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This annual review marks the eighth in the series starting with Baillie et al. (2016) Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation. Its format is to highlight important aspects captured in synopsis followed by a commentary with relevant figure and references.
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Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.
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Carboxylic acids are key pharmacophoric elements in many molecules. They can be seen as a problem by some, due to perceived permeability challenges, potential for high plasma protein binding and the risk of forming reactive metabolites due to acyl-glucuronidation. By others they are viewed more favorably as they can decrease lipophilicity by adding an ionizable center which can be beneficial for solubility, and can add enthalpic interactions with the target protein. However, there are many instances where the replacement of a carboxylic acid with a bioisosteric group is required. This has led to the development of a number of ionizable groups which sufficiently mimic the carboxylic acid functionality whilst improving, for example, the metabolic profile of the molecule in question. An alternative strategy involves replacement of the carboxylate by neutral functional groups. This review initially details carefully selected examples whereby tetrazoles, acyl sulfonamides or isoxazolols have been beneficially utilized as carboxylic acid bioisosteres altering physicohemical properties, interactions with the target and metabolism and/or pharmacokinetics, before delving further into the binding mode of carboxylic acid derivatives with their target proteins. This analysis highlights new ways to consider the replacement of carboxylic acids by neutral bioisosteric groups which either rely on hydrogen bonds or cation-π interactions. It should serve as a useful guide for scientists working in drug discovery.
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Ácidos Carboxílicos , Ácidos Carboxílicos/química , Descoberta de Drogas , Ligação Proteica , Sulfonamidas/química , Tetrazóis/químicaRESUMO
Pre-eclampsia is a serious complication of pregnancy characterized by a state of multiorgan hypertensive disorders, with or without proteinuria and possible multiorgan dysfunction. Chronic kidney disease is an established risk factor for the development of pre-eclampsia, as angiogenic homeostasis is altered and the maternal circulation is already hypertensive. Facing pre-eclampsia in the context of chronic kidney disease is a challenging emergency for both the mother and the fetus. The clinical features and the management of this multi-organ disorder are clearly defined in the modern literature but the underlying pathophysiologic mechanisms remain not fully elucidated. Understanding the pathophysiology that mediates the onset of pre-eclampsia itself and in synergy with chronic kidney disease is fundamental for developing prompt prevention strategies, treatment planning, and patient counseling. This review aims to summarize the main molecular mechanisms involved in the process of pre-eclampsia, with a particular focus on the role of the kidneys and hormonal pathways related to renal function in normal pregnancy and pre-eclamptic syndromes.
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Hipertensão , Pré-Eclâmpsia , Insuficiência Renal Crônica , Gravidez , Feminino , Humanos , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/complicaçõesRESUMO
Metabolic dysfunction-associated fatty liver disease (MAFLD) occurs in a low-grade inflammatory milieu dependent on highly complex networks that span well-beyond the hepatic tissue injury. Dysfunctional systemic metabolism that characterizes the disease, is further induced in response to environmental cues that modify energy and metabolic cellular demands, thereby altering the availability of specific substrates that profoundly regulate, through epigenetic mechanisms, the phenotypic heterogeneity of immune cells and influence hematopoietic stem cell differentiation fate. This immuno-metabolic signaling drives the initiation of downstream effector pathways and results in the decompensation of hepatic homeostasis that precedes pro-fibrotic events. Recent evidence suggests that innate immune cells reside in different tissues in a memory effector state, a phenomenon termed trained immunity, that may be activated by subsequent exogenous (e.g., microbial, dietary) or endogenous (e.g., metabolic, apoptotic) stmuli. This process leads to long-term modifications in the epigenetic landscape that ultimately precondition the cells towards enhanced transcription of inflammatory mediators that accelerates MAFLD development and/or progression. In this mini review we aimed to present current evidence on the potential impact of trained immunity on the pathophysiology of MAFLD, shedding light on the complex immunobiology of the disease and providing novel potential therapeutic strategies to restrain the burden of the disease.
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Imunidade Inata , Hepatopatias , Humanos , Imunidade Treinada , Memória ImunológicaRESUMO
BACKGROUND: Working as a neonatologist in a neonatal intensive care unit (NICU) is stressful and involves ethically challenging situations. These situations may cause neonatologists to experience high levels of moral distress, especially in the context of caring for extremely premature infants (EPIs). In Greece, moral distress among neonatologists working in NICUs remains understudied and warrants further exploration. METHODS: This prospective qualitative study was conducted from March to August 2022. A combination of purposive and snowball sampling was used and data were collected by semi-structured interviews with twenty neonatologists. Data were classified and analyzed by thematic analysis approach. RESULTS: A variety of distinct themes and subthemes emerged from the analysis of the interview data. Neonatologists face moral uncertainty. Furthermore, they prioritize their traditional (Hippocratic) role as healers. Importantly, neonatologists seek third-party support for their decisions to reduce their decision uncertainty. In addition, based on the analysis of the interview data, multiple predisposing factors that foster and facilitate neonatologists' moral distress emerged, as did multiple predisposing factors that are sometimes associated with neonatologists' constraint distress and sometimes associated with their uncertainty distress. The predisposing factors that foster and facilitate neonatologists' moral distress thus identified include the lack of previous experience on the part of neonatologists, the lack of clear and adequate clinical practice guidelines/recommendations/protocols, the scarcity of health care resources, the fact that in the context of neonatology, the infant's best interest and quality of life are difficult to identify, and the need to make decisions in a short time frame. NICU directors, neonatologists' colleagues working in the same NICU and parental wishes and attitudes were identified as predisposing factors that are sometimes associated with neonatologists' constraint distress and sometimes associated with their uncertainty distress. Ultimately, neonatologists become more resistant to moral distress over time. CONCLUSIONS: We concluded that neonatologists' moral distress should be conceptualized in the broad sense of the term and is closely associated with multiple predisposing factors. Such distress is greatly affected by interpersonal relationships. A variety of distinct themes and subthemes were identified, which, for the most part, were consistent with the findings of previous research. However, we identified some nuances that are of practical importance. The results of this study may serve as a starting point for future research.
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Unidades de Terapia Intensiva Neonatal , Neonatologistas , Recém-Nascido , Humanos , Grécia , Estudos Prospectivos , Qualidade de Vida , Atitude do Pessoal de Saúde , Princípios MoraisRESUMO
The frail, elderly population is often characterized by poor immunogenicity post COVID-19 mRNA vaccination. "Inflame-ageing" and "immune-senescence" are pathogenetic mechanisms that might explain this phenomenon. Complex interplay with cytokines and microbiota is also implicated in this inflammatory cascade. The abovementioned population, although very important from immunologic perspective, has barely been included in the mRNA vaccination clinical trials.
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COVID-19 , Idoso Fragilizado , Humanos , Idoso , Vacinas contra COVID-19 , Eficácia de Vacinas , EnvelhecimentoRESUMO
A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.
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Distrofia Muscular de Duchenne , Animais , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Camundongos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Relação Estrutura-Atividade , Regulação para Cima , Utrofina/genética , Utrofina/metabolismo , Utrofina/uso terapêuticoRESUMO
The persistence of the coronavirus disease 2019 (COVID-19) pandemic has triggered research into limiting transmission, morbidity and mortality, thus warranting a comprehensive approach to guide balanced healthcare policies with respect to people's physical and mental health. The mainstay priority during COVID-19 is to achieve widespread immunity, which could be established through natural contact or vaccination. Deep knowledge of the immune response combined with recent specific data indicates the potential inferiority of induced immunity against infection. Moreover, the prevention of transmission has been founded on general non-pharmacological measures of protection, albeit debate exists considering their efficacy and, among other issues, their socio-psychological burden. The second line of defense is engaged after infection and is supported by a plethora of studied agents, such as antibiotics, steroids and non-steroid anti-inflammatory drugs, antiviral medications and other biological agents that have been proposed, though variability in terms of benefits and adverse events has not allowed distinct solutions, albeit certain treatments might have a role in prevention and/or treatment of the disease. This narrative review summarizes the existing literature on the advantages and weaknesses of current COVID-19 management measures, thus underlining the necessity of acting based on the classical principle of "ofeleein i mi vlaptin", that is, to help or not to harm.
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COVID-19 , SARS-CoV-2 , Humanos , Pandemias , RNA Mensageiro , VacinaçãoRESUMO
Genetic approaches for the diagnosis and treatment of inherited muscle diseases have advanced rapidly in recent years. Many of the advances have occurred in the treatment of Duchenne muscular dystrophy (DMD), a muscle wasting disease where affected boys are typically wheelchair bound by age 12 years and generally die in their twenties from respiratory failure or cardiomyopathy. Dystrophin is a 421â kD protein which links F-actin to the extracellular matrix via the dystrophin-associated protein complex (DAPC) at the muscle membrane. In the absence of dystrophin, the DAPC is lost, making the muscle membrane more susceptible to contraction-induced injury. The identification of the gene causing DMD in 1986 resulted in improved diagnosis of the disease and the identification of hotspots for mutation. There is currently no effective treatment. However, there are several promising genetic therapeutic approaches at the preclinical stage or in clinical trials including read-through of stop codons, exon skipping, delivery of dystrophin minigenes and the modulation of expression of the dystrophin related protein, utrophin. In spite of significant progress, the problem of targeting all muscles, including diaphragm and heart at sufficiently high levels, remains a challenge. Any therapy also needs to consider the immune response and some treatments are mutation specific and therefore limited to a subgroup of patients. This short review provides a summary of the current status of DMD therapy with a particular focus on those genetic strategies that have been taken to the clinic.
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Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/terapia , Sistemas CRISPR-Cas , Códon de Terminação , Distrofina/genética , Éxons , Terapia Genética/métodos , Humanos , Masculino , Distrofia Muscular de Duchenne/genéticaRESUMO
Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture.
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Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease arising from mutations in the dystrophin gene. Upregulation of utrophin to compensate for the missing dystrophin offers a potential therapy independent of patient genotype. The first-in-class utrophin modulator ezutromid/SMT C1100 was developed from a phenotypic screen through to a Phase 2 clinical trial. Promising efficacy and evidence of target engagement was observed in DMD patients after 24â weeks of treatment, however trial endpoints were not met after 48â weeks. The objective of this study was to understand the mechanism of action of ezutromid which could explain the lack of sustained efficacy and help development of new generations of utrophin modulators. Using chemical proteomics and phenotypic profiling we show that the aryl hydrocarbon receptor (AhR) is a target of ezutromid. Several lines of evidence demonstrate that ezutromid binds AhR with an apparent KD of 50â nm and behaves as an AhR antagonist. Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies.
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Benzoxazóis/química , Naftalenos/química , Proteômica/métodos , Receptores de Hidrocarboneto Arílico/metabolismo , Utrofina/metabolismo , Animais , Benzoxazóis/metabolismo , Benzoxazóis/farmacologia , Benzoxazóis/uso terapêutico , Reação de Cicloadição , Desenho de Fármacos , Humanos , Cinética , Camundongos , Sondas Moleculares/química , Distrofia Muscular de Duchenne/tratamento farmacológico , Mioblastos/citologia , Mioblastos/metabolismo , Naftalenos/metabolismo , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Ligação Proteica , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Regulação para Cima/efeitos dos fármacos , Utrofina/agonistas , Utrofina/genéticaRESUMO
Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase inhibitors (ARIs) have been gaining attention over the years. In the present work, in order to address the poor membrane permeation of previously reported ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa≥7.4, were synthesized and evaluated for aldose reductase inhibitory activity. The 2-fluorophenol group proved the most promising moiety, and further modifications were explored. The most active compound (31), identified as a submicromolar inhibitor (IC50=0.443µM), was also selective against the homologous enzyme aldehyde reductase. Cross-docking revealed that 31 displays a peculiar interaction network that may be responsible for high affinity. Physicochemical profiling of 31 showed a pKa of 7.64, rendering it less than 50% ionized in the physiological pH range, with potentially favorable membrane permeation. The latter was supported from the successful inhibition of sorbitol formation in rat lenses and the ability to permeate rat jejunum.
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Aldeído Redutase/antagonistas & inibidores , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Jejuno/efeitos dos fármacos , Fenóis/farmacologia , Pirróis/farmacologia , Aldeído Redutase/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Jejuno/citologia , Jejuno/metabolismo , Lentes , Masculino , Modelos Moleculares , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Pirróis/síntese química , Pirróis/química , Ratos , Ratos Wistar , Sorbitol/antagonistas & inibidores , Sorbitol/metabolismo , Relação Estrutura-AtividadeRESUMO
The total fertility rate is influenced over an extended period of time by shifts in population socioeconomic characteristics and attitudes and values. However, it may be impacted by macroeconomic trends in the short term, although these effects are likely to be minimal when fertility is low. With the objective of forecasting monthly deliveries, this study concentrates on the analysis of registered births in Scotland. Through this approach, we examine the significance of precisely forecasting fertility trends, which can subsequently aid in the anticipation of demand in diverse sectors by allowing policymakers to anticipate changes in population dynamics and customize policies to tackle emerging demographic challenges. Consequently, this has implications for fiscal stability, national economic accounts and the environment. In conducting our analysis, we incorporated non-linear machine learning methods alongside traditional statistical approaches to forecast monthly births in an out-of-sample exercise that occurs one step in advance. The outcomes underscore the efficacy of machine learning in generating precise predictions within this particular domain. In sum, this research will comprehensively demonstrate a cutting-edge model of machine learning that utilizes several attributes to assist in clinical decision-making, predict potential complications during pregnancy and choose the appropriate delivery method, as well as help in medical diagnosis and treatment.