Molecular Analysis of HLA Genes in Romanian Patients with Chronic Hepatitis B Virus Infection.

Hepatitis B, a persistent inflammatory liver condition, stands as a significant global health issue. In Romania, the prevalence of chronic hepatitis B virus (CHB) infection ranks among the highest in the European Union. The HLA genotype significantly impacts hepatitis B virus infection progression, indicating that certain HLA variants can affect the infection's outcome. The primary goal of the present work is to identify HLA alleles and specific amino acid residues linked to hepatitis B within the Romanian population. The study enrolled 247 patients with chronic hepatitis B; HLA typing was performed using next-generation sequencing. This study's main findings include the identification of certain HLA alleles, such as DQB1*06:03:01, DRB1*13:01:01, DQB1*06:02:01, DQA1*01:03:01, DRB5*01:01:01, and DRB1*15:01:01, which exhibit a significant protective effect against HBV. Additionally, the amino acid residue alanine at DQB1_38 is associated with a protective role, while valine presence may signal an increased risk of hepatitis B. The present findings are important in addressing the urgent need for improved methods of diagnosing and managing CHB, particularly when considering the disease's presence in diverse population groups and geographical regions.

Radioactive Iodine Therapy of Graves' Disease in Patients Pretreated With Methimazole Without Radioiodine Uptake for Dose Estimation.

OBJECTIVE: To assess response predictors to radioactive iodine (RAI) therapy without using thyroid uptake for dose estimate in patients pretreated with methimazole. METHODS: Retrospective analysis was performed of patients with Graves' disease treated with RAI doses determined without using uptake studies. RESULTS: In 242 patients (median age, 41.9 years; 66.1% female), initial mean free thyroxine (FT4) level was 4.7 ng/dL with an estimated thyroid size of 49.15 g. Prior to RAI therapy, average methimazole dose was 22.7 mg/day. Mean RAI dose was 737.0 ±199.4 MBq (19.9 ± 5.4 mCi). Two hundred eight patients (85.9%) responded to RAI therapy; 185 (88.9%) became hypothyroid and 23 (11.1%) became euthyroid. The majority (90.4%) responded within 6 months of therapy with a quicker response (13.9 ± 8.3 vs 17.5 ± 13.5 weeks) for those treated with doses per gram of ≥14.8 MBq (0.4 mCi). Thirty-four nonresponders had a higher initial FT4 level and larger thyroid size with a lower RAI dose per gram of thyroid tissue. In multivariate analysis, the independent response predictor to therapy was dose per gram of thyroid tissue of ≥14.8 MBq (0.4 mCi) (hazard ratio, 3.18; 95% CI, 1.1-9.7). Doses per gram of 14.8 to 18.1 MBq (0.4-0.5 mCi) achieved maximal response rate without added advantage of higher doses. Thyroid size prior to RAI therapy, FT4 levels at diagnosis, and age were inversely related to response. CONCLUSION: RAI therapy for Graves' disease without uptake studies for dose estimates is an effective treatment method. In patients pretreated with methimazole, an RAI dose per gram of thyroid tissue of ≥14.8 MBq (0.4 mCi) showed high response rate. Prospective studies are needed to confirm the viability of this simplified and cost-effective approach.

Epithelial Sodium Channel Inhibition by Amiloride Addressed with THz Spectroscopy and Molecular Modeling.

THz spectroscopy is important for the study of ion channels because it directly addresses the low frequency collective motions relevant for their function. Here we used THz spectroscopy to investigate the inhibition of the epithelial sodium channel (ENaC) by its specific blocker, amiloride. Experiments were performed on A6 cells' suspensions, which are cells overexpressing ENaC derived from Xenopus laevis kidney. THz spectra were investigated with or without amiloride. When ENaC was inhibited by amiloride, a substantial increase in THz absorption was noticed. Molecular modeling methods were used to explain the observed spectroscopic differences. THz spectra were simulated using the structural models of ENaC and ENaC-amiloride complexes built here. The agreement between the experiment and the simulations allowed us to validate the structural models and to describe the amiloride dynamics inside the channel pore. The amiloride binding site validated using THz spectroscopy agrees with previous mutagenesis studies. Altogether, our results show that THz spectroscopy can be successfully used to discriminate between native and inhibited ENaC channels and to characterize the dynamics of channels in the presence of their specific antagonist.

Senescence-induced immunophenotype, gene expression and electrophysiology changes in human amniocytes.

The aim of the study was to evidence replicative senescence-induced changes in human amniocytes via flow cytometry, quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) and automated/manual patch-clamp. Both cryopreserved and senescent amniocytes cultured in BIO-AMF-2 medium featured high percentages of pluripotency cell surface antigens SSEA-1, SSEA-4, TRA1-60, TRA1-81 (assessed by flow cytometry) and expression of pluripotency markers Oct4 (Pou5f1) and Nanog (by qRT-PCR). We demonstrated in senescent vs cryopreserved amniocytes decreases in mesenchymal stem cell surface markers. Senescence-associated ß-galactosidase stained only senescent amniocytes, and they showed no deoxyuridine incorporation. The gene expression profile revealed a secretory phenotype of senescent amniocytes (increased interleukin (IL)-1α, IL-6, IL-8, transforming growth factor ß, nuclear factor κB p65 expression), increases for cell cycle-regulating genes (p16INK4A ), cytoskeletal elements (ß-actin); HMGB1, c-Myc, Bcl-2 showed reduced changes and p21, MDM2 decreased. Via patch-clamp we identified five ion current components: outward rectifier K+ current, an inactivatable component, big conductance Ca2+ -dependent K+ channels (BK) current fluctuations, Na+ current, and inward rectifier K+ current. Iberiotoxin 100 nmol/L blocked 71% of BK fluctuations, and lidocaine 200 µmol/L exerted use-dependent Na+ current block. Transient receptor potential (TRP)M7-like current density at -120 mV was significantly increased in senescent amniocytes. The proinflammatory profile acquired by senescent amniocytes in vitro may prevent their use in clinical therapies for immunosuppression, antiapoptotic and healing effects.

CXCL1 and CXCL2 Inhibit the Axon Outgrowth in a Time- and Cell-Type-Dependent Manner in Adult Rat Dorsal Root Ganglia Neurons.

The ability to regrow their axons after an injury is a hallmark of neurons in peripheral nervous system which distinguish them from central nervous system neurons. This ability is influenced by their intrinsic capacity to regrow and by the extracellular environment which needs to be supportive of regrowth. CXCL1 [Chemokine (C-X-C motif) Ligand 1] and CXCL2 [Chemokine (C-X-C motif) Ligand 2] are two low-molecular-weight chemokines which can influence neuronal proliferation, differentiation and neurogenesis, but which are also upregulated by injury or inflammation. In this study we investigated the effects of long-term incubation (24, 48 and 72 h) with different concentrations of CXCL1 (0.4, 4 or 40 nM) or CXCL2 (0.36, 3.6 or 36 nM) on the axon outgrowth of adult rat dorsal root ganglia neurons in culture. The results showed that both chemokines significantly inhibited the axon outgrowth, with large and medium NF200 (NeuroFilament 200) (+) dorsal root ganglia neurons affected quicker, compared to small IB4 (Isolectin B4) (+) dorsal root ganglia neurons which were affected after longer exposure. Blocking CXCR2 (C-X-C motif chemokine receptor 2) which mediates the effects of CXCL1 and CXCL2 prevented these effects, suggesting that CXCR2 may represent a new therapeutic target for promoting the axon outgrowth after a peripheral nerve injury.

Endothelial Dysfunction is Related to Glycemic Variability and Quality and Duration of Sleep in Adults With Type 1 Diabetes.

BACKGROUND: Elevated cardiovascular disease risk in people with type 1 diabetes (T1DM) is incompletely understood. Glycemic control, glycemic variability, and sleep quality and duration may relate to cardiovascular disease risk in this population via endothelial dysfunction. OBJECTIVE: The aim of this study was to examine relationships among glycemic control, glycemic variability, sleep quality and duration, and endothelial function in adults with T1DM. METHODS: Endothelial function was measured using flow-mediated dilation. Glycemic control and glycemic variability were measured using A1C and a continuous glucose monitor, respectively; sleep quality and duration were measured with the Pittsburgh Sleep Quality Index. RESULTS: Twenty subjects were recruited. Reduced flow-mediated dilation and higher glucose levels were associated with poorer sleep quality (r = -0.51, P = .01; r = 0.52, P = .03). Subjects with shorter sleep duration had greater glycemic variability. CONCLUSIONS: Endothelial dysfunction (a precursor to cardiovascular disease) relates to glycemic control, glycemic variability, and sleep quality in T1DM.

Poor sleep quality is associated with nocturnal glycaemic variability and fear of hypoglycaemia in adults with type 1 diabetes.

AIMS: To examine sleep quality and its associations with glycaemic control, glycaemic variability (GV), and fear of hypoglycaemia (FOH) in adults with type 1 diabetes. BACKGROUND: Poor sleep quality has negative health consequences and is a frequent complaint among adults with type 1 diabetes. Sleep quality in adults with type 1 diabetes is likely affected by glucose levels as well as stressors associated with managing a chronic condition. DESIGN: A retrospective secondary analysis of pooled data from two previous cross-sectional studies was conducted. METHODS: We examined subjective sleep quality, FOH; objective measures of glycaemic control (HbA1c); and GV (3-day continuous glucose monitoring) in 48 men and women aged 18-45 years with type 1 diabetes. The data were collected over 3 years in 2013-2016. RESULTS/FINDINGS: Poor sleep quality was reported by 46% of patients. Those with poor sleep quality had significantly greater nocturnal GV and FOH. Nocturnal GV and FOH were significantly associated with poor sleep quality. The interaction effect of GV and FOH was significant. CONCLUSION: These findings suggest that glycaemic control and FOH are targets for intervention to improve sleep quality in those with type 1 diabetes.

N-glycosylation of the transient receptor potential melastatin 8 channel is altered in pancreatic cancer cells.

Transient receptor potential melastatin 8 (TRPM8), a membrane ion channel, is activated by thermal and chemical stimuli. In pancreatic ductal adenocarcinoma, TRPM8 is required for cell migration, proliferation, and senescence and is associated with tumor size and pancreatic ductal adenocarcinoma stages. Although the underlying mechanisms of these processes have yet to be described, this cation-permeable channel has been proposed as an oncological target. In this study, the glycosylation status of the TRPM8 channel was shown to affect cell proliferation, cell migration, and calcium uptake. TRPM8 expressed in the membrane of the Panc-1 pancreatic tumoral cell line is non-glycosylated, whereas human embryonic kidney cells transfected with human TRPM8 overexpress a glycosylated protein. Moreover, our data suggest that Ca2+ uptake is modulated by the glycosylation status of the protein, thus affecting cell proliferation.

Effects of Cd2+ on the epithelial Na+ channel (ENaC) investigated by experimental and modeling studies.

The function of the epithelial Na+ channel from the apical membrane of many Na+ transporting epithelia is modulated by various chemical compounds from the extracellular space, such as heavy metals, protons or chloride ions. We have studied the effect of extracellular Cd2+ on the function of the epithelial Na+ channel (ENaC) in heterologously expressed Xenopus laevis oocytes and Na+-transporting epithelia. We assayed channel function as the amiloride-sensitive sodium current (I(Na)). Cd2+ rapidly and voltage-independently inhibited INa in oocytes expressing αßγ Xenopus ENaC (xENaC). The extracellular Cd2+ inhibited Na+ transport and showed no influence on ENaC trafficking, as revealed by concomitant measurements of the transepithelial current, conductance and capacitance in Na+-transporting epithelia. Instead, amiloride inhibition was noticeably diminished in the presence of Cd2+ on the apical membrane. Using molecular modeling approaches, we describe the amiloride binding sites in rat and xENaC structures, and we present four putative binding sites for Cd2+. These results indicate that ENaC functions as a sensor for external Cd2+.

Pre-operative radiological measurement of femoral rotation for prosthetic positioning in total knee arthroplasty.

PURPOSE: This study outlines the benefits of the seated view radiograph of the knee in evaluation of the pre-operative individual distal femoral torsion (DFT) and for the follow-up of the post-operative rotational positioning of the femoral component in total knee arthroplasty. METHODS: Study on 20 patients who underwent total knee arthroplasty and the correlation between the DFT measured before surgery with this radiology view, the intra-operative external rotation (ER) necessary for the parallel positioning of the femoral component with the transepicondylar axis (TEA) and the post-operative femoral rotational alignment of the prosthesis on the same view. RESULTS: In 90 % of cases the values of internal DFT were between -1(0) and -8(0), while the mean value of the internal rotation (IR) was -4.45(0). The mean value of the ER applied to the posterior bone resection was 4.25(0) (0(0)-7(0)), showing a statistically significant correlation between the pre-operative measurement and the intra-operative one of the posterior condylar angle (PCA) (r = 0.890, p = 0.000). Residual internal femoral malrotation has been identified in four cases, its mean value being 0.4(0). In three patients the pre-operative value of the PCA was higher than the intra-operative one and an internal malrotation of the post-operative femoral component was observed. CONCLUSIONS: The results are encouraging for the further use of this pre-operative view with the premises of increasing the accuracy of prosthetic positioning and reducing the mechanical complications.

The association between glycemic control and clinical outcomes after kidney transplantation.

OBJECTIVE: To analyze the relationship between glycemic control after renal transplantation and subsequent graft function and complications. METHODS: We conducted a retrospective chart review of 202 consecutive patients undergoing kidney transplantation to analyze the association between perioperative and chronic glycemic control and clinical outcomes of rejection, infection, and hospital readmission during the first year after kidney transplantation. RESULTS: Mean in-hospital blood glucose (BG) was 157 ± 34.5 mg/dL. Mean hemoglobin A1c (HbA1c) during the first 12 months posttransplantation was 6.84 ± 1.46%. Fiftyfour patients (27%) were treated for acute or chronic rejection, 88 (44%) for infection, and 149 (74%) patients were readmitted at least once within the first year after transplantation. There were no significant differences in the risks for rejection, infection, or readmission across the 5 mean initial inpatient BG or subsequent HbA1c quintiles. In addition, there was no significant relationship between the percentage of BG measurements that fell in the "tight control" range of 80 to 110 mg/dL for each patient and any of the outcomes. CONCLUSION: We did not find an association between glycemic control (perioperative or chronic) and the outcomes of graft rejection, infection, or hospital readmission in the first 12 months after renal transplantation. Our results suggest that "near normal" glycemic targets are not necessary for managing hyperglycemia after renal transplantation.

Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.

Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components of spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) and a trigger of many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or Mad2 binding to specific partners (cell-division cycle protein 20 (Cdc20) or Mad1) were targets of previous pharmacogenomics studies. Here, Mad2 binding to Cdc20 and the interconversion rate from open to closed Mad2 were predicted and the molecular features with a critical contribution to these processes were determined by extending the quantitative structure-activity relationship (QSAR) method to large-size proteins such as Mad2. QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes. The most relevant descriptors identified for predicting Mad2 native and mutants action mechanism and their involvement in genetic disorders are the steric (van der Waals area and solvent accessible area and their subdivided) and energetic van der Waals energy descriptors. The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q2 (0.53-0.65) and fitted correlation r2 (0.82-0.90). Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN.

Efficiency of vanilla, patchouli and ylang ylang essential oils stabilized by iron oxide@C14 nanostructures against bacterial adherence and biofilms formed by Staphylococcus aureus and Klebsiella pneumoniae clinical strains.

Biofilms formed by bacterial cells are associated with drastically enhanced resistance against most antimicrobial agents, contributing to the persistence and chronicization of the microbial infections and to therapy failure. The purpose of this study was to combine the unique properties of magnetic nanoparticles with the antimicrobial activity of three essential oils to obtain novel nanobiosystems that could be used as coatings for catheter pieces with an improved resistance to Staphylococcus aureus and Klebsiella pneumoniae clinical strains adherence and biofilm development. The essential oils of ylang ylang, patchouli and vanilla were stabilized by the interaction with iron oxide@C14 nanoparticles to be further used as coating agents for medical surfaces. Iron oxide@C14 was prepared by co-precipitation of Fe+2 and Fe+3 and myristic acid (C14) in basic medium. Vanilla essential oil loaded nanoparticles pelliculised on the catheter samples surface strongly inhibited both the initial adherence of S. aureus cells (quantified at 24 h) and the development of the mature biofilm quantified at 48 h. Patchouli and ylang-ylang essential oils inhibited mostly the initial adherence phase of S. aureus biofilm development. In the case of K. pneumoniae, all tested nanosystems exhibited similar efficiency, being active mostly against the adherence K. pneumoniae cells to the tested catheter specimens. The new nanobiosystems based on vanilla, patchouli and ylang-ylang essential oils could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with anti-adherence and anti-biofilm properties.

FREE: A randomized controlled feasibility trial of a cognitive behavioral therapy and technology-assisted intervention to reduce fear of hypoglycemia in young adults with type 1 diabetes.

OBJECTIVE: The purpose of this study was to test the preliminary effectiveness of a cognitive behavioral therapy intervention (Fear Reduction Efficacy Evaluation [FREE]) designed to reduce fear of hypoglycemia in young adults with type 1 diabetes. The primary outcome was fear of hypoglycemia, secondary outcomes were A1C, and glycemic variability. METHODS: A randomized clinical trial was used to test an 8-week intervention (FREE) compared to an attention control (diabetes education) in 50 young adults with type 1 diabetes who experienced fear of hypoglycemia at baseline. All participants wore a continuous glucose monitor for the 8-week study period. Self-reported fear of hypoglycemia point-of-care A1C testing, continuous glucose monitor-derived glucose variability were measured at baseline, Week 8, and Week 12 (post-program). RESULTS: Compared to controls, those participating in the FREE intervention experienced a reduction in fear of hypoglycemia (SMD B = -8.52, p = 0.021), change in A1C (SMD B = 0.04, p = 0.841) and glycemic variability (glucose standard deviation SMD B = -2.5, p = 0.545) by the end of the intervention. This represented an 8.52% greater reduction in fear of hypoglycemia. CONCLUSION: A cognitive behavioral therapy intervention (FREE) resulted in improvements in fear of hypoglycemia. CLINICALTRIALS: govNCT03549104.

Biomedical Promise of Sustainable Microwave-Engineered Symmetric Curcumin Derivatives.

Curcumin is a polyphenol of the Curcuma longa plant, which can be used for various medicinal purposes, such as inflammation and cancer treatment. In this context, two symmetric curcumin derivatives (D1-(1E,6E)-1,7-bis(4-acetamidophenyl)hepta-1,6-diene-3,5-dione and D2-p,p-dihydroxy di-cinnamoyl methane) were obtained by the microwave-based method and evaluated for their antitumoral effect on human cervix cancer in comparison with toxicity on non-tumoral cells, taking into account that they were predicted to act as apoptosis agonists or anti-inflammatory agents. The HeLa cell line was incubated for 24 and 72 h with a concentration of 50 µg/mL of derivatives that killed almost half of the cells compared to the control. In contrast, these compounds did not alter the viability of MRC-5 non-tumoral lung fibroblasts until 72 h of incubation. The nitric oxide level released by HeLa cells was higher compared to MRC-5 fibroblasts after the incubation with 100 µg/mL. Both derivatives induced the decrease of catalase activity and glutathione levels in cancer cells without targeting the same effect in non-tumoral cells. Furthermore, the Western blot showed an increased protein expression of HSP70 and a decreased expression of HSP60 and MCM2 in cells incubated with D2 compared to control cells. We noticed differences regarding the intensity of cell death between the tested derivatives, suggesting that the modified structure after synthesis can modulate their function, the most prominent effect being observed for sample D2. In conclusion, the outcomes of our in vitro study revealed that these microwave-engineered curcumin derivatives targeted tumor cells, much more specifically, inducing their death.

Half-Curcuminoids Encapsulated in Alginate-Glucosamine Hydrogel Matrices as Bioactive Delivery Systems.

The therapeutic effects of curcumin and its derivatives, based on research in recent years, are limited by their low bioavailability. To improve bioavailability and develop the medical field of application, different delivery systems have been developed that are adapted to certain environments or the proposed target type. This study presents some half-curcuminoids prepared by the condensation of acetylacetone with 4-hydroxybenzaldehyde (C1), 4-hydroxy-3-methoxybenzaldehyde (C2), 4-acetamidobenzaldehyde (C3), or 4-diethylaminobenzaldehyde (C4), at microwaves as a simple, solvent-free, and eco-friendly method. The four compounds obtained were characterized in terms of morphostructural and photophysical properties. Following the predictions of theoretical studies on the biological activities related to the molecular structure, in vitro tests were performed for compounds C1-C3 to evaluate the antitumor properties and for C4's possible applications in the treatment of neurological diseases. The four compounds were encapsulated in two types of hydrogel matrices. First, the alginate-glucosamine network was generated and then the curcumin analogs were loaded (G1, G3, G5-G7, and G9). The second type of hydrogels was obtained by loading the active compound together with the generation of the hydrogel carrier matrices, by simply dissolving (G4 and G10) or by chemically binding half-curcuminoid derivatives to glucosamine (G2 and G8). Thus, two types of curcumin analog delivery systems were obtained, which could be applied in various types of medical treatments.

The Impact of ZnO and Fe2O3 Nanoparticles on Sunflower Seed Germination, Phenolic Content and Antiglycation Potential.

The enhancement of seed germination by using nanoparticles (NPs) holds the potential to elicit the synthesis of more desired compounds with important biomedical applications, such as preventing protein glycation, which occurs in diabetes. Here, we used 7 nm and 100 nm ZnO and 4.5 nm and 16.7 nm Fe2O3 NPs to treat sunflower seeds. We evaluated the effects on germination, total phenolic content, and the anti-glycation potential of extracted polyphenols. Sunflower seeds were allowed to germinate in vitro after soaking in NP solutions of different concentrations. Polyphenols were extracted, dosed, and used in serum albumin glycation experiments. The germination speed of seeds was significantly increased by the 100 nm ZnO NPs and significantly decreased by the 4.5 nm Fe2O3 NPs. The total phenolic content (TPC) of seeds was influenced by the type of NP, as ZnO NPs enhanced TPC, and the size of the NPs, as smaller NPs led to improved parameters. The polyphenols extracted from seeds inhibited protein glycation, especially those extracted from seeds treated with 7 nm ZnO. The usage of NPs impacted the germination speed and total polyphenol content of sunflower seeds, highlighting the importance of NP type and size in the germination process.

Pharmacological descriptors related to the binding of Gp120 to CD4 corresponding to 60 representative HIV-1 strains.

The standardization of HIV-1 strains for vaccine tests include the use of viral reference panels. We determined a series of pharmacological descriptors (molecular surfaces, volumes, electrostatic energies, solvation energies, number of atoms, number of hydrogen donors or acceptors and number of rigid bonds) for the gp120 CD4-binding sites structures in the unliganded state from a reference panel of 60 diverse strains of HIV-1. We identified the descriptors that varied significantly between the strains, the outliner strains for each descriptor set and the possible correlations between the descriptors. Our results improve the knowledge about gp120, its molecular and possible neutralization properties.

Adult multifocal pigmented villonodular synovitis--clinical review.

Pigmented villonodular synovitis (PVNS) is a rare, benign proliferative disease of the synovial tissue that affects a single joint or a tendon sheath. Data from the literature present only a few cases of multifocal PVNS. This paper presents multifocal PVNS in the adult. This disease can affect bilateral shoulders, hips and knees. The diagnosis may be delayed by the slow evolution of the disease (up to ten years); some patients may be seen with late-stage degenerative joints, serious complications, painful and functionally uncompensated, with significant locomotion deficit. PVNS requires a radical treatment with prosthetic arthroplasty associated with synovectomy. Complex imaging (X-Rays, magnetic resonance imaging (MRI), ultrasound) and macroscopic appearance of the lesions during surgery confirms the clinical diagnosis of multifocal PVNS with secondary bone lesions. Histology marks the final diagnosis of multifocal PVNS. The postoperative results are good, with recovery in functional parameters of the joints with endoprosthesis.

Aspartame Safety as a Food Sweetener and Related Health Hazards.

Aspartame is the methyl-ester of the aspartate-phenylalanine dipeptide. Over time, it has become a very popular artificial sweetener. However, since its approval by the main food safety agencies, several concerns have been raised related to neuropsychiatric effects and neurotoxicity due to its ability to activate glutamate receptors, as well as carcinogenic risks due to the increased production of reactive oxygen species. Within this review, we critically evaluate reports concerning the safety of aspartame. Some studies evidenced subtle mood and behavioral changes upon daily high-dose intake below the admitted limit. Epidemiology studies also evidenced associations between daily aspartame intake and a higher predisposition for malignant diseases, like non-Hodgkin lymphomas and multiple myelomas, particularly in males, but an association by chance still could not be excluded. While the debate over the carcinogenic risk of aspartame is ongoing, it is clear that its use may pose some dangers in peculiar cases, such as patients with seizures or other neurological diseases; it should be totally forbidden for patients with phenylketonuria, and reduced doses or complete avoidance are advisable during pregnancy. It would be also highly desirable for every product containing aspartame to clearly indicate on the label the exact amount of the substance and some risk warnings.