Atypical pyoderma gangrenosum in a patient with osteomyelofibrosis

Background. Atypical forms of pyoderma gangrenosum generally appear on the upper extremities; most frequently they are associated with myeloproliferative disorders, including osteomyelofibrosis. A response to systemic steroids is more pronounced than in classical form. Sometimes it may be the first sign of an underlying malignancy. Case report. We reported a patient with atypical pyoderma gangrenosum developed during the course of a myeloid malignancy - osteomyelofibrosis. The lesions occurred after a minor trauma. Painful blistering plaques, with an elevated, bluish-gray border were located on the dorsal aspect of hands. No skin malignancy was found. The lesions resolved rapidly to systemic steroids. Conclusion. Considering the unusual clinical presentation which makes the diagnosis difficult, as well as the fact that atypical forms of pyoderma gangrenosum can be the first sign of malignancies, especially myeloproliferative ones, recognizing this entity enables timely guiding future investigations toward their prompt detection

Association of functional variants of phase i and ii genes with chronic obstructive pulmonary disease in a Serbian population

Background: Chronic obstructive pulmonary disease (COPD) is a complex disorder characterized by increased oxidative stress. Functional genetic variants of phase I and II genes are implicated in oxidants antioxidants imbalance and may be involved in COPD development. In this study, we aimed to investigate the role of cytochrome P450 (CYP), glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) functional variants in the pathogenesis of COPD in a Serbian population. Methods: The genotypes of 122 COPD patients and 100 controls with normal lung function were determined for CYP1A1 *1A/*2A, CYP2E1 *1A/*5B, GSTM1 null, GSTT1 null GSTP1 11e105Val, mEH Tyr113His and mEH His139Arg gene variants. Results: Results obtained showed that GSTM1 null variant was significantly more represented in COPD patients than in controls (61.5% vs. 47.0%; OR=1.80; p=0.042). Also, a significant difference was observed for combinations of GSTM1 null and GSTP1 105Val/(Val) (38.5% vs. 24.0%; OR=1.98; p=0.029), as well as for CYP1A1 *1A/*2A, GSTM1 null and mEH 113His/(His) genotypes (7.4% vs. 1.0%; OR=7.88; p=0.025). Conclusions: These are the first data concerning the analysis of the variants of phase I and II genes in the pathogenesis of COPD in a Serbian population. Results obtained in this study open up the possibility for thorough analyses of the role of genetic factors in COPD on larger cohorts. Also, they implicate the importance of previously described genetic associations with COPD in our population, as well as reveal a new one, not reported so far

Association of functional variants of phase I and II genes with chronic obstructive pulmonary disease in a Serbian population

Uvod: Hronična opstruktivna bolest pluća (HOBP) jeste složeno oboljenje koje karakteriše povišen oksidativni stres. Funkcionalne varijante gena faze I i II ksenobiotičkog metabolizma mogu uticati na ravnotežu oksidanti-antioksidanti i mogu dovesti do razvoja HOBP. Cilj ove studije je bio ispitivanje uloge funkcionalnih genskih varijanti u genima za citohrom P450 (CYP), glutation S-transferazu (GST) i mikrozomalnu epoksidnu hidrolazu (mEH) u patogenezi HOBP u srpskoj populaciji. Metode: U ovoj studiji analizirane su genske varijante CYP1A1 *1A/*2A, CYP2E1 *1A/*5B, GSTM1 null, GSTT1 null, GSTP1 Ile105Val, mEH Tyr113His i mEH His139Arg u grupi obolelih od HOBP koja je obuhvatala 122 ispitanika i kontrolnoj grupi koja je obuhvatala 100 ispitanika sa normalnom funkcijom pluća. Rezultati: Dobijeni rezultati su pokazali da je GSTM1 null varijanta statistički značajno povišena u grupi obolelih od HOBP u poređenju sa kontrolnom grupom (61,5% i 47,0%; or = 1,80; p = 0,042). Takođe, uočena je značajna razlika u zastupljenosti kombinacije genotipova GSTM1 null i GSTP1 105Val/(Val) (38,5% i 24,0%; or = 1,98; p = 0,029), kao i kombinacije CYP1A1 *1A/*2A, GSTM1 null i mEH 113H is/(H is) (7,4% i 1,0% ; or = 7 ,88; p = 0,025). Zaključak: Ovo su prvi podaci o ulozi genskih varijanti gena faze I i II u patogenezi HOBP u srpskoj populaciji. Rezultati dobijeni u ovoj studiji otvaraju mogućnost za detaljniju analizu uloge genetičkih faktora u HOBP na većim grupama ispitanika. Pored toga, podaci dobijeni u našoj studiji potvrđuju važnost genetičkih determinanti povezanih sa HOBP u prethodnim studijama, ali takođe otkrivaju nove genetičke faktore, koji nisu objavljeni do sada.Background: Chronic obstructive pulmonary disease (COPD) is a complex disorder characterized by increased oxidative stress. Functional genetic variants of phase I and II genes are implicated in oxidants-antioxidants imbalance and may be involved in COPD development. In this study, we aimed to investigate the role of cytochrome P450 (CYP), glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) functional variants in the pathogenesis of COPD in a Serbian population. Methods: The genotypes of l2 2 COPD patients and 100 controls with normal lung function were determined for CYP1A1 *1A /*2A , CYP2E1 *1 A /*5B , GSTM1 null, GSTT1 null GSTP1 Ile105Val, mEH Tyr113His and mEH His139Arg gene variants. Results: Results obtained showed that GSTM1 null variant was significantly more represented in COPD patients than in controls (61.5% vs. 47.0%; or = 1.80; p = 0.042). Also, a significant difference was observed for combinations of GSTM1 null and GSTP1 105Val/(Val) (38.5% vs. 24.0%; or = 1.98; p = 0.029), as well as for CYP1A1 *1A/*2A, GSTM1 null and mEH 113His/(His) genotypes (7.4% vs. 1.0%; or = 7.88; p = 0.025). Conclusions: These are the first data concerning the analysis of the variants of phase I and II genes in the pathogenesis of COPD in a Serbian population. Results obtained in this study open up the possibility for thorough analyses of the role of genetic factors in COPD on larger cohorts. Also, they implicate the importance of previously described genetic associations with COPD in our population, as well as reveal a new one, not reported so far

DPP-4 inhibitors in the prevention/treatment of pulmonary fibrosis, heart and kidney injury caused by covid-19-a therapeutic approach of choice in type 2 diabetic patients?

Since the outbreak of SARS-CoV-2 virus more than 12,500,000 cases have been reported worldwide. Patients suffering from diabetes and other comorbidities are particularly susceptible to severe forms of the COVID-19, which might result in chronic complications following recovery. Dipeptidyl peptidase-4 inhibitors exert beneficial effects in prevention/treatment of pulmonary fibrosis, heart, and kidney injury, and since they may be a long-term consequence caused by COVID-19, it is reasonable to expect that DPP-4 inhibitors might be beneficial in alleviating long-term consequences of COVID-19. With that in mind, we would like to voice our concerns over chronic implications following recovery from COVID-19, especially not only in diabetic but also in non-diabetic patients, and to indicate that some preventive measures could be undertaken by application of DPP-4 inhibitors

3′-Aminothiocyclohexanespiro-5′-hydantoin and Its Pt(II) Complex—Synthesis, Cytotoxicity and Xanthine Oxidase Inhibitory Activity

Herein, we report the synthesis of platinum(II) complex bearing 3′-aminothiocyclohexanespiro-5′-hydantoin as ligand. The complex was characterized by IR, NMR spectral analyses, elemental analyses and density functional theory (DFT) calculations. Cytotoxicity and inhibitory potential on xanthine oxidase (XO) were evaluated by performed docking calculations. The cytotoxic activities of the 3′-aminothiocyclohexanespiro-5′-hydantoin (1), its Pt(II) complex (2), thiocyclohexanespiro-5′-hydantoin (3), and its platinum complex (4) were assessed against HL-60 and MDA-MB-231 cells in comparison with the antiproliferative activity of cisplatin as a referent. The ligands (1 and 3) did not exhibit in vitro antitumor efficacy on either of the human tumor cell lines. Complex 2 showed higher antitumor activity (IC50 = 42.1 ± 2.8 μM on HL-60 and 97.8 ± 7.5 μM against MDA-MB-231 cells) than complex 4 (IC50 = 89.6 ± 2.8 μM on HL-60 and 112.5 ± 4.2 μM in MDA-MB-231 cells). IC50 values of cisplatin as referent were 8.7 ± 2.4 μM on HL-60 and 31.6 ± 5.4 μM on MDA-MB-231 cell lines. The inhibitory activity of ligands and complexes against XO, evaluated in vitro, were compared with allopurinol (IC50 = 1.70 ± 0.51 μM) as standard inhibitor. The platinum(II) complexes (2 and 4) inhibited the activity of XO, with IC50 values 110.33 ± 26.38 μM and 115.45 ± 42.43 μM, respectively, while the ligands 1 and 3 did not show higher degrees of inhibition at concentrations lower than 150 μM. The inhibitory potential against XO might be a possible precedent resulting in improved profile and anticancer properties

3′-Aminothiocyclohexanespiro-5′-hydantoin and Its Pt(II) Complex—Synthesis, Cytotoxicity and Xanthine Oxidase Inhibitory Activity

Herein, we report the synthesis of platinum(II) complex bearing 3′-aminothiocyclohexanespiro-5′-hydantoin as ligand. The complex was characterized by IR, NMR spectral analyses, elemental analyses and density functional theory (DFT) calculations. Cytotoxicity and inhibitory potential on xanthine oxidase (XO) were evaluated by performed docking calculations. The cytotoxic activities of the 3′-aminothiocyclohexanespiro-5′-hydantoin (1), its Pt(II) complex (2), thiocyclohexanespiro-5′-hydantoin (3), and its platinum complex (4) were assessed against HL-60 and MDA-MB-231 cells in comparison with the antiproliferative activity of cisplatin as a referent. The ligands (1 and 3) did not exhibit in vitro antitumor efficacy on either of the human tumor cell lines. Complex 2 showed higher antitumor activity (IC50 = 42.1 ± 2.8 μM on HL-60 and 97.8 ± 7.5 μM against MDA-MB-231 cells) than complex 4 (IC50 = 89.6 ± 2.8 μM on HL-60 and 112.5 ± 4.2 μM in MDA-MB-231 cells). IC50 values of cisplatin as referent were 8.7 ± 2.4 μM on HL-60 and 31.6 ± 5.4 μM on MDA-MB-231 cell lines. The inhibitory activity of ligands and complexes against XO, evaluated in vitro, were compared with allopurinol (IC50 = 1.70 ± 0.51 μM) as standard inhibitor. The platinum(II) complexes (2 and 4) inhibited the activity of XO, with IC50 values 110.33 ± 26.38 μM and 115.45 ± 42.43 μM, respectively, while the ligands 1 and 3 did not show higher degrees of inhibition at concentrations lower than 150 μM. The inhibitory potential against XO might be a possible precedent resulting in improved profile and anticancer properties

Association of Functional Variants of Phase I and II Genes with Chronic Obstructive Pulmonary Disease in a Serbian Population / Udruženost Funkcionalnih Varijanti Gena Faze I I Ii Sa Hroničnom Opstruktivnom Bolešću Pluća U Srpskoj Populaciji

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex disorder characterized by increased oxidative stress. Functional genetic variants of phase I and II genes are implicated in oxidants–antioxidants imbalance and may be involved in COPD development. In this study, we aimed to investigate the role of cytochrome P450 (CYP), glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) functional variants in the pathogenesis of COPD in a Serbian population. METHODS: The genotypes of 122 COPD patients and 100 controls with normal lung function were determined for CYP1A1 *1A/*2A, CYP2E1 *1A/*5B, GSTM1 null, GSTT1 null GSTP1 Ile105Val, mEH Tyr113His and mEH His139Arg gene variants. RESULTS: Results obtained showed that GSTM1 null variant was significantly more represented in COPD patients than in controls (61.5% vs. 47.0%; OR=1.80; p=0.042). Also, a significant difference was observed for combinations of GSTM1 null and GSTP1 105Val/(Val) (38.5% vs. 24.0%; OR=1.98; p=0.029), as well as for CYP1A1 *1A/*2A, GSTM1 null and mEH 113His/(His) genotypes (7.4% vs. 1.0%; OR=7.88; p=0.025). CONCLUSIONS: These are the first data concerning the analysis of the variants of phase I and II genes in the pathogenesis of COPD in a Serbian population. Results obtained in this study open up the possibility for thorough analyses of the role of genetic factors in COPD on larger cohorts. Also, they implicate the importance of previously described genetic associations with COPD in our population, as well as reveal a new one, not reported so far

Gene-environment interaction between the MMP9 C-1562T promoter variant and cigarette smoke in the pathogenesis of chronic obstructive pulmonary disease

The aetiology of chronic obstructive pulmonary disease (COPD) is complex. While cigarette smoking is a well-established cause of COPD, a myriad of assessed genetic factors has given conflicting data. Since gene-environment interactions are thought to be implicated in aetiopathogenesis of COPD, we aimed to examine the matrix metalloproteinase (MMP) 9 C-1562T (rs3918242) functional variant and cigarette smoke in the pathogenesis of this disease. The distribution of the MMP9 C-1562T variant was analyzed in COPD patients and controls with normal pulmonary function from Serbia. Interaction between the C-1562T genetic variant and cigarette smoking was assessed using a case-control model. The response of the C-1562T promoter variant to cigarette smoke condensate (CSC) exposure was examined using a dual luciferase reporter assay. The frequency of T allele carriers was higher in the COPD group than in smoker controls (38.4% vs. 20%; OR=2.7, P=0.027). Interaction between the T allele and cigarette smoking was identified in COPD occurrence (OR=4.38, P=0.005) and severity (P=0.001). A functional analysis of the C-1562T variant demonstrated a dose-dependent and allele-specific response (P lt 0.01) to CSC. Significantly higher MMP9 promoter activity following CSC exposure was found for the promoter harboring the T allele compared to the promoter harboring the C allele (P lt 0.05). Our study is the first to reveal an interaction between the MMP9-1562T allele and cigarette smoke in COPD, emphasising gene-environment interactions as a possible cause of lung damage in the pathogenesis of COPD. Environ. Mol. Mutagen. 57:447-454, 2016

Benzo[4,5]thieno[2,3-d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase-4

A small library of benzo[4,5]thieno[2,3-d]pyrimidine phthalimide and amine derivatives was evaluated for inhibitory activity against dipeptidyl peptidase-4 (DPP-4). The phthalimide derivatives exhibited better activity than the amine precursors, with 2-(2-(3-chlorobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)isoindoline-1,3-dione (compound 14) as the most effective inhibitor (IC50 = 34.17 +/- 5.11 mu M). The five most potent selected inhibitors did not show cytotoxicity to a greater extent on Caco-2 cells, even at a concentration of 250 mu M. Compound 14 is considered as a novel representative of the rare noncompetitive DPP-4 inhibitors. Molecular docking and dynamics simulation indicated the importance of the Tyr547, Lys554, and Trp629 residues of DPP-4 in the formation of the enzyme-inhibitor complex. These observations could be potentially utilized for the rational design and optimization of novel (structurally similar, with phthalimide moiety, or different) noncompetitive DPP-4 inhibitors, which are anyway rare, but favorable in terms of the saturation of substrate competition