Search Results (130)

The consumption of nuts is widespread globally and constitutes a significant component of the human diet due to its nutritional value. However, the presence of mycotoxins in food products, including nuts, is a global public health concern. Mycotoxins are toxic metabolites produced by contaminating fungi such as Aspergillus spp. and Penicillium spp., which can contaminate crops during growth, harvesting, storage, or transport. The aim of this study was to conduct monitoring for the presence of mycotoxins in nuts already on the market. Specifically, secondary metabolites produced by Penicillium spp., including ochratoxin A, patulin, citrinin, cyclopiazonic acid, citreoviridin, griseofulvin, meleagrin, mycophenolic acid, penitrem A, roquefortine C, penicillins G and V, sulochrin, andrastin A, asterriquinone, chaetoglobosin A, cyclopenin, cyclopenol, and viridicatin, were investigated. Commercial products were purchased from various retail outlets in different formats, origins, and cultivation methods to assess potential influences of these factors on mycotoxin presence. Regarding Penicillium-toxins, 37% of the samples showed the presence of at least one of them, and 9% showed the simultaneous presence of two or more Penicillium-toxins. Peanuts had the highest incidence of Penicillium-toxin contamination, with at least one metabolite detected in 60% of the analyzed samples. The most common secondary metabolite among the samples was patulin (14%), while the secondary metabolite with the highest concentration was viridicatin in a walnut sample (151.40 ± 64.30 µg/kg). Besides Penicillium-toxins, aflatoxins were also analyzed with another validated LC-MS/MS method, but they were not detected in any sample. Although most Penicillium-toxins, and in particular patulin in nuts, are not currently regulated in the international legislation, they exert toxic effects on humans and animals, and their occurrence can represent a food safety risk. Full article

Background: Mycophenolic acid (MPA) is frequently used in pediatric renal transplantation as part of immunosuppressive therapy, yet therapeutic drug monitoring (TDM) remains challenging. Accurate monitoring is essential due to MPA’s narrow therapeutic window, variable pharmacokinetics, and high protein binding. This study examined whether saliva could serve as a non-invasive alternative to plasma for measuring MPA exposure. Methods and Results: Concentrations of MPA and its primary glucuronide metabolite (MPAG) were determined in plasma, capillary blood, plasma ultrafiltrate, wet saliva, and dried saliva collected using volumetric absorptive microsampling (VAMS). A novel LC–MS/MS method for quantifying MPA and MPAG in dried saliva collected with the Mitra™ device was developed and validated within a 1–700 μg/L calibration range, demonstrating robust analytical performance. Dried and wet saliva showed high correlation (r = 0.99 and 0.98 for MPA and MPAG, respectively). However, both salivary matrices—dried saliva collected with Mitra™ (vsMPA, vsMPAG) and wet saliva (sMPA, sMPAG)—exhibited poor correlation with unbound (fMPA, fMPAG) and total plasma concentrations (tMPA, tMPAG). A modest, yet positive, correlation was observed between the measured concentrations for the following pairs: sMPA versus fMPA (r = 0.376, p = 0.1036), sMPA versus tMPA (r = 0.305, p = 0.1904), sMPAG versus fMPAG (r = 0.205, p = 0.3851), and sMPAG versus tMPAG (r = 0.472, p = 0.0012). Pharmacokinetic parameters supported these findings, highlighting discrepancies between saliva and plasma. Conclusions: From a clinical perspective, saliva sampling—although minimally invasive and patient-friendly—does not offer a reliable substitute for plasma in routine TDM of MPA and MPAG. Capillary blood collected through VAMS remains a promising alternative for long-term monitoring of pediatric patients; however, several considerations still need to be addressed. Full article

Background/Objectives: Cytokine release during organ transplantation contributes to primary graft dysfunction and requires careful immunomodulation. CytoSorb, a hemoadsorption device developed to reduce circulating cytokine levels, is increasingly used in critically ill patients. However, its impact on concurrent immunosuppressive therapy remains unclear. Methods: In this ex vivo study, we investigated the adsorption of five immunosuppressants—cyclosporine A, tacrolimus, methylprednisolone, mycophenolic acid, and 6-mercaptopurine—using a scaled-down CytoSorb hemoadsorption circuit and compared results to chronic and acute dialysis. Additionally, a whole blood model was used to assess the functional impact of CytoSorb treatment on leukocyte activation, using LPS and anti-CD3 stimulation and subsequent cytokine measurement (TNF-α, IL-1β, IL-6, IL-8). Results: CytoSorb significantly reduced serum levels of methylprednisolone (92 ± 3%), mycophenolate (80 ± 2%), 6-mercaptopurine (65 ± 32%), and cyclosporine A (61 ± 16%), but had no significant effect on tacrolimus. Dialysis effectively removed methylprednisolone and 6-mercaptopurine, while strongly protein-bound drugs such as cyclosporine A and tacrolimus remained largely unaffected. In the whole blood model, CytoSorb treatment did not significantly alter cytokine release after immunostimulation, suggesting preserved immunosuppressive efficacy. Conclusions: CytoSorb treatment reduces the plasma concentration of selected immunosuppressants. However, short-term treatment appears to have minimal impact on immunosuppressive function. These findings support the cautious use of CytoSorb in transplant settings but highlight the need for in vivo confirmation. Full article

Background/Objectives: Pre-analytical variation is a major challenge in metabolomics, yet most stability studies have focused on healthy volunteers and have overlooked the impact of disease and medication. To address this gap, we conducted a pilot study in systemic lupus erythematosus (SLE) to assess serum metabolite stability under delayed centrifugation. Methods: Peripheral blood from 10 SLE patients and 5 healthy controls (HC) was stored at room temperature for 1–24 h before processing and analyzed by untargeted LC-MS-based metabolomics. This design enabled direct evaluation of the effect of pre-analytical delay within the context of clinical heterogeneity. Results: Principal component trajectories showed reproducible temporal shifts in HC but dispersed patterns in SLE, indicating disease- and treatment-related influences. Linear mixed-effects models identified metabolites with condition-specific kinetics, including glucose, choline, glycerophosphocholine, and pyroglutamic acid. Mycophenolate intake was further associated with distinct AMP dynamics. Conclusions: These findings demonstrate that both disease state and medication reshape apparent metabolite stability, highlighting the need for strictly controlled sample handling and well-characterized clinical cohorts in metabolomics studies. Full article

Background and Clinical Significance: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in adults, typically following a chronic course that often leads to end-stage kidney disease. Rapidly progressive glomerulonephritis is a rare and severe variant of IgAN with a poor prognosis. Case Presentation: We present the clinical case of a 68-year-old Caucasian female with a history of systemic lupus erythematosus and untreated chronic hepatitis B, who was admitted to the Transplant-Nephrology Department, University Hospital Martin, with acute kidney injury and nephrotic syndrome accompanied by hematuria. The clinical picture was marked by lower limb oedema and poorly controlled hypertension, both of which responded well to conservative management. Extrarenal causes were excluded through otolaryngologic, stomatologic, and gynecologic assessments, and autoantibody screening was negative. Renal biopsy revealed crescentic glomerulonephritis with endocapillary and mesangial proliferation and IgA deposits. Due to active hepatitis B, initial treatment was limited to corticosteroids. Following a decrease in viral load, pulse therapy with cyclophosphamide was administered, followed by mycophenolic acid; however, renal function did not recover. Conclusions: The rapidly progressive form of IgA nephropathy in the context of active hepatitis B presents a rare and challenging clinical case. Management requires a highly individualised, multidisciplinary approach due to the risk of infectious complications and the need to preserve renal function. Full article

Influenza A virus (IAV) poses a major threat to global public health, exerting immense pressure on human health and the economy. The IAV nucleoprotein (NP) is an ideal target for antiviral drug development. Through Mini-genome and Surface Plasmon Resonance assays, this study discovered and verified that mycophenolic acid methyl ester (MAE), a secondary metabolite produced by the marine algal-associated fungus Phaeosphaeria spartinae, can target the viral nucleoprotein to exert anti-IAV activity. Pull-down assays and immunofluorescence have revealed that MAE blocks the nuclear import of viral ribonucleoprotein complexes (vRNP) by interfering with the interaction between NP and IMP-α. It also affects the vRNP assembly process by regulating NP oligomerization and the interaction between NP and PB2. In addition, Sandwich ELISA and Electron Microscopy experiments showed that MAE can also inactivate viral particles to reduce the risk of infection. Comprehensive research results indicate that MAE exerts its effects by inhibiting the viral NP protein, which has laid an important foundation for the development of marine-derived NP-targeted drugs. Full article

Background/Objective: Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target. Methods: Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines. Results: Here, we identify Inosine monophosphate dehydrogenase-2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, as a novel substrate of ALK and SRC. We show that phosphorylation at the conserved Y233 residue within the allosteric domain enhances IMPDH2 activity, linking TK signaling to metabolic reprogramming in cancer cells. We further identify PI3P as a natural lipid inhibitor that binds IMPDH2 and suppresses its enzymatic function. Using structure-based virtual screening, we developed Comp-10, a first-in-class allosteric IMPDH inhibitor. Unlike classical active-site inhibitors such as mycophenolic acid (MPA), Comp-10 decreases IMPDH1/2 protein levels, blocks filament (rod/ring) formation, and inhibits the growth of ALK and BTK inhibitor-resistant lymphoma cells. Comp-10 acts post-transcriptionally and avoids compensatory IMPDH upregulation observed with MPA (rod/ring) formation, and inhibited growth in TKI-resistant lymphoma cells. Notably, Comp-10 avoided the compensatory IMPDH upregulation observed with MPA. Conclusion: These findings uncover a novel TK–IMPDH2 signaling axis and provide mechanistic and therapeutic insight into the allosteric regulation of IMPDH2. Comp-10 represents a promising therapeutic candidate for targeting metabolic vulnerabilities in tyrosine kinase driven cancers. Full article

Background/Objectives: Mycophenolic acid (MPA) is used as part of first-line combination immunosuppressive therapy for renal transplant recipients. Personalized dosing approaches are needed to balance efficacy and minimize toxicity due to the pharmacokinetic variability of the drug. In this study, population pharmacokinetic (PopPK) modeling and machine learning (ML) techniques are coupled to provide valuable insights into optimizing MPA therapy. Methods: Using data from 76 renal transplant patients, two PopPK models were developed to describe and predict MPA levels for two different formulations (enteric-coated mycophenolate sodium and mycophenolate mofetil). Covariate effects on drug clearance were assessed, and Monte Carlo simulations were used to evaluate exposure under normal and reduced clearance conditions. ML techniques, including principal component analysis (PCA) and ensemble tree models (bagging and boosting), were applied to identify predictive factors and explore associations between MPA plasma/saliva concentrations and the examined covariates. Results: Total daily dose and post-transplant time (PTP) were identified as key covariates affecting clearance. PCA highlighted MPA dose as the primary determinant of plasma levels, with urea and PTP also playing significant roles. Boosted tree analysis confirmed these findings, demonstrating strong predictive accuracy (R² > 0.91). Incorporating saliva MPA levels improved predictive performance, suggesting that saliva may be a complementary monitoring tool, although plasma monitoring remained superior. Simulations allowed exploring potential dosing adjustments for patients with reduced clearance. Conclusions: This study demonstrates the potential of integrating machine learning with population pharmacokinetic modeling to improve the understanding of MPA variability and support individualized dosing strategies in renal transplant recipients. The developed PopPK/ML models provide a methodological foundation for future research toward more personalized immunosuppressive therapy. Full article

Background/Objectives: Some lung transplant (LungTx) recipients do not achieve the expected lung function within the first year, a condition known as baseline lung allograft dysfunction (BLAD). Our objective was to analyze the risk factors associated with BLAD, focusing on the variables associated with a higher risk of developing a more intense alloimmune response. Methods: We carried out a prospective study including 88 LungTx recipients. BLAD was defined as failure to reach 80% of the predicted value for forced expiratory volume in one second (FEV1) and/or forced vital capacity (FVC) on two tests conducted at least three weeks apart. Tacrolimus time in therapeutic range (TTR) and mycophenolic acid area under the curve (MPA AUC_0–12h) were measured at the third month. Donor–recipient compatibility was assessed using HLA eplet mismatch analysis, performed via HLA Matchmaker 3.1. Results: BLAD patients showed greater eplet mismatch burden (67, IQR 20 vs. 55, IQR 22, p = 0.018) and had been exposed to a lower TTR (26.6%, IQR 14.0% vs. 39.6%, IQR 24.3%, p = 0.039) and less frequently to an adequate third-month MPA AUC_0–12 > 30 mg × h/L (57.1% vs. 89.2%, p = 0.020). DR/DQ eplet mismatches (β = −0.348, p = 0.002) and third-month MPA AUC_0–12 (β = 0.285, p = 0.009) were independently associated with six-month predicted FEV1%. Conclusions: Among other variables, BLAD and initial lung graft function are associated with greater eplet discordance and lower immunosuppressive drug exposure, suggesting a potential role of underlying alloimmune responses in their pathogenesis. Full article

Background/Objectives: Immune-mediated necrotizing myopathy (IMNM) is a severe inflammatory myopathy marked by proximal muscle weakness, elevated creatine kinase (CK), and the presence of anti-HMGCR antibodies. Statin exposure is a recognized trigger for anti-HMGCR-positive IMNM, which may persist despite statin withdrawal. This pilot case series explores, for the first time, the use of bempedoic acid—a liver-specific lipid-lowering agent with minimal muscle toxicity—as an alternative to statins in these patients. Methods: We report 10 anti-HMGCR-antibody-positive IMNM patients (6 females, 4 males) previously on statins for primary prevention (8 on atorvastatin, 2 on simvastatin) without prior cardiovascular events. Statins were discontinued at myositis onset. All patients received prednisone and immunosuppressants (methotrexate in 7, mycophenolate in 3), plus bempedoic acid. Anti-HMGCR antibodies were measured using a chemiluminescence method. Results: Their mean anti-HMGCR antibody levels decreased significantly from 390.93 ± 275.22 to 220.89 ± 113.37 CU/L (p = 0.027) after 6 months of treatment. Their CK levels dropped from 1278.9 ± 769.39 to 315.1 ± 157.72 IU/L (p = 0.001), and aldolase dropped from 11.63 ± 2.18 to 6.61 ± 1.22 U/L (p = 0.0001). The mean LDL-C value was 96.1 ± 8.16 mg/dL. No disease recurrence was observed. Autoimmune panels were negative for other myositis-associated and/or -specific antibodies. Conclusions: Bempedoic acid appears to be a safe, effective, and cost-efficient lipid-lowering alternative in statin-intolerant IMNM patients. Larger studies are warranted to confirm its efficacy across different subgroups and to optimize dyslipidemia management in this setting. Full article

Immunosuppressants are essential for preventing allograft rejection; however, they require therapeutic drug monitoring to maintain efficacy and to prevent severe complications such as opportunistic infections. Calcineurin inhibitors (CIs) are primarily distributed in red blood cells, whereas mycophenolic acid (MPA) and its metabolites are found in plasma. These differences necessitate separate analyses for each drug, increasing laboratory workload, analytical complexity, and patient burden. We developed a liquid chromatography–tandem mass spectrometry method for simultaneous quantification of CIs such as tacrolimus (Tac), everolimus (Eve), sirolimus (Sir), cyclosporine A (CycA) and MPA in 2.8-µL whole-blood samples, with a hematocrit-based correction to estimate plasma-equivalent MPA concentrations. Performance of this method was assessed by comparison with conventional immunoassay results using linear regression and Bland–Altman analyses, demonstrating excellent agreement, with strong linearity (R² > 0.995) at <2 to 35 ng/mL for three CIs, 26.0 to 1866 ng/mL for CycA, and 0.1 to 50 μg/mL for MPA. Furthermore, MPA and tacrolimus concentrations closely aligned with routine clinical results (R² > 0.900), indicating high accuracy and reproducibility. This new approach may be particularly beneficial for hospitalized patients with limited venous access, pediatric populations, and in remote care settings where frequent blood sampling is challenging because of simultaneous quantification and fewer sample volume requirements. Full article

The standard immunosuppressive treatments in heart transplantation are calcineurin inhibitors, corticosteroids, and antimetabolite agents or inhibitors of the mammalian target of rapamycin. Pharmacogenetic studies show the impact on clinical course of genetic variability in genes that encode transporters, metabolizers, or molecular targets of immunosuppressants. The aim of this systematic review is to elucidate the role that pharmacogenetics of immunosuppressant drugs plays in clinical outcomes upon heart transplantation. PubMed, EMBASE, the Cochrane Central Register, and the Database of Abstracts of Reviews of Effects were searched without restrictions. The 64 studies analyzed followed these criteria: (1) were based on clinical data on heart transplantation patients; (2) analyzed the associations between polymorphisms and clinical response; (3) analyzed the impact of polymorphisms on immunosuppressant safety. CYP3A4/5 variants were associated with higher doses of tacrolimus, whereas POR*28 variants with lower doses—ABCB1, ABCC2, SLCO1B1, and SLC13A1—contribute to interindividual variability in drug absorption, distribution, and toxicity. An ABCC2 polymorphism (rs717620) was related to higher risk of graft rejection in pediatrics. Variations in HLA-G, TNF-α and TGF-β genes influence transplant rejection risk and immune response. Implementing pharmacogenetic screening of polymorphisms could enhance therapeutic outcomes by improving drug efficacy, reducing toxicity, and ultimately increasing heart graft survival rates. Strong evidence supports genotyping for CYP3A5 and TPMT, but further research is required for transporter genes and cytokine polymorphisms. Full article

Background/Objectives: Systemic sclerosis (SSc) is a progressive autoimmune disease characterized by widespread fibrosis, including skin thickening. Mycophenolate mofetil (MMF) is commonly used in SSc-associated interstitial lung disease, but its efficacy in improving skin fibrosis has not been systematically evaluated. This study aimed to assess the therapeutic effect of MMF on cutaneous sclerosis in SSc, as measured by the modified Rodnan skin score (mRSS). Methods: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. PubMed, Embase, and Web of Science were searched from January 2000 to March 2025. Studies reporting mRSS outcomes in SSc patients treated with MMF were included, provided that the effect of MMF could be separately evaluated when used alongside other therapies. Risk of bias was assessed using the Cochrane RoB 2.0 tool for randomized controlled trials and the ROBINS-I tool for non-randomized studies. A random-effects model was used to estimate the pooled mean change in mRSS. Heterogeneity and publication bias were evaluated. Results: Eight studies involving 569 patients were included. The pooled mean reduction in mRSS following MMF treatment was −5.82 (95% CI: −7.46 to −4.19), exceeding the minimal clinically important difference. Heterogeneity across studies was substantial (I² = 82.6%). A post hoc exploratory subgroup analysis suggested greater improvement in early disease (<2 years), though this finding requires confirmation in prospective studies. MMF was generally well tolerated, with low discontinuation rates due to adverse events. Conclusions: MMF is associated with a statistically and clinically significant improvement in skin fibrosis in patients with SSc. These findings support its use as a frontline therapy for progressive cutaneous involvement, although further prospective studies are needed to identify optimal candidates for treatment. Full article

Background/Objectives: Potassium-competitive acid blockers (P-CABs) offer rapid gastric acid inhibition and lower toxicity compared to proton pump inhibitors (PPIs). This study investigates the drug–drug interaction between P-CABs and immunosuppressants tacrolimus and mycophenolate in kidney transplant recipients (KTRs). Methods: Sixty-two KTRs were randomized to receive either 50 mg of tegoprazan or 20 mg of pantoprazole. Patients were monitored using a smart clinical trial platform incorporating remote monitoring and safety management systems, which tracked drug adherence and vital signs. General and gastrointestinal (GI) symptoms were surveyed via a self-developed app on patients’ phones. Trough levels of tacrolimus and mycophenolate were measured every 4 weeks over 12 weeks. Results: Medication adherence was 100% in both groups. A total of 13,726 biometric data points and 5031 questionnaire responses were collected, with 5704 feedback messages and 56 video visits conducted. At 12 weeks, the mean trough levels of tacrolimus and mycophenolate were similar between the tegoprazan and pantoprazole groups (5.5 ± 1.6 vs. 5.8 ± 2.0 ng/mL, p = 0.50 and 2.7 ± 1.4 vs. 2.6 ± 1.4 µg/mL, p = 0.57, respectively). The intragroup difference in trough levels from baseline to week 12 was not significant in either group. GI symptoms scores, vital signs, and allograft function remained stable and comparable between groups. Conclusions: Tegoprazan does not alter the blood trough levels of tacrolimus and mycophenolate during the 12-week follow-up in KTRs and has a similar impact on GI symptoms as pantoprazole. This study confirms the feasibility and safety of using a smart clinical trial system with remote monitoring for randomized trials. Full article

Background/Objectives: Mycophenolate mofetil (MMF) has emerged as a valuable immunosuppressive agent used in the management of oral mucocutaneous diseases, particularly in autoimmune and inflammatory conditions, such as pemphigus vulgaris (PV), oral lichen planus (OLP), mucous membrane pemphigoid (MMP), systemic lupus erythematosus (SLE), erythema multiforme (EM) and recurrent aphthous stomatitis (RAS). This review consolidates the current evidence regarding MMF’s efficacy, safety and clinical applications across these conditions. Methods: A comprehensive review of literature was performed, focusing on the mechanism of action, dosing strategies, therapeutic outcomes and adverse effects associated with MMF therapy in oral mucocutaneous diseases. The potential of therapeutic drug monitoring (TDM) in optimizing MMF therapy and minimizing adverse effects was also explored. Results: The review demonstrates that MMF is effective in inducing disease remission in up to 80% of patients with PV, with notable steroid-sparing effects. In OLP, MMF provided significant clinical improvement, especially in patients with severe and refractory forms of the disease. For MMP, MMF showed an 89% response rate, particularly when combined with corticosteroids, though gastrointestinal side effects were noted in some patients. In SLE, MMF was effective in managing both renal and non-renal manifestations, with favorable remission rates observed in patients receiving MMF therapy. For EM, MMF’s effectiveness was limited, with only a small number of patients responding to therapy. In RAS, there is limited evidence of MMF’s efficacy, with only partial improvement in severe cases reported. MMF is a promising immunomodulatory therapy for oral mucocutaneous diseases, particularly in reducing corticosteroid dependence and improving patient outcomes. However, the variability in the study designs, dosages and patient populations complicates the generalization of these findings. Conclusions: There is a pressing need for randomized controlled trials to validate MMF’s efficacy and long-term safety across all disease categories. The integration of therapeutic drug monitoring (TDM) shows potential for improving disease control and minimizing adverse effects, making it a key consideration for future research. Full article