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Authors = Nebojsa Simic

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11 pages, 281 KB  
Article
Lifestyle and Health Characteristics of the Adult Population of Serbia with Type 2 Diabetes Mellitus
by Elijah Kiprono Toroitich, Olgica Mihaljevic, Snezana Radovanovic, Ivana Simic Vukomanovic, Jovana Radovanovic Selakovic, Viktor Selakovic, Mateja Zdravkovic, Nebojsa Zdravkovic, Vladislava Stojic, Svetlana Radevic, Katarina Janicijevic, Milos Stepovic, Melanija Tepavcevic, Simonida Delic and Dejan Jeremic
Medicina 2026, 62(4), 740; https://doi.org/10.3390/medicina62040740 - 13 Apr 2026
Cited by 1 | Viewed by 1152
Abstract
Background and Objectives: Diabetes is one of the most common chronic non-communicable diseases and represents a major public health problem. At the global level, the epidemic character of diabetes mellitus can be attributed to an extended life expectancy but also to lifestyle. [...] Read more.
Background and Objectives: Diabetes is one of the most common chronic non-communicable diseases and represents a major public health problem. At the global level, the epidemic character of diabetes mellitus can be attributed to an extended life expectancy but also to lifestyle. The aim of this study was to examine the sociodemographic, health, and lifestyle characteristics of adults with type 2 diabetes mellitus in Serbia. Materials and Methods: The research is part of the Serbian Population Health Survey conducted in the period from October to December 2019 by the Republic Statistical Office, in cooperation with the Institute of Public Health of Serbia “Dr Milan Jovanović Batut” and the Ministry of Health of the Republic of Serbia. The research instrument was standardized questionnaires constructed in accordance with the European Health Interview Survey (EHIS—European Health Interview Survey, wave 3) questionnaire, which were adapted to the specifics of our area. The research was conducted as a cross-sectional study on a representative sample of the adult population of Serbia. Results: Among 1138 adults with type 2 diabetes in Serbia (52.8% female; mean age 66.0 ± 11.9 years), overweight and obesity were highly prevalent (40.1% and 34.4%, respectively), with Obesity I predominating. Significant gender differences were observed: female more often reported obesity, multimorbidity, and depressive symptoms, whereas men were more physically active and more frequently overweight. Most participants were physically inactive, consumed breakfast and bread daily, and had low engagement in cycling and sports. Alcohol consumption was significantly higher in men, while dietary habits differed by gender for bread intake. These findings highlight substantial gender- and lifestyle-related disparities among adults with type 2 diabetes in Serbia. Conclusions: Targeted interventions promoting healthy lifestyle, physical activity, psychosocial support, and chronic disease management are urgently needed to address gender- and lifestyle-related disparities in adults with type 2 diabetes in Serbia. Full article
(This article belongs to the Section Epidemiology & Public Health)
39 pages, 4781 KB  
Article
Cardiovascular Disease Risk Prediction Utilizing Two-Tier Classification Framework Optimized with Adapted Variable Neighborhood Search Algorithm
by Saramma John Villoth, Petar Dabic, Tamara Zivkovic, Miodrag Zivkovic, Svetlana Andjelic, Milos Mravik, Vladimir Simic, Mahmoud Abdel-Salam and Nebojsa Bacanin
Algorithms 2026, 19(2), 130; https://doi.org/10.3390/a19020130 - 5 Feb 2026
Cited by 7 | Viewed by 1437
Abstract
Accurately assessing a patient’s likelihood of developing cardiovascular conditions is essential for proper case classification and for ensuring timely, targeted medical intervention. To address this need, the present study employs a carefully optimized machine learning framework to predict such risks within cardiology settings. [...] Read more.
Accurately assessing a patient’s likelihood of developing cardiovascular conditions is essential for proper case classification and for ensuring timely, targeted medical intervention. To address this need, the present study employs a carefully optimized machine learning framework to predict such risks within cardiology settings. A hybrid architecture is proposed that combines convolutional neural networks (CNNs) with cutting-edge gradient boosting classifiers, namely CatBoost and LightGBM, whose performance is further enhanced by metaheuristic optimization. The system adopts a two-layer design capable of capturing complex data structures while supporting accurate classification of cardiac patients and their risk of developing cardiovascular disease. Extensive evaluation on real-world data confirms the framework’s effectiveness for binary classification, with the best models reaching an accuracy of slightly over 92%. To complement predictive performance, explainable AI methods were applied to clarify model decisions, yielding practical insights that can guide future data collection strategies and improve diagnostic precision. Full article
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11 pages, 589 KB  
Article
Long-Term Prognosis in Patients with ST-Elevation Myocardial Infarction Complicated by Heart Failure with Preserved Left Ventricular Ejection Fraction
by Lidija Savic, Damjan Simic, Ratko Lasica, Gordana Krljanac, Dragan Matic, Milika Asanin, Sanja Stankovic, Nebojsa Antonijevic and Igor Mrdovic
J. Cardiovasc. Dev. Dis. 2025, 12(7), 272; https://doi.org/10.3390/jcdd12070272 - 16 Jul 2025
Cited by 1 | Viewed by 2777
Abstract
Background/aim: We aimed to analyze eight-year mortality in patients with ST-elevation myocardial infarction (STEMI) complicated by the development of in-hospital heart failure with preserved ejection fraction (HFpEF). Method: We analyzed 3260 STEMI patients treated with primary PCI (pPCI). Reduced EF was defined as [...] Read more.
Background/aim: We aimed to analyze eight-year mortality in patients with ST-elevation myocardial infarction (STEMI) complicated by the development of in-hospital heart failure with preserved ejection fraction (HFpEF). Method: We analyzed 3260 STEMI patients treated with primary PCI (pPCI). Reduced EF was defined as value <50% and preserved EF as value ≥50%. Patients were divided in three groups: without HF, with HFpEF, and with HF with reduced EF (HFrEF). Patients with cardiogenic shock at admission were excluded. Results: In-hospital HF was registered in 759 (23.2%) patients. Among the patients with in-hospital HF, 80 (10.5%) patients had HFpEF. Patients with HFpEF had significantly higher 8-year mortality compared with patients without HF (11.2% vs. 3.5%, respectively, p < 0.001), but significantly lower mortality compared with patients with HFrEF: 11.2% vs. 25.1%, respectively, p < 0.001. In the Cox regression model, HFpEF and HFrEF were independent predictors for 8-year mortality-HFpEF: HR1.85 (95%CI 1.26–4.25); HFrEF: 4.89 (95%CI 3.19–6.42). Conclusion: Development of in-hospital HFpEF in STEMI patients was an independent predictor for long-term mortality. The negative prognostic impact of HFpEF was weaker when compared to the impact of in-hospital HFrEF. Full article
(This article belongs to the Section Cardiovascular Clinical Research)
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12 pages, 857 KB  
Article
The Role of Glutathione Transferase Omega-Class Variant Alleles in Individual Susceptibility to Ovarian Cancer
by Petar Simic, Vesna Coric, Igor Pljesa, Ana Savic-Radojevic, Nebojsa Zecevic, Jovana Kocic, Tatjana Simic, Vladimir Pazin and Marija Pljesa-Ercegovac
Int. J. Mol. Sci. 2024, 25(9), 4986; https://doi.org/10.3390/ijms25094986 - 3 May 2024
Cited by 9 | Viewed by 2406
Abstract
The tumor microenvironment is affected by reactive oxygen species and has been suggested to have an important role in ovarian cancer (OC) tumorigenesis. The role of glutathione transferases (GSTs) in the maintenance of redox balance is considered as an important contributing factor in [...] Read more.
The tumor microenvironment is affected by reactive oxygen species and has been suggested to have an important role in ovarian cancer (OC) tumorigenesis. The role of glutathione transferases (GSTs) in the maintenance of redox balance is considered as an important contributing factor in cancer, including OC. Furthermore, GSTs are mostly encoded by highly polymorphic genes, which further highlights their potential role in OC, known to originate from accumulated genetic changes. Since the potential relevance of genetic variations in omega-class GSTs (GSTO1 and GSTO2), with somewhat different activities such as thioltransferase and dehydroascorbate reductase activity, has not been clarified as yet in terms of susceptibility to OC, we aimed to investigate whether the presence of different GSTO1 and GSTO2 genetic variants, individually or combined, might represent determinants of risk for OC development. Genotyping was performed in 110 OC patients and 129 matched controls using a PCR-based assay for genotyping single nucleotide polymorphisms. The results of our study show that homozygous carriers of the GSTO2 variant G allele are at an increased risk of OC development in comparison to the carriers of the referent genotype (OR1 = 2.16, 95% CI: 0.88–5.26, p = 0.08; OR2 = 2.49, 95% CI: 0.93–6.61, p = 0.06). Furthermore, individuals with GST omega haplotype H2, meaning the concomitant presence of the GSTO1*A and GSTO2*G alleles, are more susceptible to OC development, while carriers of the H4 (*A*A) haplotype exhibited lower risk of OC when crude and adjusted haplotype analysis was performed (OR1 = 0.29; 95% CI: 0.12–0.70; p = 0.007 and OR2 = 0.27; 95% CI: 0.11–0.67; p = 0.0054). Overall, our results suggest that GSTO locus variants may confer OC risk. Full article
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19 pages, 972 KB  
Review
Pain Catastrophizing: How Far Have We Come
by Katarina Simic, Boris Savic and Nebojsa Nick Knezevic
Neurol. Int. 2024, 16(3), 483-501; https://doi.org/10.3390/neurolint16030036 - 26 Apr 2024
Cited by 50 | Viewed by 15212
Abstract
The perception of pain is strongly influenced by various social, emotional, and cognitive factors. A psychological variable which has consistently been shown to exert its influence on pain is a cognitive process referred to as pain catastrophizing. Numerous studies have found it to [...] Read more.
The perception of pain is strongly influenced by various social, emotional, and cognitive factors. A psychological variable which has consistently been shown to exert its influence on pain is a cognitive process referred to as pain catastrophizing. Numerous studies have found it to be a strong predictor of pain intensity and disability across different clinical populations. It signifies a maladaptive response to pain marked by an exaggerated negative assessment, magnification of symptoms related to pain, and, in general, a tendency to experience marked pain-related worry, as well as experiencing feelings of helplessness when it comes to dealing with pain. Pain catastrophizing has been correlated to many adverse pain-related outcomes, including poor treatment response, unsatisfactory quality of life, and high disability related to both acute and chronic pain. Furthermore, there has been consistent evidence in support of a correlation between pain catastrophizing and mental health disorders, such as anxiety and depression. In this review, we aim to provide a comprehensive overview of the current state of knowledge regarding pain catastrophizing, with special emphasis on its clinical significance, and emerging treatment modalities which target it. Full article
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28 pages, 4991 KB  
Article
Marine Vessel Classification and Multivariate Trajectories Forecasting Using Metaheuristics-Optimized eXtreme Gradient Boosting and Recurrent Neural Networks
by Aleksandar Petrovic, Robertas Damaševičius, Luka Jovanovic, Ana Toskovic, Vladimir Simic, Nebojsa Bacanin, Miodrag Zivkovic and Petar Spalević
Appl. Sci. 2023, 13(16), 9181; https://doi.org/10.3390/app13169181 - 11 Aug 2023
Cited by 40 | Viewed by 3747
Abstract
Maritime vessels provide a wealth of data concerning location, trajectories, and speed. However, while these data are meticulously monitored and logged to maintain course, they can also provide a wealth of meta information. This work explored the potential of data-driven techniques and applied [...] Read more.
Maritime vessels provide a wealth of data concerning location, trajectories, and speed. However, while these data are meticulously monitored and logged to maintain course, they can also provide a wealth of meta information. This work explored the potential of data-driven techniques and applied artificial intelligence (AI) to tackle two challenges. First, vessel classification was explored through the use of extreme gradient boosting (XGboost). Second, vessel trajectory time series forecasting was tackled through the use of long-short-term memory (LSTM) networks. Finally, due to the strong dependence of AI model performance on proper hyperparameter selection, a boosted version of the well-known particle swarm optimization (PSO) algorithm was introduced specifically for tuning the hyperparameters of the models used in this study. The introduced methodology was applied to real-world automatic identification system (AIS) data for both marine vessel classification and trajectory forecasting. The performance of the introduced Boosted PSO (BPSO) was compared to contemporary optimizers and showed promising outcomes. The XGBoost model tuned using boosted PSO attained an overall accuracy of 99.72% for the vessel classification problem, while the LSTM model attained a mean square error (MSE) of 0.000098 for the marine trajectory prediction challenge. A rigid statistical analysis of the classification model was performed to validate outcomes, and explainable AI principles were applied to the determined best-performing models, to gain a better understanding of the feature impacts on model decisions. Full article
(This article belongs to the Special Issue Intelligent Systems Applied to Maritime Environment Monitoring)
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13 pages, 500 KB  
Article
The Polymorphisms in GSTO Genes (GSTO1 rs4925, GSTO2 rs156697, and GSTO2 rs2297235) Affect the Risk for Testicular Germ Cell Tumor Development: A Pilot Study
by Milos Petrovic, Tatjana Simic, Tatjana Djukic, Tanja Radic, Ana Savic-Radojevic, Milica Zekovic, Otas Durutovic, Aleksandar Janicic, Bogomir Milojevic, Boris Kajmakovic, Marko Zivkovic, Nebojsa Bojanic, Uros Bumbasirevic and Vesna Coric
Life 2023, 13(6), 1269; https://doi.org/10.3390/life13061269 - 27 May 2023
Cited by 6 | Viewed by 3231
Abstract
Members of the omega class of glutathione transferases (GSTs), GSTO1, and GSTO2, catalyze a range of reduction reactions as a part of the antioxidant defense system. Polymorphisms of genes encoding antioxidant proteins and the resultant altered redox profile have already been associated with [...] Read more.
Members of the omega class of glutathione transferases (GSTs), GSTO1, and GSTO2, catalyze a range of reduction reactions as a part of the antioxidant defense system. Polymorphisms of genes encoding antioxidant proteins and the resultant altered redox profile have already been associated with the increased risk for testicular germ cell cancer (GCT) development. The aim of this pilot study was to assess the individual, combined, haplotype, and cumulative effect of GSTO1rs4925, GSTO2rs156697, and GSTO2rs2297235 polymorphisms with the risk for testicular GCT development, in 88 patients and 96 matched controls, through logistic regression models. We found that carriers of the GSTO1*C/A*C/C genotype exhibited an increased risk for testicular GCT development. Significant association with increased risk of testicular GCT was observed in carriers of GSTO2rs2297235*A/G*G/G genotype, and in carriers of combined GSTO2rs156697*A/G*G/G and GSTO2rs2297235*A/G*G/G genotypes. Haplotype H7 (GSTO1rs4925*C/GSTO2rs2297235*G/GSTO2rs156697*G) exhibited higher risk of testicular GCT, however, without significant association (p > 0.05). Finally, 51% of testicular GCT patients were the carriers of all three risk-associated genotypes, with 2.5-fold increased cumulative risk. In conclusion, the results of this pilot study suggest that GSTO polymorphisms might affect the protective antioxidant activity of GSTO isoenzymes, therefore predisposing susceptible individuals toward higher risk for testicular GCT development. Full article
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13 pages, 675 KB  
Article
Interplay between Comprehensive Inflammation Indices and Redox Biomarkers in Testicular Germ-Cell Tumors
by Uros Bumbasirevic, Nebojsa Bojanic, Tatjana Simic, Bogomir Milojevic, Marko Zivkovic, Tijana Kosanovic, Boris Kajmakovic, Aleksandar Janicic, Otas Durutovic, Milan Radovanovic, Veljko Santric, Milica Zekovic and Vesna Coric
J. Pers. Med. 2022, 12(5), 833; https://doi.org/10.3390/jpm12050833 - 20 May 2022
Cited by 15 | Viewed by 4685
Abstract
Sustained and dysregulated inflammation, concurrent tumor-induced immune suppression, and oxidative stress are profoundly involved in cancer initiation, presentation, and perpetuation. Within this prospective study, we simultaneously analyzed the preoperative indices of systemic inflammatory response and the representative byproducts of oxidative DNA, protein, and [...] Read more.
Sustained and dysregulated inflammation, concurrent tumor-induced immune suppression, and oxidative stress are profoundly involved in cancer initiation, presentation, and perpetuation. Within this prospective study, we simultaneously analyzed the preoperative indices of systemic inflammatory response and the representative byproducts of oxidative DNA, protein, and lipid damage with the aim of evaluating their clinical relevance among patients diagnosed with testicular germ-cell tumors (GCT). In the analytical cohort (n = 88, median age 34 years), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and C-reactive protein (CRP) were significantly altered in patients with a higher tumor stage (p < 0.05). Highly suggestive correlations were found between NLR, dNLR, and SII and modified nucleoside 8-OHdG. CRP and albumin-to-globulin ratio (AGR) significantly correlated with thiols group level and maximal tumor dimension (p < 0.05). Based on receiver operating characteristic (ROC) curve analyses, all the evaluated pre-orchiectomy inflammation markers demonstrated strong performance in predicting metastatic disease; optimal cut-off points were determined for each indicator. Although further large-scale studies are warranted, inflammatory and redox indices may both complement the established tumor markers and standard clinicopathological prognostic variables and contribute to enhanced personalized risk-assessment among testicular GCT patients. Full article
(This article belongs to the Special Issue Precision Medicine and Molecular Diagnosis for Urogenital Cancer)
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12 pages, 642 KB  
Article
The Polymorphisms of Genes Encoding Catalytic Antioxidant Proteins Modulate the Susceptibility and Progression of Testicular Germ Cell Tumor
by Uros Bumbasirevic, Nebojsa Bojanic, Marija Pljesa-Ercegovac, Marko Zivkovic, Tatjana Djukic, Milica Zekovic, Bogomir Milojevic, Boris Kajmakovic, Aleksandar Janicic, Tatjana Simic and Vesna Coric
Cancers 2022, 14(4), 1068; https://doi.org/10.3390/cancers14041068 - 20 Feb 2022
Cited by 10 | Viewed by 4543
Abstract
The simultaneous analysis of redox biomarkers and polymorphisms encoding for regulatory and catalytic antioxidant proteins was performed in order to evaluate their potential role in the development of testicular germ cell tumor (GCT), as well as the progression of the disease. NRF2 (rs6721961), [...] Read more.
The simultaneous analysis of redox biomarkers and polymorphisms encoding for regulatory and catalytic antioxidant proteins was performed in order to evaluate their potential role in the development of testicular germ cell tumor (GCT), as well as the progression of the disease. NRF2 (rs6721961), GSTM3 (rs1332018), SOD2 (rs4880) and GPX3 (rs8177412) polymorphisms were assessed in 88 patients with testicular GCT (52 with seminoma) and 88 age-matched controls. The plasma levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), thiol groups and the plasma activity of glutathione peroxidase were measured. A significant association between variant GPX3*TC+CC genotype and risk of overall testicular GCT, as well as seminoma development, was found. Moreover, carriers of variant SOD2*TT genotype were at almost 3-fold increased risk of seminoma development. Interestingly, combined SOD2*TT/GPX3*TC+CC genotype conferred a 7-fold higher risk for testicular GCT development. Finally, variant GSTM3*AC+CC genotype was associated with a higher risk for the development of advanced diseased. The presence of assessed genetic variants was not associated with significantly higher levels of redox biomarkers in both testicular GCT patients, as well as in those diagnosed with seminoma. In conclusion, the polymorphic expression of certain antioxidant enzymes might affect susceptibility toward testicular GCT development, as well as the progression of the disease. Full article
(This article belongs to the Special Issue Testicular Cancer)
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15 pages, 6410 KB  
Article
Hepatoprotective Effect of Mixture of Dipropyl Polysulfides in Concanavalin A-Induced Hepatitis
by Dragana Arsenijevic, Bojana Stojanovic, Jelena Milovanovic, Aleksandar Arsenijevic, Milos Simic, Marija Pergal, Igor Kodranov, Olga Cvetkovic, Danilo Vojvodic, Elizabeta Ristanovic, Dragan Manojlovic, Marija Milovanovic and Nebojsa Arsenijevic
Nutrients 2021, 13(3), 1022; https://doi.org/10.3390/nu13031022 - 22 Mar 2021
Cited by 9 | Viewed by 4388
Abstract
The main biologically active components of plants belonging to the genus Allium, responsible for their biological activities, including anti-inflammatory, antioxidant and immunomodulatory, are organosulfur compounds. The aim of this study was to synthetize the mixture of dipropyl polysulfides (DPPS) and to test their [...] Read more.
The main biologically active components of plants belonging to the genus Allium, responsible for their biological activities, including anti-inflammatory, antioxidant and immunomodulatory, are organosulfur compounds. The aim of this study was to synthetize the mixture of dipropyl polysulfides (DPPS) and to test their biological activity in acute hepatitis. C57BL/6 mice were administered orally with DPPS 6 h before intravenous injection of Concanavalin A (ConA). Liver inflammation, necrosis and hepatocytes apoptosis were determined by histological analyses. Cytokines in liver tissue were determined by ELISA, expression of adhesive molecules and enzymes by RT PCR, while liver mononuclear cells were analyzed by flow cytometry. DPPS pretreatment significantly attenuated liver inflammation and injury, as evidenced by biochemical and histopathological observations. In DPPS-pretreated mice, messenger RNA levels of adhesion molecules and NADPH oxidase complex were significantly reduced, while the expression of SOD enzymes was enhanced. DPPS pretreatment decreased protein level of inflammatory cytokines and increased percentage of T regulatory cells in the livers of ConA mice. DPPS showed hepatoprotective effects in ConA-induced hepatitis, characterized by attenuation of inflammation and affection of Th17/Treg balance in favor of T regulatory cells and implicating potential therapeutic usage of DPPS mixture in inflammatory liver diseases. Full article
(This article belongs to the Section Phytochemicals and Human Health)
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14 pages, 12641 KB  
Article
Identification and Characterization of a Streptomyces albus Strain and Its Secondary Metabolite Organophosphate against Charcoal Rot of Sorghum
by Subramaniam Gopalakrishnan, Rajan Sharma, Vadlamudi Srinivas, Nimmala Naresh, Suraj P. Mishra, Sravani Ankati, Sambangi Pratyusha, Mahalingam Govindaraj, Susana V. Gonzalez, Sondre Nervik and Nebojsa Simic
Plants 2020, 9(12), 1727; https://doi.org/10.3390/plants9121727 - 7 Dec 2020
Cited by 24 | Viewed by 5458
Abstract
Streptomycesalbus strain CAI-21 has been previously reported to have plant growth-promotion abilities in chickpea, pigeonpea, rice, and sorghum. The strain CAI-21 and its secondary metabolite were evaluated for their biocontrol potential against charcoal rot disease in sorghum caused by Macrophomina phaseolina. [...] Read more.
Streptomycesalbus strain CAI-21 has been previously reported to have plant growth-promotion abilities in chickpea, pigeonpea, rice, and sorghum. The strain CAI-21 and its secondary metabolite were evaluated for their biocontrol potential against charcoal rot disease in sorghum caused by Macrophomina phaseolina. Results exhibited that CAI-21 significantly inhibited the growth of the pathogen, M. phaseolina, in dual-culture (15 mm; zone of inhibition), metabolite production (74% inhibition), and blotter paper (90% inhibition) assays. When CAI-21 was tested for its biocontrol potential under greenhouse and field conditions following inoculation of M. phaseolina by toothpick method, it significantly reduced the number of internodes infected (75% and 45% less, respectively) and length of infection (75% and 51% less, respectively) over the positive control (only M. phaseolina inoculated) plants. Under greenhouse conditions, scanning electron microscopic analysis showed that the phloem and xylem tissues of the CAI-21-treated shoot samples were intact compared to those of the diseased stem samples. The culture filtrate of the CAI-21 was purified by various chromatographic techniques, and the active compound was identified as “organophosphate” by NMR and MS. The efficacy of organophosphate was found to inhibit the growth of M. phaseolina in the poisoned food technique. This study indicates that S.albus CAI-21 and its active metabolite organophosphate have the potential to control charcoal rot in sorghum. Full article
(This article belongs to the Special Issue Biological Control of Plant Diseases)
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16 pages, 296 KB  
Article
Benzoylated Uronic Acid Building Blocks and Synthesis of N-Uronate Conjugates of Lamotrigine
by Aslan M. Esmurziev, Arne Reimers, Trygve Andreassen, Nebojsa Simic, Eirik Sundby and Bård Helge Hoff
Molecules 2012, 17(1), 820-835; https://doi.org/10.3390/molecules17010820 - 16 Jan 2012
Cited by 3 | Viewed by 9367
Abstract
A chemoenzymatic approach towards benzoylated uronic acid building blocks has been investigated starting with benzoylated hexapyranosides using regioselective C-6 enzymatic hydrolysis as the key step. Two of the building blocks were reacted with the antiepileptic drug lamotrigine. Glucuronidation of lamotrigine using methyl (2,3,4-tri- [...] Read more.
A chemoenzymatic approach towards benzoylated uronic acid building blocks has been investigated starting with benzoylated hexapyranosides using regioselective C-6 enzymatic hydrolysis as the key step. Two of the building blocks were reacted with the antiepileptic drug lamotrigine. Glucuronidation of lamotrigine using methyl (2,3,4-tri-O-benzoyl-α-D-glycopyranosyl bromide)uronate proceeded to give the N2-conjugate. However, lamotrigine-N2-glucuronide was most efficiently synthesised from methyl (2,3,4-tri-O-acetyl-α-D-glucopyranosyl bromide)uronate. Employing nitromethane as solvent with CdCO3 as a base lamotrigine-N2 glucuronide was prepared in a high yield (41%). Also methyl (2,3-di-O-benzoyl-4-deoxy-4-fluoro-α-D-glucosyl bromide)uronate underwent N-glucuronidation, but the product was unstable, eliminating hydrogen fluoride to give the corresponding enoate conjugate. Full article
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