The Risk of Congenital Heart Anomalies Following Prenatal Exposure to Serotonin Reuptake Inhibitors—Is Pharmacogenetics the Key?

Serotonin reuptake inhibitors (SRIs) are often prescribed during pregnancy. Previous studies that found an increased risk of congenital anomalies, particularly congenital heart anomalies (CHA), with SRI use during pregnancy have created concern among pregnant women and healthcare professionals about the safety of these drugs. However, subsequent studies have reported conflicting results on the association between CHA and SRI use during pregnancy. These discrepancies in the risk estimates can potentially be explained by genetic differences among exposed individuals. In this review, we explore the potential pharmacogenetic predictors involved in the pharmacokinetics and mechanism of action of SRIs, and their relation to the risk of CHA. In general, the risk is dependent on the maternal concentration of SRIs and the foetal serotonin level/effect, which can be modulated by the alteration in the expression and/or function of the metabolic enzymes, transporter proteins and serotonin receptors involved in the serotonin signalling of the foetal heart development. Pharmacogenetics might be the key to understanding why some children exposed to SRIs develop a congenital heart anomaly and others do not.     

eif4ebp3l—A New Affector of Zebrafish Angiogenesis and Heart Regeneration?

The eukaryotic initiation factor 4E binding protein (4E-BP) family is involved in translational control of cell proliferation and pro-angiogenic factors. The zebrafish eukaryotic initiation factor 4E binding protein 3 like (eif4ebp3l) is a member of the 4E-BPs and responsible for activity-dependent myofibrillogenesis, but whether it affects cardiomyocyte (CM) proliferation or heart regeneration is unclear. We examined eif4ebp3l during zebrafish vascular development and heart regeneration post cryoinjury in adult zebrafish. Using morpholino injections we induced silencing of eif4ebp3l in zebrafish embryos, which led to increased angiogenesis at 94 h post fertilization (hpf). For investigation of eif4ebp3l in cardiac regeneration, zebrafish hearts were subjected to cryoinjury. Regenerating hearts were analyzed at different time points post-cryoinjury for expression of eif4ebp3l by in situ hybridization and showed strongly decreased eif4ebp3l expression in the injured area. We established a transgenic zebrafish strain, which overexpressed eif4ebp3l under the control of a heat-shock dependent promotor. Overexpression of eif4ebp3l during zebrafish heart regeneration caused only macroscopically a reduced amount of fibrin at the site of injury. Overall, these findings demonstrate that silencing of eif4ebp3l has pro-angiogenic properties in zebrafish vascular development and when eif4ebp3l is overexpressed, fibrin deposition tends to be altered in zebrafish cardiac regeneration after cryoinjury.     

A Glimpse at the Size of the Fetal Liver—Is It Connected with the Evolution of Gestational Diabetes?

Gestational diabetes mellitus (GDM) is defined as an impairment of glucose tolerance, manifested by hyperglycemia, which occurs at any stage of pregnancy. GDM is more common in the third trimester of pregnancy and usually disappears after birth. It was hypothesized that the glycemic status of the mother can modulate liver development and growth early during the pregnancy. The simplest modality to monitor the evolution of GDM employs noninvasive techniques. In this category, routinely obstetrical ultrasound (OUS) examinations (simple or 2D/3D) can be employed for specific fetal measurements, such as fetal liver length (FLL) or volume (FLV). FLL and FLV may emerge as possible predictors of GDM as they positively relate to the maternal glycated hemoglobin (HbA1c) levels and to the results of the oral glucose tolerance test. The aim of this review is to offer insight into the relationship between GDM and fetal nutritional status. Risk factors for GDM and the short- and long-term outcomes of GDM pregnancies are also discussed, as well as the significance of different dietary patterns. Moreover, the review aims to fill one gap in the literature, investigating whether fetal liver growth can be used as a predictor of GDM evolution. To conclude, although studies pointed out a connection between fetal indices and GDM as useful tools in the early detection of GDM (before 23 weeks of gestation), additional research is needed to properly manage GDM and offspring health.     

Staphylococcus aureus—A Known Opponent against Host Defense Mechanisms and Vaccine Development—Do We Still Have a Chance to Win?

The main purpose of this review is to present justification for the urgent need to implement specific prophylaxis of invasive Staphylococcus aureus infections. We emphasize the difficulties in achieving this goal due to numerous S. aureus virulence factors important for the process of infection and the remarkable ability of these bacteria to avoid host defense mechanisms. We precede these considerations with a brief overview of the global necessitiy to intensify the use of vaccines against other pathogens as well, particularly in light of an impasse in antibiotic therapy. Finally, we point out global trends in research into modern technologies used in the field of molecular microbiology to develop new vaccines. We focus on the vaccines designed to fight the infections caused by S. aureus, which are often resistant to the majority of available therapeutic options.     

The Role of MicroRNAs in Myocarditis—What Can We Learn from Clinical Trials?

Myocarditis is an inflammatory disease of the heart with a viral infection as the most common cause. It affects most commonly young adults. Although endomyocardial biopsy and cardiac magnetic resonance are used in the diagnosis, neither of them demonstrates all the required qualities. There is a clear need for a non-invasive, generally available diagnostic tool that will still remain highly specific and sensitive. These requirements could be possibly met by microribonucleic acids (miRNAs), which are small, non-coding RNA molecules that regulate many fundamental cell functions. They can be isolated from cells, tissues, or body fluids. Recently, several clinical studies have shown the deregulation of different miRNAs in myocarditis. The phase of the disease has also been evidenced to influence miRNA levels. These changes have been observed both in adult and pediatric patients. Some studies have revealed a correlation between the change in particular miRNA concentration and the degree of cardiac damage and inflammation. All of this indicates miRNAs as potential novel biomarkers in the diagnosis of myocarditis, as well as a prognostic tool for this condition. This review aims to summarize the current knowledge about the role of miRNAs in myocarditis based on the results of clinical studies.     

Starve to Sustain—An Ancient Syrian Landrace of Sorghum as Tool for Phosphorous Bio-Economy?

Phosphorus (P) is an essential macronutrient, playing a role in developmental and metabolic processes in plants. To understand the local and systemic responses of sorghum to inorganic phosphorus (P_i) starvation and the potential of straw and ash for reutilisation in agriculture, we compared two grain (Razinieh) and sweet (Della) sorghum varieties with respect to their morpho-physiological and molecular responses. We found that P_i starvation increased the elongation of primary roots, the formation of lateral roots, and the accumulation of anthocyanin. In Razinieh, lateral roots were promoted to a higher extent, correlated with a higher expression of SbPht1 phosphate transporters. Infrared spectra of straw from mature plants raised to maturity showed two prominent bands at 1371 and 2337 cm⁻¹, which could be assigned to P-H(H₂) stretching vibration in phosphine acid and phosphinothious acid, and their derivates, whose abundance correlated with phosphate uptake of the source plant and genotype (with a higher intensity in Razinieh). The ash generated from these straws stimulated the shoot elongation and root development of the rice seedlings, especially for the material derived from Razinieh raised under P_i starvation. In conclusion, sorghum growing on marginal lands has potential as a bio-economy alternative for mineral phosphorus recycling.     

CpG Island Methylator Phenotype—A Hope for the Future or a Road to Nowhere?

The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and pathological characteristics of CIMP in CRC and other tumour types has rapidly expanded. Concordant and widespread hypermethylation of multiple CpG islands observed in CIMP in multiple cancers raised hopes for future epigenetically based diagnostics and treatments of solid tumours. However, studies on CIMP in solid tumours were hampered by a lack of generalisability and reproducibility of epigenetic markers. Moreover, CIMP was not a satisfactory marker in predicting clinical outcomes. The idea of targeting epigenetic abnormalities such as CIMP for cancer therapy has not been implemented for solid tumours, either. Twenty-one years after its discovery, we aim to cover both the fundamental and new aspects of CIMP and its future application as a diagnostic marker and target in anticancer therapies.     

Enrofloxacin—The Ruthless Killer of Eukaryotic Cells or the Last Hope in the Fight against Bacterial Infections?

Enrofloxacin is a compound that originates from a group of fluoroquinolones that is widely used in veterinary medicine as an antibacterial agent (this antibiotic is not approved for use as a drug in humans). It reveals strong antibiotic activity against both Gram-positive and Gram-negative bacteria, mainly due to the inhibition of bacterial gyrase and topoisomerase IV enzymatic actions. The high efficacy of this molecule has been demonstrated in the treatment of various animals on farms and other locations. However, the use of enrofloxacin causes severe adverse effects, including skeletal, reproductive, immune, and digestive disorders. In this review article, we present in detail and discuss the advantageous and disadvantageous properties of enrofloxacin, showing the benefits and risks of the use of this compound in veterinary medicine. Animal health and the environmental effects of this stable antibiotic (with half-life as long as 3–9 years in various natural environments) are analyzed, as are the interesting properties of this molecule that are expressed when present in complexes with metals. Recommendations for further research on enrofloxacin are also proposed.     

Seed Quantity or Quality?—Reproductive Responses of Females of Two Dioecious Woody Species to Long-Term Fertilisation

Although seed quality and quantity, as well as reproductive performance are important life history stages of plants, little is known about the reproductive responses of trees to environmental changes such as increased anthropogenic deposition of nitrogen (N) and phosphorus (P). Dioecious plants are good models with which to test the environmental impact on female or male reproductive responses individually. We analysed effects of different long-term nutritional availability on the reproductive performance of two dioecious species (Taxus baccata L. and Juniperus communis L.) characterised by different life histories. By using pot experiments with vegetatively propagated plants grown in different fertilisation conditions, we observed an increase in plant growth and strobili production but a decrease in seed efficiency. Seeds produced by fertilised plants had greater seed mass. Fertiliser addition did not change C or N content nor the C/N ratio of T. baccata seeds, but increased N content and the N/P ratio; however, it did lower the C/N ratio in J. communis. Fertilisation did not change the metabolite profile in T. baccata but 18 metabolites were changed in J. communis. The study revealed new links between species life history, environmental changes, and reproduction. The findings imply that future environmental conditions may alter both seed productivity, and quality, as well as plant reproductive behaviour.     

PIMS-TS,the New Paediatric Systemic Inflammatory Disease Related to Previous Exposure to SARS-CoV-2 Infection—“Rheumatic Fever” of the 21st Century?

Paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) is a new systemic inflammatory disease that mainly affects children. Its course in many features resembles that of acute rheumatic fever (ARF). Therefore, it is interesting that the experiences with ARF can be used in the management of patients with PIMS-TS. The aim of the article is to analyse the current data on PIMS-TS in relation to ARF. PIMS-TS and ARF are associated with an abnormal immune response to specific pathogens (SARS-CoV-2 and group A streptococcus, respectively). The main symptoms of both diseases are fever and cardiac involvement. Current therapy for PIMS-TS is based on anti-inflammatory treatment: intravenous immunoglobulin (first-line), intravenous glucocorticoids (second-line), or biological therapy (third-line; including interleukin [IL]-1 antagonists, IL-6 receptor blockers, and anti-tumour necrosis factor agents). Vaccination might be good prophylaxis, but the efficacy and safety of the vaccines against SARS-CoV-2 have not yet been established in children. Interesting insights may be gained by considering PIMS-TS in light of what is known of ARF due to their similar courses, but there are still many unanswered questions surrounding this disease and its pathogenesis.     

Indoleamine 2,3 Dioxygenase 1—The Potential Link between the Innate Immunity and the Ischemia-Reperfusion-Induced Acute Kidney Injury?

Ischemia-reperfusion injury (IRI) is of the most common causes of acute kidney injury (AKI); nevertheless, the mechanisms responsible for both early kidney injury and the reparative phase are not fully recognised. The inflammatory response following ischemia is characterised by the crosstalk between cells belonging to the innate immune system—dendritic cells (DCs), macrophages, neutrophils, natural killer (NK) cells, and renal tubular epithelial cells (RTECs). A tough inflammatory response can damage the renal tissue; it may also have a protective effect leading to the repair after IRI. Indoleamine 2,3 dioxygenase 1 (IDO1), the principal enzyme of the kynurenine pathway (KP), has a broad spectrum of immunological activity from stimulation to immunosuppressive activity in inflamed areas. IDO1 expression occurs in cells of the innate immunity and RTECs during IRI, resulting in local tryptophan (TRP) depletion and generation of kynurenines, and both of these mechanisms contribute to the immunosuppressive effect. Nonetheless, it is unknown if the above mechanism can play a harmful or preventive role in IRI-induced AKI. Despite the scarcity of literature in this field, the current review attempts to present a possible role of IDO1 activation in the regulation of the innate immune system in IRI-induced AKI.     

New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?

Mercury (Hg) is a highly toxic and widespread pollutant. We previously reported that the exposure of Mytilus galloprovincialis for 24 h to doses of HgCl₂ similar to those found in seawater (range 1–100 pM) produced alterations in the properties of protamine-like (PL) proteins that rendered them unable to bind and protect DNA from oxidative damage. In the present work, to deepen our studies, we analyzed PL proteins by turbidimetry and fluorescence spectroscopy and performed salt-induced release analyses of these proteins from sperm nuclei after the exposure of mussels to HgCl2 at the same doses. Turbidity assays indicated that mercury, at these doses, induced PL protein aggregates, whereas fluorescence spectroscopy measurements showed mercury-induced conformational changes. Indeed, the mobility of the PLII band changed in sodium dodecyl sulphate-polyacrylamide gel electrophoresis, particularly after exposure to 10-pM HgCl₂, confirming the mercury-induced structural rearrangement. Finally, exposure to HgCl₂ at all doses produced alterations in PL-DNA binding, detectable by DNA absorption spectra after the PL protein addition and by a decreased release of PLII and PLIII from the sperm nuclei. In conclusion, in this paper, we reported Hg-induced PL protein alterations that could adversely affect mussel reproductive activity, providing an insight into the molecular mechanism of Hg-related infertility.     

Nucleobindin-2/Nesfatin-1—A New Cancer Related Molecule?

Cancer is a heterogeneous disease, and even tumors with similar clinicopathological characteristics show different biology, behavior, and treatment responses. As a result, there is an urgent need to define new prognostic and predictive markers to make treatment options more personalized. According to the latest findings, nucleobindin-2/nesfatin-1 (NUCB2/NESF-1) is an important factor in cancer development and progression. Nucleobindin-2 is a precursor protein of nesfatin-1. As NUCB2 and nesfatin-1 are colocalized in each tissue, their expression is often analyzed together as NUCB2. The metabolic function of NUCB2/NESF-1 is related to food intake, glucose metabolism, and the regulation of immune, cardiovascular and endocrine systems. Recently, it has been demonstrated that high expression of NUCB2/NESF-1 is associated with poor outcomes and promotes cell proliferation, migration, and invasion in, e.g., breast, colon, prostate, endometrial, thyroid, bladder cancers, or glioblastoma. Interestingly, nesfatin-1 is also considered an inhibitor of the proliferation of human adrenocortical carcinoma and ovarian epithelial carcinoma cells. These conflicting results make NUCB2/NESF-1 an interesting target of study in the context of cancer progression. The present review is the first to describe NUCB2/NESF-1 as a new prognostic and predictive marker in cancers.     

Targeting Persistent Neuroinflammation after Hypoxic-Ischemic Encephalopathy—Is Exendin-4 the Answer?

Hypoxic-ischemic encephalopathy is brain injury resulting from the loss of oxygen and blood supply around the time of birth. It is associated with a high risk of death or disability. The only approved treatment is therapeutic hypothermia. Therapeutic hypothermia has consistently been shown to significantly reduce the risk of death and disability in infants with hypoxic-ischemic encephalopathy. However, approximately 29% of infants treated with therapeutic hypothermia still develop disability. Recent preclinical and clinical studies have shown that there is still persistent neuroinflammation even after treating with therapeutic hypothermia, which may contribute to the deficits seen in infants despite treatment. This suggests that potentially targeting this persistent neuroinflammation would have an additive benefit in addition to therapeutic hypothermia. A potential additive treatment is Exendin-4, which is a glucagon-like peptide 1 receptor agonist. Preclinical data from various in vitro and in vivo disease models have shown that Exendin-4 has anti-inflammatory, mitochondrial protective, anti-apoptotic, anti-oxidative and neurotrophic effects. Although preclinical studies of the effect of Exendin-4 in perinatal hypoxic-ischemic brain injury are limited, a seminal study in neonatal mice showed that Exendin-4 had promising neuroprotective effects. Further studies on Exendin-4 neuroprotection for perinatal hypoxic-ischemic brain injury, including in large animal translational models are warranted to better understand its safety, window of opportunity and effectiveness as an adjunct with therapeutic hypothermia.     

Double Gamers—Can Modified Natural Regulators of Higher Plants Act as Antagonists against Phytopathogens? The Case of Jasmonic Acid Derivatives

As key players in biotic stress response of plants, jasmonic acid (JA) and its derivatives cover a specific and prominent role in pathogens-mediated signaling and hence are promising candidates for a sustainable management of phytopathogenic fungi. Recently, JA directed antimicrobial effects on plant pathogens has been suggested, supporting the theory of oxylipins as double gamers in plant-pathogen interaction. Based on these premises, six derivatives (dihydrojasmone and cis-jasmone, two thiosemicarbazonic derivatives and their corresponding complexes with copper) have been evaluated against 13 fungal species affecting various economically important herbaceous and woody crops, such as cereals, grapes and horticultural crops: Phaeoacremonium minimum, Neofusicoccum parvum, Phaeomoniella chlamydospora, Fomitiporia mediterranea, Fusarium poae, F. culmorum, F. graminearum, F. oxysporum f. sp. lactucae, F. sporotrichioides, Aspergillus flavus, Rhizoctonia solani, Sclerotinia spp. and Verticillium dahliae. The biological activity of these compounds was assessed in terms of growth inhibition and, for the two mycotoxigenic species A. flavus and F. sporotrichioides, also in terms of toxin containment. As expected, the inhibitory effect of molecules greatly varied amongst both genera and species; cis-jasmone thiosemicarbazone in particular has shown the wider range of effectiveness. However, our results show that thiosemicarbazones derivatives are more effective than the parent ketones in limiting fungal growth and mycotoxins production, supporting possible applications for the control of pathogenic fungi.