Search Results (454)

Background/Objectives: Despite the decades-old ban on lead in fuel, plumbing, consumer goods, industrial processes, and various materials, it remains a public health threat due to its persistent nature. Zebrafish (Danio rerio) are highly effective for modeling several disorders, including those affecting neurological and behavioral functions, and are well-suited for assessing the impact of environmental toxins like lead. This study aimed to investigate the neurodevelopmental effects of embryonic lead exposure using the zebrafish model system. Methods: Embryos were exposed to lead acetate (PbAc) at concentrations ranging from 0.3 to 0.7 µg/mL using an exposure window of 6 to 48 h post-fertilization (hpf). Results: PbAc exposure produced sublethal teratogenic effects in a subset of larvae across concentrations, including tail and spinal deformities, craniofacial abnormalities, and uninflated swim bladder observed at 7 dpf. At 3 days post-fertilization (dpf), spontaneous circle swimming behavior suspected to be seizure-like was observed in the lead-exposed larvae and was more pronounced under light conditions in a dose-dependent manner. Electrophysiological recordings confirmed that larvae exhibiting circle swimming behavior had heightened neural activity, indicating a potential seizure-like phenotype driven by lead exposure. Conclusions: Our findings suggest that embryonic lead exposure leads to morphological defects and seizure susceptibility, demonstrating lead’s neurotoxic potential during early development. Seizure-like behaviors occurred in a non-linear concentration-dependent manner with a photosensitive component, and elevated baseline neural excitability was confirmed by local field potential (LFP) recordings. Full article

Atrial septal defect (ASD) has become increasingly common in the USA and now affects 1 in 11.3 children in some places, but space–time analysis has not been applied to this emerging trend. ASD rate (ASDR) data were obtained from the National Birth Defects Prevention Network 2003–2020. Substance (cigarettes, alcohol, cannabis, analgesics, cocaine) use data were obtained from the National Survey of Drug Use and Health. Income data were obtained from the US Census. Analysis was limited to the Non-Hispanic White population by technical factors. Time-sequential univariate and bivariate maps were prepared for both covariates and outcomes and their combinations. Spatial regression of the ASDR was performed using the R package splm. A total of 7.6% of data was interpolated by linear regression. A total of 110,107 ASD cases were identified amongst 17,751,437 live births in 27 US states across 10 reporting periods. Time series maps showed that ASDR showed concordant patterns with indices of cannabis use rather than other substances. This was confirmed by multivariate spatial regression where cannabis and cannabinoids alone were found to significantly relate to ASDR, with p = 0.00002 for cannabidiol. Cannabis legal status similarly tracked with ASDR. Compared to states where cannabis was not legal, ASDR was more prevalent in cannabis-legal states (OR = 2.73 (2.66, 2.80); E-Value 4.90 (lower C.I. 4.76)). Twenty-seven of 34 (79.4%) E-values were >9 (high range) and 34/34 were > 1.25 (causal threshold). Data show that cannabis, including cannabis legalization, is driving the US ASD epidemic. While most high-ASDR states have high rates of cannabis use, Midwestern states where cannabis is farmed, such as Kentucky, Tennessee and Missouri, do not, suggesting other routes of exposure, potentially implicating environmental contamination. ASD is a bellwether marker for cannabinoid teratogenicity, indicating that communities should carefully control cannabinoid exposure and limit transgenerational cannabinoid genotoxicity more generally. Full article

Background and Objectives: Visceral artery aneurysms (VAAs) are rare but potentially catastrophic vascular abnormalities, particularly in pregnant patients or women of childbearing age. Rupture is often fatal for both mother and fetus, with mortality rates exceeding 70% in some series. While most VAAs are found incidentally, a subset may present acutely with nonspecific abdominal or flank pain, making early recognition and appropriate referral essential. This review article aims to provide General Practitioners (GPs) and emergency department (ED) clinicians with a practical approach to the recognition, investigation, initial management, and escalation pathways for VAAs. Results: Physiological and hormonal adaptations in pregnancy heighten aneurysm rupture risk. Despite this, imaging is frequently delayed. Computed tomography angiography (CTA) remains the gold standard for diagnosis and is safe in pregnancy when clinically justified, with fetal radiation exposure well below teratogenic thresholds. Guidelines from major vascular societies uniformly recommend repairing VAAs in pregnancy or women planning pregnancy irrespective of aneurysm size, and treating pseudoaneurysms urgently in all patients. Endovascular intervention is first-line where anatomy permits, while open or hybrid approaches remain essential in unstable presentations. The manuscript outlines practical steps for ED and GP settings, including haemodynamic stabilization, early obstetric involvement, transfer considerations for rural environments, reproductive counselling, and post-repair surveillance. Conclusions: With an increasing number of abdominal scans being performed in primary and tertiary settings, there is an associated increased volume of incidental findings that require work-up. This article outlines a practical investigation and management strategy for clinicians presented with VAAs, including in high-risk cohorts, emphasizing early imaging, inter-specialty coordination, and guideline-supported thresholds for intervention. Full article

(1) Background: The management of epilepsy during pregnancy requires balancing effective seizure control against potential teratogenic effects of antiseizure medications (ASMs). Data on the safety of lacosamide (LCM), a third-generation ASM, during pregnancy and breastfeeding are limited. (2) Methods: To evaluate the safety and efficacy of LCM during pregnancy and breastfeeding, we report a single-centre case series and provide a comprehensive narrative review of the literature. (3) Results: In total, 22 cases of maternal exposure to LCM throughout pregnancy (1 monotherapy, 21 polytherapy) were identified, resulting in 21 live births (95.5%). Congenital malformations (atrial septal defect) were observed in one offspring exposed to LCM and levetiracetam (4.8%). Twelve newborns were breastfed (57.1%) without neurodevelopmental delay after twelve months. The literature search identified 16 studies, overall reporting data on 627 pregnancies with LCM (236 monotherapy, 391 polytherapy). Among 632 available pregnancy outcomes (3 twin pregnancies and 1 triplet in the polytherapy group) the proportion of live births was 81.3% (514/632). Major congenital malformations were reported in 2.5% (6/236) with LCM monotherapy and 11.9% (47/396) with polytherapy. (4) Conclusions: According to the literature, no major safety concerns, especially in LCM monotherapy, and no specific malformations associated with LCM exposure were identified. Conclusions are limited by the heterogeneity of studies and the small number of monotherapy-exposed cases. Larger, prospective studies with longer follow-up are required. Full article

Benzydamine is a nonsteroidal anti-inflammatory drug widely used in topical formulations but occasionally misused orally at high doses for psychoactive effects. Data regarding the safety of benzydamine at supratherapeutic doses are limited and mainly focus on central nervous system effects. Even less information is available concerning its safety during pregnancy, despite the increased risk of unplanned pregnancies among users of psychoactive substances. In this preliminary study, we aimed to evaluate the maternal and fetotoxic potential of benzydamine to support future targeted reproductive toxicity investigations. Pregnant Wistar rats received benzydamine throughout gestation, followed by cesarean section and evaluation of fetal viability, fetal body weight at term, and macroscopic abnormalities. Maternal biochemical parameters related to hepatic, renal, and metabolic function, and oxidative stress markers, were also assessed. Results were compared with those of a control group. No significant differences in routine biochemical parameters were observed between groups; however, benzydamine exposure was associated with reduced fetal body weight and increased maternal plasma malondialdehyde levels. These findings suggest that benzydamine may impair fetal growth through indirect maternal toxicity and oxidative stress rather than direct teratogenic effects. Full article

Myasthenia gravis (MG) is a prevalent autoimmune disorder affecting neuromuscular junctions, typically characterized by muscle weakness due to autoantibodies targeting acetylcholine receptors (AChR) or muscle-specific kinase (MuSK). Generalized MG is a more severe form of the condition than ocular MG. Although MG can strike at any age, young adult women are typically affected, especially in their reproductive years. MG is rare during pregnancy, with the first trimester and the postpartum period being the most common times for exacerbations. The influence of MG on pregnancy outcomes remains ambiguous, with some studies finding larger prevalence of issues such as preterm birth and small-for-gestational-age babies, while others indicate results similar to the general population. Management of MG during pregnancy necessitates careful monitoring and drug adjustments. Teratogenic concerns make several immunosuppressive drugs, such mycophenolate mofetil and methotrexate, contraindicated. In contrast, medications like prednisolone and pyridostigmine are generally recognized as safe. Women with MG may have flare-ups after giving birth, and infants may have transient neonatal myasthenia gravis. Comprehensive prenatal treatment and multidisciplinary assistance are crucial for promoting maternal and fetal health during pregnancy in women with MG. This paper examines the relevance of immunological biomarkers, RNAs, and other novel biomarkers in myasthenia gravis (MG). It emphasizes the need for more investigation to determine their role in the pathogenesis of MG, evaluate biomarker profiles across subgroups, and look at changes after treatment. The study also underlines the significance of high-throughput investigations to detect new biomarkers and reveal genetic variables impacting MG pathogenesis. Full article

Zika virus (ZIKV), a unique flavivirus with neurotropic and teratogenic potential, can cross the blood–brain barrier and persist in human brain microvascular endothelial cells (BMECs); however, no approved vaccines or specific antivirals exist, and its barrier-crossing and neuroinvasive mechanisms remain elusive. Innovative strategies to identify additional host factors mediating ZIKV infection could yield key insights and help address these challenges. To uncover novel host factors, we established the first tree shrew (Tupaia belangeri) genome-wide CRISPR/Cas9 knockout (GeCKO) library and performed a screen in BMECs, identifying ring finger protein 6 (RNF6) as a novel proviral factor for ZIKV. ZIKV infection in BMECs was significantly reduced following RNF6 knockout or knockdown but enhanced upon RNF6 overexpression or rescue. Mechanistically, RNF6 interacts with the ZIKV NS5 protein and acts as a potential negative regulator of the type I interferon and MAPK signaling pathways. Evolutionary and structural analyses revealed that RNF6 is highly conserved between humans and tree shrews; molecular docking further identified shared NS5-binding residues (Gln-59, Arg-140), supporting the conserved proviral role of human RNF6 in ZIKV infection. Our findings highlight tree shrew GeCKO screening as an efficient approach for identifying novel host factors and establish RNF6 as a critical proviral factor for ZIKV replication in BMECs, providing new insights into ZIKV neurotropic pathogenesis and informing potential antiviral strategies. Full article

Background: Heterocycle compounds with acridine, quinoline, indole, and pyridine nuclei are potentially active for anticancer activity since they can promote inhibition of vital enzymes, decreasing cell survival after binding to biomolecules. However, unspecific biological interactions can result in unwanted effects, which should be defined during the synthesis and proposition of new molecules. Thus, the objective of this study was to investigate the biological and teratogenic effects of four nitrogen heterocycles proposed for anticancer therapy. Methods: Four 2-cyano-N-phenylacrylamine type derivatives containing acridine (3a), quinoline (3b), indole (3c), and pyridine (3d) nuclei were synthesized and characterized. They were evaluated for their ability to interact with DNA, physicochemical and pharmacokinetic predictions, in vitro and in silico methodologies, besides in vitro inhibition of the Topoisomerase IIα enzyme, antiproliferative activity in tumor and non-tumor cells, hemolytic activity with human erythrocytes, and in vivo toxicological studies with zebrafish embryos. Results: UV–vis absorption studies with ssDNA revealed different spectroscopic effects, with binding constants (Kb) ranging from 1.41 × 10⁵ to 6.46 × 10⁴ M⁻¹. The fluorescence quenching constant (Ksv) with ethidium bromide (EB) varied between 0.53 and 0.67 × 10³ M⁻¹. The compounds intercalated into DNA base pairs, a mechanism confirmed by molecular docking, with 3b (quinoline) showing the most substantial interaction. All derivatives exhibited antitopoisomerase IIα activity at 100 μM and were cytotoxic against MCF-7 and T47-D breast tumor cells, particularly against the more aggressive T47-D lineage. No hemolytic activity was observed in human erythrocytes. In vivo assays in zebrafish embryos showed no toxicological or cardiotoxic effects. However, all compounds altered superoxide dismutase (SOD) and catalase (CAT) enzymatic activity, requiring further studies on reactive oxygen species (ROS) generation to assess potential adverse effects. Furthermore, significant results were observed in the physicochemical and pharmacokinetic parameters of the synthesized compounds. Conclusions: The findings highlight the quinoline derivative (3b) as the most promising nitrogen heterocycle due to its antiproliferative activity and biomolecular interactions without adverse effects in zebrafish embryos, distinguishing it from clinically available agents. Full article

Background/Objectives: Emerging evidence has suggested that choline is an effective treatment for at least some of the neurobehavioral deficits associated with Fetal Alcohol Spectrum Disorders (FASD). However, the mechanism of how choline works to ameliorate ethanol’s teratogenic effects, and whether it acts directly on the fetus or indirectly by altering the uterine environment, remains unknown. Previous work from our lab demonstrated that 4 BXD mouse strains that show high levels of ethanol-induced cell death on embryonic day 9.5 (E9.5) have differential responses to choline supplementation. This differential response in mouse strains highlights a need to further understand the role of genetics in choline metabolism. Because the liver is the central organ for choline metabolism, and the embryonic liver of mice is not functional this early in gestation, we focused on choline metabolism in the liver of the dam. Methods: Using a bioinformatics approach, the goals were to assess whether (1) genetic differences in liver choline metabolism in the dam could affect ethanol-induced cell death in a genotype-specific manner and (2) any of these candidate genes in the liver of the dam could be linked to differential response to choline amongst the strains. By performing a literature review, haplotype analysis among the 4 BXD strains, and liver protein expression analysis among 3 strains, we show that there are genetic differences in choline metabolic genes that are consistent with the hypothesis that maternal choline metabolism could mediate differential sensitivity. Results: While we identified two genes as promising candidates for the variable responses to choline supplementation among the four previously identified BXD strains choline/ethanolamine phosphotransferase 1 (cept1) and choline transporter gene solute carrier family 44 member 1 (slc44a1), the wealth of data on slc44a1 makes it the stronger candidate and suggests that it should be further explored. Conclusions: Genetic differences in maternal choline metabolism are present and may underlie variable therapeutic responses to choline, warranting a hypothesis that requires further investigation across animal models and human populations. Full article

Background and Objectives: Pemphigus vulgaris (PV) is a rare autoimmune blistering disease caused by IgG au-toantibodies against desmoglein 1 and/or desmoglein 3, leading to flaccid blisters on the skin and mucous membranes. The course of PV during pregnancy represents a special clinical challenge due to immunological changes accompanying physiological immunosuppression and the need to protect the developing fetus. Materials and Methods: To analyze the current state of knowledge, a literature review was performed covering the years 2015–2025. Publications describing PV diagnosed during pregnancy or in neonates were screened, and nine case reports discussing ten patients meeting the inclusion criteria were selected for detailed analysis. In this study, we also present our own clinical case of PV in pregnancy to complement the literature review and provide practical insight into disease management. Results: In most cases, the disease was diagnosed in the first trimester of pregnancy, and the most common symptoms were flaccid blisters and erosions of the oral mucosa. The diagnosis was confirmed by direct immunofluorescence (DIF) and ELISA testing. The first-line treatment remained systemic glucocorticosteroids (GCS), mainly prednisolone, which is considered the safest. In resistant cases, intravenous immunoglobulins (IVIg) were used, which were considered effective and safe, though their use may limit the transplacental transfer of autoantibodies to the fetus. In newborns, the symptoms rarely occurred, were mild, and resolved spontaneously. Drugs with proven teratogenic effects, such as methotrexate, cyclophosphamide, and mycophenolate mofetil, are contraindicated during pregnancy. In the case of rituximab therapy, it is recommended to postpone pregnancy for at least 12 months after the completion of treatment to minimize the potential risk of immunosuppression in the newborn. Conclusions: The treatment of PV during pregnancy requires close interdisciplinary cooperation. Therapy should be carefully individualized, taking into account both therapeutic efficacy and fetal safety. Perhaps then, pregnancy-related pemphigus diseases, given their peculiarities, should be classified as a distinct variety within the desmosomal type of autoimmune blistering diseases. Full article

Background: Oxidative stress is a key contributor to many chronic diseases. Natural biocompounds with antioxidant activity are of growing therapeutic interest. Brassica macrocarpa, a plant from the Brassicaceae family, has shown in vitro safety and antioxidant potential due to its rich content of glucosinolates and phenolics. However, in vivo, its effects remain poorly characterized. This study aimed to evaluate the in vivo safety and biological effects of Brassica macrocarpa leaf extract in zebrafish embryos and to assess its potential to counteract copper sulphate (CuSO₄)-induced oxidative stress. Methods: Zebrafish embryos were exposed to Brassica macrocarpa extract at concentrations from 125 to 2000 µg/mL. Embryonic mortality and malformations were monitored daily to determine sub-lethal concentrations (125–500 µg/mL) for further behavioural and biochemical analysis. Antioxidant properties were tested in a CuSO₄-induced oxidative stress model. Results: No teratogenic effects were observed over 96 h. Larvae showed normal swimming and no behavioural changes. Pre-treatment with the extract significantly reduced CuSO₄-induced ROS and NO production, modulated antioxidant enzyme (SOD, CAT) activity, and lowered lipid peroxidation and protein oxidation, slightly affecting DNA damage. Conclusions: Brassica macrocarpa extract in vivo appears safe at sub-lethal doses and shows promising antioxidant effects, suggesting its potential role in managing oxidative stress-related conditions. Full article

Oxytropis glabra DC, a Fabaceae species distributed across Central Asia, is characterized by a dual biological profile encompassing pronounced toxicity alongside promising pharmacological potential. This review synthesizes current knowledge on its phytochemistry, bioactivity, and toxicological liabilities to clarify the plant’s risk–benefit landscape. The objectives are to summarize the dominant classes of metabolites identified in O. glabra, evaluate their toxicological and therapeutic relevance, and identify key gaps limiting translational research. O. glabra contains a diverse array of secondary metabolites, with quinolizidine and indolizidine alkaloids, including swainsonine, anagyrine, thermopsine, and sparteine, representing the primary determinants of toxicity. These compounds are associated with teratogenicity, neurotoxicity, and locoism through mechanisms involving α-mannosidase inhibition, disruption of glycoprotein processing, and impaired lysosomal homeostasis. In contrast, flavonoids such as quercetin, isoquercitrin, and kaempferol derivatives exhibit antioxidant, anti-inflammatory, hepatoprotective, and cardioprotective effects, while triterpenoid saponins and fatty acids contribute additional cytoprotective and metabolic activities. Despite extensive reports on both toxic and bioactive constituents, critical gaps remain regarding chemotype variability, dose–response relationships, and pharmacokinetics, which currently constrain therapeutic exploitation. Future research should prioritize defining safe exposure thresholds, elucidating structure–activity relationships, and developing standardized extracts or optimized derivatives that balance efficacy and safety. This integrative perspective highlights O. glabra as a chemically rich but biologically ambivalent species whose toxicological risks and pharmacological opportunities warrant systematic mechanistic investigation. Full article

Microalgae are extremely diverse photosynthetic organisms, adapted to live in different habitat conditions, from freshwater to marine environments. This adaptability is also associated with the ability to produce several metabolites. Polyunsaturated aldehydes (PUAs), first identified in 1999 in Thalassiosira gravida and Skeletonema costatum, are known to influence the development of their predators, having teratogenic effects and blocking their development. PUAs have shown several activities, such as antitumor, antimicrobial and antiparasite. Another relevant compound is pheophorbide a (PPBa), a chlorophyll degradation product, which has previously shown properties useful to be considered as a photosensitizer in photodynamic therapy, demonstrating cytotoxic effects on various tumor cell lines. It has also been shown to have activity against some bacteria and fungi. Considering the growing problem of multi-antibiotic resistance of human pathogenic bacteria and the increasing market demand for new drugs, the aim of our work was to screen two PUAs, i. e., 2,4-octadienal and trans,trans-2,4-decadienal, and PPBa against a panel of human pathogenic bacteria and fungi: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus fumigatus. The antimicrobial activity was evaluated through MIC (Minimum Inhibitory Concentration) and MFC/MBC (Minimum Fungicidal/Bactericidal Concentration), demonstrating that the two PUAs had a greater antimicrobial activity than PPBa on both bacteria and fungi, except for P. aeruginosa, where the antimicrobial activity was low. The compound 2,4-Octadienal showed extremely high antifungal activity, especially against the fungus A. fumigatus, where the MIC and MFC were 0.001 µL/mL and 0.004 µL/mL, respectively. These results are shedding light on the antimicrobial activity of microalgal compounds and their possible applications for different human infection diseases. Full article

Background/Objectives: Risk minimization measures, including a pregnancy prevention program (PPP), have been established by the European Medicine Agency to strengthen the restrictions on valproate (VPA) use in pregnant women/women with childbearing potential. We aimed to assess pharmacists’ awareness of the new measures and behavior in terms of compliance to PPP recommendations. Methods: We performed a cross-sectional, national, non-interventional survey among pharmacists between December 2024 and February 2025. No sample size calculations were performed. Inclusion criteria were pharmacists active in community pharmacies in Romania. Results: In total, 267 pharmacists were included, balanced in terms of age groups, with a slight predominance for 31–40 year olds (33.7%) and mostly female (93.3%). More than half (60.7%) did not recall receiving any type of PPP information (direct healthcare professional communication [DHPC] or educational materials [EMs]). Participants generally read the DHPC, fully (64.1%) or partially (21.4%); all reportedly read the EMs, generally fully (73.0%). Half (145, 54.2%) dispensed VPA at least once during the last 12 months. Among this subgroup, 15.2% used the EMs, 38.6% counseled the patient regarding the VPA teratogenic risk, and 32.4% counseled on the importance of effective contraceptive measures at every VPA dispensing. Neither awareness nor behavior met the pre-established success criteria; therefore, the overall PPP compliance was not demonstrated. Conclusions: Despite notable proportions of pharmacists offering counseling when dispensing, overall PPP compliance and EM use could be enhanced. More research is needed to identify why some measures are not properly adhered to, in order to increase the overall risk mitigation efficacy. Full article

Background/Objectives: All-trans retinoic acid (atRA), a potent derivative of vitamin A, is recognized as a significant teratogen for inducing cleft palate in both humans and mice. The molecular mechanisms underlying it remain intricate and incompletely elucidated. The advent of single-cell sequencing technology offers novel methodologies to investigate the mechanisms by which atRA induces cleft palate. Methods: In this study, we use C57BL/6 mice to conduct cleft palate models, comprising a control group and an atRA-exposed group. Palatal shelves were collected at embryonic day 12.5 (E12.5) for 10x single-cell sequencing analysis to discern and compare the cellular and molecular disparities between the two groups. Validation of the findings was performed using Quantitative real-time polymerase chain reaction and Western blot techniques. Results: The findings indicate that at E12.5, atRA predominantly affects the mesenchymal and epithelial cells of the palatal shelves, inhibiting cellular proliferation and migration. The primary mechanism of atRA’s effect involves modulation of the Wnt and TGF-β signaling pathways. Furthermore, the Ppp1r14b gene was identified as a critical mediator in atRA’s interaction with these pathways. Conclusions: This study provides a more comprehensive understanding of the mechanisms underlying atRA-induced cleft palate formation. It highlights the significance of the Wnt and TGF-β pathways, as well as the Ppp1r14b gene during this procedure. Full article