Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

© 2024 The Author(s). Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: The placenta exerts a crucial role in fetus growth and development during gestation, protecting the fetus from maternal drugs and chemical exposure. However, diverse drugs and chemicals (xenobiotics) can penetrate the maternal placental barrier, leading to deleterious, adverse effects concerning fetus health. Moreover, placental enzymes can metabolize drugs and chemicals into more toxic compounds for the fetus. Thus, evaluating the molecular mechanisms through which drugs and chemicals transfer and undergo metabolism across the placental barrier is of vital importance. In this aspect, this comprehensive literature review aims to provide a holistic approach by critically summarizing and scrutinizing the potential molecular processes and mechanisms governing drugs and chemical transfer and metabolism across the placental barrier, which may lead to fetotoxicity effects, as well as analyzing the currently available experimental methodologies used to assess xenobiotics placental transfer and metabolism. Methods: A comprehensive and in-depth literature review was conducted in the most accurate scientific databases such as PubMed, Scopus, and Web of Science by using relevant and effective keywords related to xenobiotic placental transfer and metabolism, retrieving 8830 published articles until 5 February 2024. After applying several strict exclusion and inclusion criteria, a final number of 148 relevant published articles were included. Results: During pregnancy, several drugs and chemicals can be transferred from the mother to the fetus across the placental barrier by either passive diffusion or through placental transporters, resulting in fetus exposure and potential fetotoxicity effects. Some drugs and chemicals also appear to be metabolized across the placental barrier, leading to more toxic products for both the mother and the fetus. At present, there is increasing research development of diverse experimental methodologies to determine the potential molecular processes and mechanisms of drug and chemical placental transfer and metabolism. All the currently available methodologies have specific strengths and limitations, highlighting the strong demand to utilize an efficient combination of them to obtain reliable evidence concerning drug and chemical transfer and metabolism across the placental barrier. To derive the most consistent and safe evidence, in vitro studies, ex vivo perfusion methods, and in vivo animal and human studies can be applied together with the final aim to minimize potential fetotoxicity effects. Conclusions: Research is being increasingly carried out to obtain an accurate and safe evaluation of drug and chemical transport and metabolism across the placental barrier, applying a combination of advanced techniques to avoid potential fetotoxic effects. The improvement of the currently available techniques and the development of novel experimental protocols and methodologies are of major importance to protect both the mother and the fetus from xenobiotic exposure, as well as to minimize potential fetotoxicity effects.Peer reviewe

Evaluating the Relationship between Circadian Rhythms and Sleep, Metabolic and Cardiovascular Disorders: Current Clinical Evidence in Human Studies

Circadian rhythms are generated by the circadian clock, a self-sustained internal timing system that exhibits 24-h rhythms in the body. Many metabolic, cellular, behavioral and physiological processes are regulated by the circadian clock in coordination with environmental cues. The present study is a comprehensive review of the currently existing evidence concerning the relationship between circadian rhythms and sleep, metabolic, and cardiovascular disorders. We thoroughly searched the online databases PubMed, Scopus, and Web of Science to find the existing clinical studies from the last twenty-three years (2000–2023). Circadian misalignment was found to be associated with an increase in the risk of metabolic disorders, cardiovascular diseases, and obesity, as well as inadequate sleep quality. In this review article, all the included studies had a strength protocol design and all of them were conducted on humans. However, the most common limitations of them were the small sample size and the short time of the intervention. In conclusion, managing the factors that disrupt the optimal function of central and peripheral clocks can help to reduce the risk of metabolic and cardiovascular diseases, improving also sleep quality. Future studies should further explore the underlying mechanisms of the interconnections between circadian clocks and sleep, metabolic, and cardiovascular disorders. This may provide new opportunities for advance chronotherapy approach

Chrononutrition in the Prevention and Management of Metabolic Disorders: A Literature Review

Background: The concept of time-restricted eating (TRE) or time-restricted feeding (TRF) promotes daily periods of feeding and fasting to determine whole-body physiology. Chronic misalignment of circadian rhythms or chrono-disruption is related to an increased risk of diverse metabolic disorders. The progression of non-communicable diseases seems to be affected by the timing of meals. As a result, intermittent fasting is a promising approach for their management. The aim of the present literature review is to examine and scrutinize the TRE protocols in the fields of prevention and management of metabolic disorders. Methods: This is a thorough literature review of the reported associations among circadian rhythm, metabolic disorders, diabetes mellitus, obesity, TRE, TRF, dietary habits, circadian disruption, cardiovascular diseases, atherosclerosis, and non-alcoholic fatty liver to find the already existing clinical studies from the last decade (2014–2024) in the most precise scientific online databases, using relevant specific keywords. Several inclusion and exclusion criteria were applied to scrutinize only longitudinal, cross-sectional, descriptive, and prospective clinical human studies. Results: The currently available clinical findings remain scarce and suggest that chrononutrition behaviors such as TRE or TRF may promote several metabolic benefits, mainly in body weight control and fat loss. Improvements in glucose levels and lipid profiles are currently quite controversial since some clinical studies show little or no effect. As far as liver diseases are concerned, the efficacy of intermittent fasting seems to be stronger in the management of non-alcoholic fatty liver disease due to body weight decline and fat loss. Conclusions: Even if there has been a gradual increase in clinical studies in the last few years, providing promising perspectives, currently, there is no conclusive evidence for the role of chrononutrition in metabolic disorders. Future studies should be well-designed with longer duration and larger sample sizes. Moreover, it is important to examine the best timing of the eating window and its feasibility

Exercise and nutrition impact on osteoporosis and sarcopenia—the incidence of osteosarcopenia: A narrative review

Osteoporosis and sarcopenia are diseases which affect the myoskeletal system and often occur in older adults. They are characterized by low bone density and loss of muscle mass and strength, factors which reduce the quality of life and mobility. Recently, apart from pharmaceutical interventions, many studies have focused on non-pharmaceutical approaches for the prevention of osteoporosis and sarcopenia with exercise and nutrition to being the most important and well studied of those. The purpose of the current narrative review is to describe the role of exercise and nutrition on prevention of osteoporosis and sarcopenia in older adults and to define the incidence of osteosarcopenia. Most of the publications which were included in this review show that resistance and endurance exercises prevent the development of osteoporosis and sarcopenia. Furthermore, protein and vitamin D intake, as well as a healthy diet, present a protective role against the development of the above bone diseases. However, current scientific data are not sufficient for reaching solid conclusions. Although the roles of exercise and nutrition on osteoporosis and sarcopenia seem to have been largely evaluated in literature over the recent years, most of the studies which have been conducted present high heterogeneity and small sample sizes. Therefore, they cannot reach final conclusions. In addition, osteosarcopenia seems to be caused by the effects of osteoporosis and sarcopenia on elderly. Larger meta-analyses and randomized controlled trials are needed designed based on strict inclusion criteria, in order to describe the exact role of exercise and nutrition on osteoporosis and sarcopenia

Vitamin D and Calcium in Osteoporosis, and the Role of Bone Turnover Markers: A Narrative Review of Recent Data from RCTs

Osteoporosis is a common disease, defined primarily by a low measured bone density, which is associated with an increased risk of fragility fractures. Low calcium intake and vitamin D deficiency seem to be positively correlated with the prevalence of osteoporosis. Although they are not suitable for the diagnosis of osteoporosis, the biochemical markers of bone turnover can be measured in serum and/or urine, enabling the assessment of the dynamic bone activity and the short-term effectiveness of the osteoporosis treatment. Calcium and vitamin D are essential for maintaining bone health. The aim of this narrative review is to summarize the effects of vitamin D and calcium supplementation separately and in combination, on bone density and circulating serum and blood plasma vitamin D, calcium, parathyroid hormone levels, markers of bone metabolism concentrations, and clinical outcomes, such as falls and osteoporotic fractures. We searched the PubMed online database to find clinical trials from the last five years (2016–April 2022). A total of 26 randomized clinical trials (RCTs) were included in this review. The present reviewed evidence suggests that vitamin D alone or in combination with calcium increases circulating 25(OH)D. Calcium with concomitant vitamin D supplementation, but not vitamin D alone, leads to an increase in BMD. In addition, most studies did not detect significant changes in circulating levels of plasma bone metabolism markers, nor in the incidence of falls. Instead, there was a decrease in blood serum PTH levels in the groups receiving vitamin D and/or Ca supplementation. The plasma vitamin D levels at the beginning of the intervention, and the dosing regimen followed, may play a role in the observed parameters. However, further study is needed to determine an appropriate dosing regimen for the treatment of osteoporosis and the role of bone metabolism markers

The Key Role of Nutritional Elements on Sport Rehabilitation and the Effects of Nutrients Intake

Adequate nutrition is of utmost importance for athletes, especially during rehabilitation after injury in order to achieve fast healing and return to sports. The aim of this narrative review is to define the proper nutritional elements for athletes to meet their needs and facilitate their fast return to sports after surgery or injury, as well as determine the effects of specific nutrients intake. Studies on antioxidants, which are substances that protect against free radicals, for the injured athlete are few and unclear, yet poly-phenols and especially flavonoids might improve healing and inflammation following an injury. Benefits of vitamin C or E on muscle damage are disputable in relevant studies, while optimal levels of vitamin D and calcium contribute to bone healing. Minerals are also essential for athletes. Other supplements suggested for muscle damage treatment and protein synthesis include leucine, creatine, and hydroxymethylbutyrate. Diets that include high-quality products, rich in micronutrients (like vitamins, minerals, etc.) bio-active compounds and other nutritional elements (like creatine) are suggested, while an individualized nutrition program prescribed by a trained dietitian is important. Further studies are needed to clarify the underlying mechanisms of these nutritional elements, especially regarding injury treatment

Therapeutic Drug Monitoring (TDM) Implementation in Public Hospitals in Greece in 2003 and 2021: A Comparative Analysis of TDM Evolution over the Years

Therapeutic drug monitoring (TDM) is the clinical practice of measuring drug concentrations. TDM can be used to determine treatment efficacy and to prevent the occurrence or reduce the risk of drug-induced side effects, being, thus, a tool of personalized medicine. Drugs for which TDM is applied should have a narrow therapeutic range and exhibit both significant pharmacokinetic variability and a predefined target concentration range. The aim of our study was to assess the current status of TDM in Greek public hospitals and estimate its progress over the last 20 years. All Greek public hospitals were contacted to provide data and details on the clinical uptake of TDM in Greece for the years 2003 and 2021 through a structured questionnaire. Data from 113 out of 132 Greek hospitals were collected in 2003, whereas for 2021, we have collected data from 98 out of 122 hospitals. Among these, in 2003 and 2021, 64 and 51 hospitals, respectively, performed TDM. Antiepileptics and antibiotics were the most common drug categories monitored in both years. The total number of drug measurement assays decreased from 2003 to 2021 (153,313 ± 7794 vs. 90,065 ± 5698; p = 0.043). In direct comparisons between hospitals where TDM was performed both in 2003 and 2021 (n = 35), the mean number of measurements was found to decrease for most drugs, including carbamazepine (198.8 ± 46.6 vs. 46.6 ± 10.1, p p = 0.001), amikacin (147.3 ± 65.2 vs. 91.1 ± 71.4; p = 0.033), digoxin (783.2 ± 226.70 vs. 165.9 ± 28.9; p p = 0.004). Only for vancomycin, a significant increase in measurements was recorded (206.1 ± 96.1 vs. 789.1 ± 282.8; p = 0.012). In conclusion, our findings show that TDM clinical implementation is losing ground in Greek hospitals. Efforts and initiatives to reverse this trend are urgently needed

Nutritional and Nutrition-Related Biomarkers as Prognostic Factors of Sarcopenia, and Their Role in Disease Progression

Due to the multifactorial pathogenesis of sarcopenia, it is crucial to identify biomarkers that are risk factors for sarcopenia, and which therefore have a prognostic function. Aim: This narrative review aims to define a set of biomarkers associated with nutrition and sarcopenia. These biomarkers could contribute to individualized monitoring and enable preventive and therapeutic methods. Methods: Two electronic databases, PubMed and Google Scholar, were used. The search strategy was based on a controlled vocabulary (MeSH) and includes studies published up to February 2022. Discussion: Higher levels of serum uric acid are associated with higher handgrip strength and better muscle function in elderly people and, thus, may slow the progression of sarcopenia. Leptin, an adipokine secreted by adipose tissue, promotes the production of pro-inflammatory cytokines, which in turn lead to sarcopenia. This makes leptin a significant indirect biomarker for physical disability and sarcopenic obesity. Additionally, creatinine is a reliable biomarker for muscle mass status because of its easy accessibility and cost-effectiveness. Vitamin D status acts as a useful biomarker for predicting total mortality, hip fractures, early death, and the development of sarcopenia. Therefore, there is an increasing interest in dietary antioxidants and their effects on age-related losses of muscle mass and function. On the other hand, 3-Methylhistidine is a valuable biomarker for detecting increased muscle catabolism, as it is excreted through urine during muscle degradation. In addition, IGF-1, whose concentration in plasma is stimulated by food intake, is associated with the loss of skeletal muscle mass, which probably plays a crucial role in the progression of sarcopenia. Conclusions: Many nutritional biomarkers were found to be associated with sarcopenia, and can therefore be used as prognostic indexes and risk factors. Nutrition plays an important role in the prevention and management of sarcopenia, affecting muscle mass, strength, and function in elderly people

Ketogenic Diet and Vitamin D Metabolism: A Review of Evidence

The ketogenic diet (KD), which is low in carbohydrates and high to normal in fat and protein, has been traditionally used in epilepsy for the last 100 years. More recently, its application in obesity has been introduced. The present review aimed to investigate the effects of the KD on vitamin D. In total, five studies were done in healthy adults, one in subjects with type 2 diabetes, and seven in subjects with epilepsy that assessed the levels of vitamin D pre- and post-intervention. In the majority of studies, increases in circulating vitamin D were reported. The relationship of the KD with vitamin D was explained through several mechanisms: ketone bodies, macronutrient intake, the status levels of other fat-soluble vitamins, weight loss, changes in the hormonal milieu, and effects on gut microbiota. Moreover, potential nutrient–gene-related interactions were discussed. There is still a need to conduct multiple arm studies to compare the effects of the KD versus other diets and better decipher the particular effects of the KD on vitamin D levels and metabolism. Moreover, differentiations of the diet’s effects according to sex and genetic makeup should be investigated to prescribe KDs on a more personalized basis

Omega-3 fatty acids' supplementation in Parkinson's disease: A systematic review of randomized controlled trials

Summary: Parkinson's disease (PD) is a neurodegenerative disorder, in which loss of dopaminergic neurons is present among other alterations. Lipids are key molecules in PD pathophysiology. Patients with PD may have lower levels of circulating omega-3 fatty acids, which are vital components of the brain cells' membranes, exerting anti-inflammatory properties and affecting neural function. The present systematic review of randomized controlled trials (RCTs) assessed the potential beneficial effects of omega-3 fatty acids' supplementation in patients with PD. Several accurate databases were used, including PubMed, Cochrane, and Scopus, as well as grey literature sources. Four RCTs were finally identified, in which different doses of omega-3 fatty acids were administered together with vitamin E. Three RCTs investigated the effects of omega-3 fatty acids on the progression of PD with the use of Unified Parkinson's Disease Rating Stage (UPDRS) score, and all showed beneficial effects. Moreover, some beneficial effects were reported for depression scales, as well as against insulin resistance, markers of inflammation, and oxidative stress. However, further studies are highly recommended to substantiate the role of omega-3 fatty acids' supplementation in the clinical course of PD