various factors, including dosage, individual differences, and study methodologies, contributes to the ongoing uncertainty surrounding α-tocopherol's role in atherosclerosis. Further research is needed to clarify its impact and establish clearer guidelines. Therefore, we aimed to evaluate the impact of α-tocopherol on atherogenesis in ApoE-/- fibrillin (Fbn)1C1039G/+ mice, which is a unique mouse model of advanced atherosclerosis with typical features, such as large necrotic cores, high levels of inflammation, and intraplaque neovascularization, that resemble the unstable phenotype of human plaques. ApoE-/- Fbn1C1039G+/- mice were fed a western-type diet (WD) supplemented with a high dose of α-tocopherol (500 mg/kg diet), while control mice were fed a WD containing a low dose of α-tocopherol (50 mg/kg diet). The high dose of α-tocopherol reduced plaque thickness and necrotic core area in the right common carotid artery (RCCA) after 24 weeks WD. Moreover, α-tocopherol decreased plaque formation and intraplaque neovascularization in the RCCA. In addition to its antiatherogenic effect, chronic supplementation of α-tocopherol improved cardiac function in ApoE-/- Fbn1C1039G/+ mice. However, chronic supplementation of α-tocopherol did not decrease lipid peroxidation. On the contrary, α-tocopherol acted as a prooxidant by increasing plasma levels of oxidized LDL and plaque malondialdehyde, an end product of lipid peroxidation. Our data indicate that α-tocopherol inhibits atherogenesis and improves cardiac function independent of its antioxidant properties.

GPX4 overexpression does not alter atherosclerotic plaque development in ApoE knock-out mice.

Ferroptosis is a type of regulated necrosis that is associated with iron-dependent accumulation of lipid hydroperoxides. Given that iron deposition and lipid peroxidation initiate ferroptosis in atherosclerosis and contribute to further plaque development, we hypothesized that inhibition of ferroptosis could be of value in the treatment of atherosclerosis. Glutathione peroxidase 4 (GPX4) is the only enzyme known capable of reducing lipid hydroperoxides. Previous studies have demonstrated that inactivation of GPX4 results in ferroptosis, while overexpression of GPX4 confers resistance to ferroptosis. In the present study, we examined the impact of GPX4 overexpression on the development of atherosclerotic plaques. GPX4-overexpressing mice (GPX4Tg/+) were crossbred with ApoE-/- mice and fed a western-type diet for 16 weeks. Atherosclerotic plaques of GPX4Tg/+ ApoE-/- mice showed increased GPX4 expression and a reduced amount of lipid hydroperoxides. However, plaque size and composition were not different as compared to control animals. Similarly, GPX4-overexpressing vascular smooth muscle cells and bone marrow-derived macrophages were not protected against lipid peroxidation and cell death triggered by the ferroptosis inducers erastin and 1S,3R-RSL3. We concluded that GPX4 overexpression reduces lipid peroxidation in plaques of ApoE-/- mice, yet GPX4 overexpression is not sufficiently powerful to change plaque size or composition.

Design and Synthesis of 1,3-Diarylpyrazoles and Investigation of Their Cytotoxicity and Antiparasitic Profile.

Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound 26/HIT 8. We previously identified this molecule as a 'hit' during a high-throughput screening campaign for autophagy inducers. A variety of synthetic strategies were utilized to modify the 1,3-diarylpyrazole core at its 1-, 3-, and 4-position. Compounds were assessed in vitro to identify their cytotoxicity properties. Of note, several compounds in the series displayed relevant cytotoxicity, which warrants scrutiny while interpreting biological activities that have been reported for structurally related molecules. In addition, antiparasitic activities were recorded against a range of human-infective protozoa, including Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania infantum. The most interesting compounds displayed low micromolar whole-cell potencies against individual or several parasitic species, while lacking cytotoxicity against human cells.

Insights into Orbital Symmetry: A Comprehensive Retrospective Study of 372 Computed Tomography Scans.

Background: The operation planning and production of individualized implants with the help of AI-based software after orbital fractures have become increasingly important in recent years. This retrospective study aimed to investigate the healthy orbitae of 372 patients from CT images in the bone and soft tissue windows using the Disior™ Bonelogic™ CMF Orbital software. (version 2.1.28). Methods: We analyzed the variables orbital volume, length, and area as a function of age and gender and compared bone and soft tissue windows. Results: For all variables, the intraclass correlation showed excellent agreement between the bone and soft tissue windows (p < 0.001). All variables showed higher values when calculated based on bone fenestration with, on average, 1 mL more volume, 0.35 mm more length, and 0.71 cm2 more area (p < 0.001). Across all age groups, men displayed higher values than women with, on average, 8.1 mL larger volume, a 4.78 mm longer orbit, and an 8.5 cm2 larger orbital area (p < 0.001). There was also a non-significant trend in all variables and both sexes toward growth with increasing age. Conclusions: These results mean that, due to the symmetry of the orbits in both the bone and soft tissue windows, the healthy orbit can be mirrored for surgical planning in the event of a fracture.

Medication Review: What's in a Name and What Is It about?

BACKGROUND: Medication review is a multifaceted service aimed at optimizing the use of medicines and enhancing the health outcomes of patients. Due to its complexity, it is crucial to clearly describe the service, its variants, and its components to avoid confusion and ensure a better understanding of medication review among healthcare providers. AIM: This study aims to bring clarity to the origins, definitions, abbreviations, and types of medication reviews, together with the primary criteria that delineate key features of this service. METHOD: A narrative review approach was employed to clarify the diverse terminology associated with "medication review" services. Relevant references were initially identified through searches on PubMed and Google Scholar, complementing the existing literature known to the authors. RESULTS: The study uncovers a complicated and sometimes convoluted history of "medication review" in different regions around the world. The initial optimization of medicine use had an economic purpose before evolving subsequently into a more patient-oriented approach. A selection of abbreviations, definitions, and types were outlined to enhance the understanding of the service. CONCLUSIONS: The study underscores the urgent need for comprehensive information and standardization regarding the content and quality of the services, collectively referred to as "medication review".

Programmed death of macrophages in atherosclerosis: mechanisms and therapeutic targets.

Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable and detrimental functions. Early in atherogenesis, macrophages can clear cytotoxic lipoproteins and dead cells, preventing cytotoxicity. Efferocytosis - the efficient clearance of dead cells by macrophages - is crucial for preventing secondary necrosis and stimulating the release of anti-inflammatory cytokines. In addition, macrophages can promote tissue repair and proliferation of vascular smooth muscle cells, thereby increasing plaque stability. However, advanced atherosclerotic plaques contain large numbers of pro-inflammatory macrophages that secrete matrix-degrading enzymes, induce death in surrounding cells and contribute to plaque destabilization and rupture. Importantly, macrophages in the plaque can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. Regulated necrosis has an important role in the formation and expansion of the necrotic core during plaque progression, and several triggers for necrosis are present within atherosclerotic plaques. This Review focuses on the various forms of programmed macrophage death in atherosclerosis and the pharmacological interventions that target them as a potential means of stabilizing vulnerable plaques and improving the efficacy of currently available anti-atherosclerotic therapies.

Threefold reduction of modeled uncertainty in direct radiative effects over biomass burning regions by constraining absorbing aerosols.

Absorbing aerosols emitted from biomass burning (BB) greatly affect the radiation balance, cloudiness, and circulation over tropical regions. Assessments of these impacts rely heavily on the modeled aerosol absorption from poorly constrained global models and thus exhibit large uncertainties. By combining the AeroCom model ensemble with satellite and in situ observations, we provide constraints on the aerosol absorption optical depth (AAOD) over the Amazon and Africa. Our approach enables identification of error contributions from emission, lifetime, and MAC (mass absorption coefficient) per model, with MAC and emission dominating the AAOD errors over Amazon and Africa, respectively. In addition to primary emissions, our analysis suggests substantial formation of secondary organic aerosols over the Amazon but not over Africa. Furthermore, we find that differences in direct aerosol radiative effects between models decrease by threefold over the BB source and outflow regions after correcting the identified errors. This highlights the potential to greatly reduce the uncertainty in the most uncertain radiative forcing agent.

Dexrazoxane does not mitigate early vascular toxicity induced by doxorubicin in mice.

Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established in vivo and ex vivo model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg/kg) or DOX with DEXRA (40 mg/kg) to male C57BL6/J mice. In parallel, vascular reactivity was evaluated after ex vivo incubation (16h) of murine aortic segments with DOX (1 µM) or DOX with DEXRA (10 µM). In both in vivo and ex vivo experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the ex vivo setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-IIß (TOP-IIß), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 µM), a reactive oxygen species (ROS) scavenger, was evaluated ex vivo. NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-IIß-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.

Pharmacological modulation of vascular ageing: A review from VascAgeNet.

Vascular ageing, characterized by structural and functional changes in blood vessels of which arterial stiffness and endothelial dysfunction are key components, is associated with increased risk of cardiovascular and other age-related diseases. As the global population continues to age, understanding the underlying mechanisms and developing effective therapeutic interventions to mitigate vascular ageing becomes crucial for improving cardiovascular health outcomes. Therefore, this review provides an overview of the current knowledge on pharmacological modulation of vascular ageing, highlighting key strategies and promising therapeutic targets. Several molecular pathways have been identified as central players in vascular ageing, including oxidative stress and inflammation, the renin-angiotensin-aldosterone system, cellular senescence, macroautophagy, extracellular matrix remodelling, calcification, and gasotransmitter-related signalling. Pharmacological and dietary interventions targeting these pathways have shown potential in ameliorating age-related vascular changes. Nevertheless, the development and application of drugs targeting vascular ageing is complicated by various inherent challenges and limitations, such as certain preclinical methodological considerations, interactions with exercise training and sex/gender-related differences, which should be taken into account. Overall, pharmacological modulation of endothelial dysfunction and arterial stiffness as hallmarks of vascular ageing, holds great promise for improving cardiovascular health in the ageing population. Nonetheless, further research is needed to fully elucidate the underlying mechanisms and optimize the efficacy and safety of these interventions for clinical translation.

Key elements in the quality assessment of a type 3 medication review.

Background: Medication reviews are a structured evaluation of a patient's pharmacotherapy with the aim of optimizing medicines use and improving health outcomes. This entails detecting drug related problems and recommending interventions. A high level of quality is essential for the successful implementation of this service in community pharmacies but currently there is no instrument or tool to assess that overall quality. Aim: This study investigated the development of quality criteria of type 3 medication reviews (MR3s). Methods: After surveying the literature, an electronic questionnaire was developed to gather information about quality criteria for MR3. This survey, in Dutch, was distributed electronically. Four groups were queried: 1) pharmacists, mainly working in the Netherlands, involved in practice research and contacted through the PRISMA (Practice Research In Collaboration With Pharmacists) foundation, 2) Belgian pharmacy academics and pharmacists active in professional associations (APA), 3) Belgian pharmacists trained in medication review (MR) by the Royal Pharmacists Association of Antwerp (KAVA) and 4) Belgian pharmacy students. The survey included 57 criteria, divided into eight domains, which were ranked according to their importance by the participants. The results were analyzed statistically using the nonparametric Kruskal-Wallis test. Results: The survey was completed by 95 participants, including 42 PRISMA pharmacists, 19 APA pharmacists, 18 KAVA pharmacists and 16 pharmacy students. Opinions from participants from the different groups overlapped significantly. The use of simple and understandable language in the conversation with the patient was considered essential by the majority. Discussing the usefulness and purpose of a MR3 with the patient was also rated highly by all groups. Differences of opinion were present in aspects about laboratory values, the use of specific tools, and reporting to and consultation with the treating physician. The participants themselves formulated a limited number of additional assessment criteria. Conclusion: There was widespread agreement on the hierarchy of the quality assessment criteria for MR3s. Minor differences were related to the experience of the participants. With these results and a small number of suggested extra criteria, a quality assessment instrument for MR3 can be created.

Unraveling the Antioxidant Activity of 2R,3R-dihydroquercetin.

It has been reported that in an oxidative environment, the flavonoid 2R,3R-dihydroquercetin (2R,3R-DHQ) oxidizes into a product that rearranges to form quercetin. As quercetin is a very potent antioxidant, much better than 2R,3R-DHQ, this would be an intriguing form of targeting the antioxidant quercetin. The aim of the present study is to further elaborate on this targeting. We can confirm the previous observation that 2R,3R-DHQ is oxidized by horseradish peroxidase (HRP), with H2O2 as the oxidant. However, HPLC analysis revealed that no quercetin was formed, but instead an unstable oxidation product. The inclusion of glutathione (GSH) during the oxidation process resulted in the formation of a 2R,3R-DHQ-GSH adduct, as was identified using HPLC with IT-TOF/MS detection. GSH adducts appeared on the B-ring of the 2R,3R-DHQ quinone, indicating that during oxidation, the B-ring is oxidized from a catechol to form a quinone group. Ascorbate could reduce the quinone back to 2R,3R-DHQ. No 2S,3R-DHQ was detected after the reduction by ascorbate, indicating that a possible epimerization of 2R,3R-DHQ quinone to 2S,3R-DHQ quinone does not occur. The fact that no epimerization of the oxidized product of 2R,3R-DHQ is observed, and that GSH adducts the oxidized product of 2R,3R-DHQ on the B-ring, led us to conclude that the redox-modulating activity of 2R,3R-DHQ quinone resides in its B-ring. This could be confirmed by chemical calculation. Apparently, the administration of 2R,3R-DHQ in an oxidative environment does not result in 'biotargeting' quercetin.