Search Results (131)

Objectives: To evaluate ¹⁸F-labelled fluoroazomycinarabinoside ([¹⁸F]F-FAZA) PET in post-transplant patients and examine the association of its kinetic and uptake parameters with kidney allograft function measurements, including laboratory and histopathological assessments. Methods: In this prospective pilot study, renal transplant patients were evaluated with a dedicated positron emission tomography/magnetic resonance imaging (PET/MR) protocol between 2018 and 2023. Twenty patients with impaired kidney allograft function (cases) and ten sex- and time-post-transplant-matched control patients with stable transplant allograft function (controls) were included. All patients underwent [¹⁸F]F-FAZA PET/MR, including initial dynamic and delayed static imaging. Cases underwent an ultrasound-guided biopsy for histopathological assessments. Results: From the [¹⁸F]F-FAZA PET-derived parameters, dynamic total volume distribution (V_T) was significantly higher in control patients than in cases (2.11 ± 0.55 vs. 1.62 ± 0.45; p = 0.026). When correlating [¹⁸F]F-FAZA PET parameters with creatinine levels and estimated glomerular filtration rate, V_T was again the only variable that significantly correlated with both metrics. Regarding histopathological parameters, a significant positive correlation was found between k₁ and vascular fibrous intimal thickening, a significant negative correlation between k₃ and arteriolar hyalinosis, and k₃/k₄ (binding potential) was significantly correlated with the percentage of globally sclerotic glomeruli and arteriolar hyalinosis. Additionally, V_T was significantly correlated with interstitial inflammation. SUV_mean on the static PET was significantly correlated with the percentage of globally sclerotic glomeruli. Conclusions: Non-invasive assessment of renal microcirculation using dynamic [¹⁸F]F-FAZA PET is potentially feasible. The dynamic PET-derived parameters showed strong correlations with renal function. There were also correlations with various histopathological findings. Additionally, static [¹⁸F]F-FAZA PET-derived parameters showed complementary findings with hypoxia-related end-stage histopathological indicators. Full article

Background/Objectives: Monitoring antibiotic consumption is a central component of antimicrobial stewardship because it provides a standardized way to identify changing prescribing patterns, detect potentially excessive use, and support targeted interventions. The WHO ATC/DDD framework is widely used for hospital-based utilization studies and enables comparison across wards and time periods. Methods: This single-center observational study used antibiotic data obtained from the hospital pharmacy to compare predicted and observed consumption for 2024 and 2025. Antibiotic use was expressed as DDD per 100 bed-days and analyzed for penicillins, cephalosporins, fluoroquinolones, tetracyclines, nitroimidazole derivatives, lincosamides, and aminoglycosides. The aim of this study was to quantify antibiotic consumption using ATC/DDD methodology, evaluate how closely modeled predictions matched observed values in 2024 and 2025, and identify the antibiotic classes and wards most relevant for stewardship action. Results: Cephalosporins showed the closest agreement between forecasted and observed consumption, with absolute percentage errors of 2.16% in 2024 and 4.61% in 2025 and a two-year mean absolute percentage error of 3.39%. Consumption of fluoroquinolones exceeded predictions, particularly in gynecology, while use of nitroimidazole derivatives was lower than expected, especially in 2025. Use of tetracyclines was absent in both years, and aminoglycosides and lincosamides contributed only minimally to total consumption. Ward-level analysis showed that intensive care accounted for the highest cephalosporin exposure, whereas the largest deviations from forecast were observed in gynecology and high-risk pregnancy wards. Conclusions: Predictive modeling captured antibiotic use reasonably well for some antibiotic classes but showed lower accuracy for others. Forecast accuracy varied across antibiotic groups, indicating that the model performed differently depending on the observed consumption pattern. However, the underlying reasons for these differences cannot be determined from the present aggregated consumption analysis. Full article

Dermatophytosis caused by Trichophyton spp. represents a growing public health concern, exacerbated by the increasing prevalence of difficult-to-treat infections and the emergence of resistance to standard antifungal agents, such as terbinafine. In this study, we evaluated the in vitro antifungal activity of a thiosemicarbazide derivative, 1-[(1-methyl-4-nitroimidazol-2-yl)carbonyl]-4-(3-methylphenyl)thiosemicarbazide, against a panel of anthropophilic and zoophilic Trichophyton spp. dermatophytes. Susceptibility testing was performed via the broth microdilution method to determine the minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs). The compound demonstrated antifungal efficacy against all the strains tested, with MIC values ranging from 31.25 to 125 µg/mL. Crucially, low MFC/MIC ratios (≤4) confirmed a fungicidal effect, which was further corroborated by microscopic analysis revealing severe hyphal damage in treated dermatophytes. The derivative exhibited consistent activity against both T. rubrum and T. mentagrophytes, including clinical isolates. To our knowledge, this is one of the first detailed evaluations of a nitroimidazole–thiosemicarbazide hybrid against Trichophyton spp. that combines quantitative MIC/MFC testing with morphological assessment. The tested thiosemicarbazide derivative noticeably decreased the viability of VERO and A375 cells, but even at the highest tested concentration, after 72 h of incubation, the cellular viability remained at 65%. These findings suggest that the investigated compound is a promising candidate for the development of new fungicidal drugs or disinfectants for the effective prophylaxis or management of superficial mycoses in human and veterinary medicine. Full article

As part of efforts to identify genes associated with Trichomonas vaginalis resistance to 5-nitroimidazole drugs, thirty cryopreserved T. vaginalis isolates were revived and grown using Diamond’s TYM medium. Minimum lethal concentrations (MLCs) for metronidazole (MTZ), tinidazole (TDZ), and secnidazole (SEC) were determined using a drug susceptibility assay. Transcriptome profiling was performed for 15 MTZ-sensitive (MTZ-S, MLC < 50 µg/mL) and 15 MTZ-resistant (MTZ-R, MLC ≥ 50 µg/mL) isolates using next-generation RNA sequencing. Bioinformatics analyses identified differentially expressed genes (DEGs). Among the MTZ-R isolates, six exhibited low MLCs of 50 µg/mL, five had intermediate MLCs between 100 and 200 µg/mL, and four had high MLCs ≥ 400 µg/mL. Differential gene expression analysis identified 28, 140, and 73 significantly altered genes in low-, intermediate-, and high-level MTZ resistance groups, respectively, with predominantly upregulated expression patterns. The SEC-resistant (SEC-R) isolates exhibited 136 differentially expressed genes, whereas the TDZ-resistant (TDZ-R) isolates showed minimal transcriptional changes. Focused analyses of iron transport pathways revealed reduced expression of ZIP-family iron import genes, particularly TvZIP4 (TVAG_273550), the strongest predictor of resistance in elastic-net modeling (AUC = 0.795). Resistant isolates also demonstrated coordinated upregulation of iron–sulfur cluster assembly and hydrogenosomal protein-import pathways. Weighted gene co-expression network analysis (WGCNA) identified multiple resistance-associated transcriptional modules correlated with MTZ and SEC MLCs. A comparative transcriptomic–proteomic analysis revealed concordant upregulation of iron–sulfur cluster machinery but discordant regulation of hydrogenosomal cargo proteins, likely supporting a post-transcriptional restriction model. These findings provide a broader mechanistic framework for understanding 5-nitroimidazole resistance in T. vaginalis and identifying candidate biomarkers and pathways that may support future therapeutic and diagnostic development. Full article

Background/Objectives: While MRI is effective for glioma diagnosis, it has limitations in grading, treatment planning, and prognostication. Since hypoxia is associated with higher-grade gliomas and poorer outcomes, PET imaging with hypoxia-specific tracers has been shown to improve glioma assessment. This systematic review and meta-analysis aimed to evaluate the performance of hypoxia PET imaging in glioma diagnosis and prognostication. Methods: Systematic searches were conducted across PubMed, Web of Science, and Scopus through 31 January 2025. Only studies assessing the diagnostic or prognostic value of PET with ¹⁸F-labelled nitroimidazole (¹⁸F-FMISO, ¹⁸F-FAZA, ¹⁸F-FRP170, or ¹⁸F-FETNIM) or ⁶²Cu-labelled ATSM hypoxia tracers in patients with gliomas were included. Hierarchical models were used to evaluate pooled performance on differentiating glioblastoma from lower-grade gliomas. Results: Thirty-eight articles (n = 1156 patients) were eligible for inclusion, and eleven articles (n = 296 patients) were suitable for meta-analytical calculations. The extent of hypoxia on PET imaging was generally correlated with isocitrate dehydrogenase (IDH) mutation status and histological angiogenesis. Hypoxia PET was effective at differentiating glioblastoma from lower-grade gliomas and at predicting overall and progression-free survival. In a pooled analysis, ¹⁸F-FMISO PET displayed high sensitivity (98%) and specificity (94%) for differentiating glioblastoma from lower-grade gliomas. Conclusions: Hypoxia PET has the potential to predict tumour biology, and it may be a reliable modality in combination with MRI to provide complementary information for glioma diagnosis, grading, treatment planning, and prognostication. It may be particularly useful for ruling out glioblastoma in patients with otherwise equivocal imaging; however, this would need to be validated prospectively with standardized image acquisition and interpretation criteria. Full article

Chagas disease and trichomoniasis are two neglected parasitic infections (NPIs) in need for new therapies that address both the toxicity and limited bioavailability impacting on the effectiveness of benznidazole (BZ) and nifurtimox, the only drugs available for treating the infection caused by Trypanosoma cruzi, as well as the resistance that Trichomonas vaginalis has developed to 5-nitroimidazoles. Herein, we report the outcomes of the primary screening of a series of eighteen quinoxaline-1,4-di-N-oxides (QdNOs) carried out against both protozoan parasites. Computational approaches revealed that these derivatives have adequate oral bioavailability and do not pose toxicity risks associated with their chemical structures. Meanwhile, biological studies disclosed that compounds 4b and 4m exhibit considerable activity against T. cruzi at the highest concentration tested, showing 4m a trypanocidal profile (IC₅₀ = 23.66 µM) similar to that of BZ (IC₅₀ = 21.66 µM), and a selectivity index (SI) > 5.32. Regarding the activity on T. vaginalis, derivative 4n stands out with an IC₅₀ value of 9.85 µM, showing no cytotoxicity towards mammalian cells. However, their potency decreases when tested over resistant parasites. Alterations in either the hydrogenosomal membrane potential or the production of reactive oxygen species (ROS) were also explored. The findings suggest that the trichomonacidal activity of compound 4n is not mediated by a direct disruption of hydrogenosomal bioenergetics or a pro-oxidant effect. Altogether, these preliminary results support that the QdNO scaffold could be introduced as a proper template for developing novel trypanocidal and trichomonacidal agents. Full article

Chagas disease remains a major neglected parasitic illness in Latin America and other endemic regions, and benznidazole (BZN) is still the primary trypanosomacidal drug despite its incompletely understood mechanism of action. This work provides a detailed biophysical characterization of the conformational behavior and vibrational properties of benznidazole (BZN), a first-line trypanocidal drug still widely used for the treatment of Chagas disease. Using density functional theory combined with relaxed potential energy surface scans in vacuum and implicit water, two low-energy conformers (BZN1 and BZN2) were identified, separated by moderate rotational barriers and a small energy difference, indicating that both are intrinsically accessible at room temperature. For each conformer, infrared and Raman spectra were calculated and assigned via vibrational mode analysis, then compared with FT-IR and FT-Raman spectra recorded for pharmaceutical-grade polycrystalline BZN. The theoretical and experimental spectra show excellent agreement, with a Raman band in the 1350–1400 $\mathrm{c}{\mathrm{m}}^{-1}$ region emerging as a sensitive conformational marker: the experimental maximum at $1359\mathrm{c}{\mathrm{m}}^{-1}$ matches the most intense BZN1 mode, whereas the corresponding BZN2 band appears about $13\mathrm{c}{\mathrm{m}}^{-1}$ higher in frequency. This clear spectroscopic fingerprint demonstrates that the solid drug is overwhelmingly composed of the BZN1 conformer, despite the theoretical accessibility of BZN2. Overall, the study links the conformational landscape of benznidazole to its vibrational signatures and highlights Raman spectroscopy, supported by quantum chemical calculations, as a powerful tool for conformational and potential polymorphic control of this clinically important nitroimidazole. Full article

Background and Objectives: Despite surgical intervention for remission, recurrence is nearly inevitable in patients with Crohn’s disease (CD). While several maintenance therapies are available, the optimal strategy for preventing postoperative recurrence remains uncertain. Materials and Methods: This systematic review and network meta-analysis included placebo-controlled or head-to-head randomized controlled trials (RCTs) from MEDLINE, Embase, and Cochrane Central up to 4 July 2024. Studies assessed maintenance therapies for CD after curative resection. Data were extracted from intention-to-treat (ITT) and per-protocol (PP) analyses separately. The primary outcomes were endoscopic and clinical relapse. A Bayesian network meta-analysis provided risk ratios (RRs) and 95% confidence intervals (CIs). This study is registered with PROSPERO (CRD42024629013). Results: From 1492 screened records, 45 randomized controlled trials met the inclusion criteria. Compared with placebo, clinically significant prevention of clinical recurrence was achieved with adalimumab (RR = 0.17; GRADE High), nitroimidazoles (RR = 0.35; High), infliximab (RR = 0.59; Moderate), thiopurine analogs (RR = 0.41; Moderate), and high-dose mesalamine (RR = 0.74; High), while azathioprine-metronidazole combination therapy demonstrated superior efficacy to azathioprine monotherapy. For endoscopic recurrence mitigation, therapeutic efficacy was confirmed for adalimumab (RR = 0.24; Low), infliximab (RR = 0.32; Moderate), vedolizumab (RR = 0.36; Low), and thiopurine analogs (RR = 0.64; Moderate). Conclusions: This network meta-analysis establishes pharmacological hierarchies for preventing postoperative Crohn’s disease recurrence. Adalimumab is the most effective monotherapy for clinical recurrence prevention, while combination therapies of adalimumab/azathioprine plus nitroimidazole show superior efficacy. For endoscopic recurrence prevention, adalimumab also ranks as the most effective intervention. These findings guide therapy selection but require validation for newer agents through randomized trials. Full article

Trichomonas vaginalis is the causative agent of trichomoniasis, the most common non-viral sexually transmitted infection worldwide. In these cases, 5-Nitroimidazoles, particularly metronidazole (MTZ), remain the primary treatment option; however, resistance to MTZ has been increasingly reported. This study aimed to evaluate the in vitro activity of D-form synthetic antimicrobial peptides and investigate transcriptional differences associated with MTZ resistance and peptide treatment in T. vaginalis. D-form synthetic peptides (D-TN1, D-TN3, and D-TN6) developed in the R&D Laboratory of Acibadem University were tested against metronidazole-susceptible (T. vaginalis ATCC 30236) and metronidazole-resistant (T. vaginalis ATCC 50143) strains by minimum lethal concentration (MLC) assays. D-TN1 exhibited an MLC of 16 µg/mL in both strains, whereas D-TN3 and D-TN6 exhibited MLC values of 32 µg/mL and 16–32 µg/mL, respectively. Comparative transcriptomic analysis was conducted to investigate transcriptional differences. Differential gene expression analysis identified 3395 genes between the resistant and susceptible isolates and 3060 genes in the D-TN1-treated resistant isolate (FDR < 0.05, |log₂FC| ≥ 1). D-TN1 treatment in the resistant isolate was associated with downregulation of ribosomal and metabolic pathways. If confirmed with further in vivo studies, this new antimicrobial peptide may become a new therapeutic alternative in the treatment of trichomoniasis in the future. Full article

Clostridium tertium is an emerging opportunistic pathogen typically associated with immunocompromised hosts, yet it can also cause serious infections in non-neutropenic individuals. We present a case of postoperative peritonitis and bacteremia caused by C. tertium in a non-neutropenic 75-year-old woman following emergency obturator hernia repair. Diagnosis was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and successful treatment was achieved with piperacillin–tazobactam combined with levornidazole alongside surgical source control. A review of 128 cumulative cases (including ours) revealed two distinct patterns: bacteremia in severely neutropenic patients versus a broader spectrum of localized and bloodstream infections in non-neutropenic hosts, often linked to intestinal barrier disruption. Mortality was largely driven by underlying comorbidities and polymicrobial sepsis. These findings indicate that C. tertium infection should be considered in non-neutropenic patients with postoperative or gastrointestinal barrier-disruptive infections, especially when there is a poor response to initial empiric therapy. Consequently, in such clinical scenarios, empirical therapy should be guided by its unique resistance pattern, favoring carbapenems, vancomycin, or piperacillin–tazobactam, often combined with a nitroimidazole, alongside urgent source control. Full article

Giardiasis, caused by the protozoan parasite Giardia lamblia, remains a prevalent intestinal infection worldwide and a growing concern due to increasing resistance to nitroimidazole drugs. This study proposes an alternative therapeutic strategy by targeting fructose-1,6-bisphosphate aldolase (FBPA), a key glycolytic enzyme of the parasite, through structure-based virtual screening. A curated library of microbiome-derived metabolites was computationally evaluated and compared with clinically used antigiardial drugs. Several indole-based compounds exhibited favorable binding affinities and stable interactions within the catalytic pocket of FBPA. These findings suggest that microbiome metabolites could serve as promising scaffolds for the rational design of new antiparasitic agents. Overall, the study highlights the potential of integrating metabolic and computational approaches to identify next-generation therapeutics against giardiasis. Full article

Imidazole is, from a structural point of view, a heterocycle consisting of three C atoms and two N atoms, belonging to the class of diazoles, having two N atoms at the first and third positions in the aromatic ring. Being a polar and ionizable aromatic compound, it has the role of improving the pharmacological properties of lead molecules, thus being used to optimize their solubility and bioavailability. Imidazole is a constituent of many important biological compounds, like histidine, histamine, and purine compounds, the most widespread heterocyclic compound in nature. In current practice, substituted imidazole derivatives play a major role in antifungal, antibacterial, anti-inflammatory, CNS active compounds, antiprotozoal, as well as anticancer therapy. Thus, imidazole derivatives have demonstrated significant anticancer activities by inhibiting the key metabolic pathways essential for tumor cell growth and survival. Nitroimidazoles, for instance, have been employed as hypoxia-directed therapeutic agents, targeting oxygen-deprived tumor tissues, while mercaptopurine derivatives are well-established in oncological treatments. Structural modifications of the imidazole nucleus have led to the novel compounds exhibiting increased selective cytotoxicity against cancer cells, while sparing normal healthy cells. In accordance with what has been stated, this review highlights recent research on the medicinal and pharmaceutical interest of novel imidazole derivatives, emphasizing their potential in the development of new drugs. Full article

Background: Infections caused by the protozoan Trichomonas vaginalis affect millions of people worldwide and are responsible for one of the most common sexually transmitted diseases. Despite the efficacy of 5-nitroimidazoles like metronidazole, concerns regarding widespread resistance and the absence of viable alternatives for specific patient populations necessitate the development of structurally diverse pharmacological agents. In this study, we investigated the antiparasitic activity of 1,3-thiazolidin-4-one derivatives against T. vaginalis. Methods: Thiazolidines were synthesized via multicomponent reaction (MCR) using one-pot methodology and tested in vitro against the parasite and mammalian cell lines. Results: Seventy percent of the compounds showed more than 80% antiparasitic activity at 100 μM, with compounds 4a, 4b, and 4f exhibiting IC₅₀ ≤ 20 µM. None of the molecules exhibited cytotoxic against Vero CCL-81 and HeLa cells. Evaluation of the structure–activity relationship (SAR) indicates that the substituent at the nitrogen position of the heterocycle may be involved in the antiparasitic effect of these compounds. In silico studies also revealed that the three compounds possess adequate oral bioavailability and do not present mutagenic, tumorigenic or irritating risks. Finally, molecular docking predicted strong interactions of compounds 4a, 4b, and 4f with T. vaginalis enzymes lactate dehydrogenase and purine nucleoside phosphorylase; compound 4f also interacted with methionine Ƴ-lyase. Conclusions: These preliminary results suggest that 1,3-thiazolidin-4-ones are promising scaffolds for developing new trichomonacidal agents. Full article

Background/Objectives: Giardia lamblia is an intestinal protozoan responsible for giardiasis, a globally prevalent parasitic disease. Current therapeutic options, including nitroimidazoles and benzimidazoles, have increasing treatment failures due to resistance, adverse reactions, and patient non-compliance. Drug repositioning offers a cost-effective strategy for identifying new antigiardial agents. This study aimed to evaluate the in vitro antiparasitic effects and possible mechanisms of action of the tricyclic antidepressant imipramine against G. lamblia trophozoites. Methods: Trophozoites were exposed to increasing concentrations of imipramine (25–125 µM). Growth inhibition and adhesion capacity were quantified using cell counts. Apoptosis- or necrosis-like death was evaluated through Annexin V/PI staining. The expression and distribution of α-tubulin and lipid rafts were analyzed by immunofluorescence microscopy. Finally, the effect of the drug on encystment efficiency was assessed in vitro. Results: Imipramine inhibited G. lamblia trophozoite growth in a concentration-dependent manner, with an IC₅₀ of 42.31 µM at 48 h. The drug significantly reduced adhesion capacity (>90% at 125 µM) and induced apoptosis-like cell death, as evidenced by Annexin V positivity. Immunofluorescence revealed disruption of α-tubulin distribution and lipid raft organization, accompanied by morphological rounding. Moreover, encystment efficiency decreased in a concentration-dependent mode, suggesting interference in the differentiation process. Conclusions: This investigation describes, for the first time, the antigiardial potential of imipramine, which alters cytoskeletal organization, membrane microdomains, and differentiation pathways, ultimately leading to apoptosis-like cell death. These findings position this compound as a promising lead structure and support further exploration of tricyclic antidepressants as scaffolds for the development and optimization of new antiparasitic agents, as well as future studies on their molecular targets and in vivo efficacy. Full article

Trichomoniasis is the most common non-viral sexually transmitted infection in humans, with over 200 million people affected each year. This disease is associated with pre-term birth, low birth weight, and premature membrane rupture. Its causal pathogen, Trichomonas vaginalis (TV), is a prevalent sexually transmitted protozoan parasite that infects the urogenital tract through cytoadherence. TV infection alters TV gene expression and induces host immune responses, while TV-secreted exosomes carry RNA and protein cargoes that mediate extracellular signaling. This review summarizes recent discoveries of molecules that interact with host receptors involved in cytoadherence. We also discuss human innate and adaptive immune responses to TV infection via a variety of inflammatory mediators. Recent research on concurrent or endosymbiont relationships of TV with other urogenital microbes and cancers, is also examined. These studies not only highlight the necessity of understanding host–microbe interactions in TV pathogenesis but also provide a crucial insight into potential therapeutic targets of nitroimidazole-resistant TV strains. Full article