7 research outputs found
Antimicrobial Activity of Copper(II), Nickel(II) and Zinc(II) Complexes with Semicarbazone and Thiosemicarbazone Ligands Derived from Substituted Salicylaldehydes
No full textAntibiotic resistance is a problem repeatedly reported by health authorities. Metalloantibiotics, i.e., biologically active compounds containing one or more metal ions, can be an important resource in the fight against bacteria and fungi. Here, we report the results obtained with a panel of copper(II), nickel(II) and zinc(II) complexes with thiosemicarbazone, semicarbazone and acylhydrazone ligands on Staphylococcus aureus, Escherichia coli and Candida albicans, taken as model systems of human pathogens. To increase the solubility in water, the sulfonic group was introduced on some of the ligands, isolating them as sodium salts (NaH2L4-NaH2L7). Complexes 1–14 were isolated, fully characterized and the X-ray structures of 11, 12 and 13 were obtained. While all the ligands have no antimicrobial activity, the copper(II) complexes 1 and 4 and the nickel(II) complex 2, obtained from thiosemicarbazone ligands, showed good activity, in particular against S. aureus; these complexes were investigated in depth, calculating their respective IC50 values (4.2 μM, 3.5 μM and 61.8 μM, respectively). It should be noted that nickel(II) complex 2 does not show hemolytic activity and has a favorable SI value. While all the copper(II) complexes completely degraded the plasmid DNA in presence of H2O2, nickel(II) complex 2 cleaved the plasmid DNA leading to the formation of the relaxed nicked conformation, thus suggesting a different mechanism of action
Deepening bis-(thio)carbohydrazones conformational dynamics and hydrogen bond interactions in a non-protic solvent: DFT, molecular dynamics, NMR, and Raman investigations
No full textDespite the capability of bis-(thio)carbohydrazones to coordinate metals and the remarkable biological properties of the resulting complexes, no general information is known about their individual behavior in solution. This study is focused on two recently synthesized compounds, a bis-thiocarbohydrazone (bis-TCH) and a bis-carbohydrazone (bis-CH) isolated as sodium salts, that have shown chelating properties toward copper(II) and zinc(II) metal ions along with promising cytotoxic activity. In this work, an integrated theoretical-computational, nuclear magnetic resonance (NMR), and vibrational characterization of both bis-TCH and bis-CH anions in a non-protic solvent (dimethylsulfoxide) is presented to better elucidate their properties. Their protonic NMR spectra underline the presence of cis-trans, EE isomers, characterized by a significant conformational freedom at room temperature. The presence of oxygen or sulfur heteroatoms can tune the molecular conformational dynamics driving a different interaction with the solvent, as highlighted by density functional theory calculations and atomistic molecular dynamics simulations. Our results demonstrate that a quantitative agreement with the NMR and Raman signals is achieved only when an explicit solvent description is included. The insights achieved by this study can contribute to a better understanding of the behavior of bis-carbohydrazones and bis-thiocarbohydrazones in solution, a crucial and mandatory step to improve the design of novel, more potent analogs
Synthesis and Preliminary Studies for In Vitro Biological Activity of Two NewWater-Soluble Bis(thio)carbohydrazones and Their Copper(II) and Zinc(II) Complexes
No full textResearch in the field of metallodrugs is continually increasing. However, it is often limited by the poor solubility in water of the metal complexes. To try to overcome this problem, the two new ligands bis-(sodium 3-methoxy-5-sulfonate-salicylaldehyde)thiocarbohydrazone (bis-TCH, Na2H4L1) and bis-(sodium 3-methoxy-5-sulfonate-salicylaldehyde)carbohydrazone (bis-CH, Na2H4L2) were synthesized and characterized, both achieving high solubility in water. The speciation of the ligands and their coordinating behaviour towards the biologically relevant Cu(II) and Zn(II) ions were studied spectroscopically and potentiometrically, determining the pKas of the ligands and the formation constants of the complex species. The monometallic and bimetallic Cu(II) and Zn(II) complexes were isolated, and the single-crystal X-ray structure of [Cu2(NaHL1)(H2O)7].3.5H2O was discussed. Finally, preliminary studies of the in vitro cytotoxic properties of the new compounds were started on normal (Hs27) and cancer (U937) cell lines. bis-TCH was able to induce a growth inhibition effect between 40% and 45% in both cell lines; bis-CH did not produce a reduction in cell viability in Hs27 cells but revealed mild antiproliferative activity after 72 h of treatment in U937 cancer cells (GI50 = 46.5 ± 4.94 μg/mL). Coordination of the Cu(II) ions increased the toxicity of the compounds, while, in contrast, Zn(II) complexes were not cytotoxic
Dvojezični feničko-etrurski tekst zlatnih pločica iz Pyrgija
No full textIn 1964, the archaeologists excavating the ancient Etruscan city of Pyrgi brought to light three golden plates.Two of the plates were written in Etruscan, while the third one had a Phoenician inscription on it. The archaeologists suspected immediately that the longer Etruscan inscription and the Phoenician text might be related. Yet, scholars' hopes that the promising text of the Etruscan plate might have been an Etruscan kind of "Rosetta stone" were dashed to the ground. They realized very soon that the two texts were -at best -a paraphrasis of each other but they contained no literal translation which might have offered a key to Etruscan hermeneutics. Since then, no author was able to offer a reliable interpretation of the Etruscan plate, dealing with the donation made by the Etruscan chieftain or "king" of the important city of Caere, Thefariei Velianas, to the Phoenician goddess Aštart. We therefore decided to re-examine the plates "from scratch". As a first step, we went through extant translations of the Phoenician inscription and we discovered that some of its terms had been misunderstood and/or mistranslated. After preparing a new and more reliable translation of the Phoenician lamina, we used it as a key to compare and translate the doubtful expressions of the Etruscan text. We are now glad to publish our results that represent the first integral and -in our humble opinion -creditable translation of these laminae.Arheolozi su u iskapanjima etrurskoga grada Pyrgija 1964. pronašli tri zlatne pločice, od kojih su dvije bile s tekstom na etrurskom jeziku i jedna s feničkim tekstom. Etrurski tekstovi sadržajem odgovaraju feničkomu, no ne radi se o doslovnome prijevodu. Autori iscrpno proučavaju etrurske tekstove, uspoređujući ih na nov način s feničkim tekstom, koji je dan u detaljnome prijevodu i tumačenju, te ujedno predlažu novo tumačenje etrurskih tekstova
Rationale and design of the DARWIN-T2D (DApagliflozin real world evIdeNce in Type 2 Diabetes). A multicenter retrospective nationwide Italian study and crowdsourcing opportunity
No full textBACKGROUND:
Randomized controlled trials (RCTs) in the field of diabetes have limitations inherent to the fact that design, setting, and patient characteristics may be poorly transferrable to clinical practice. Thus, evidence from studies using routinely accumulated clinical data are increasingly valued.
AIMS:
We herein describe rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes), a multicenter retrospective nationwide study conducted at 50 specialist outpatient clinics in Italy and promoted by the Italian Diabetes Society.
DATA SYNTHESIS:
The primary objective of the study is to describe the baseline clinical characteristics (particularly HbA1c) of patients initiated on dapagliflozin from marketing authorization approval to the end of 2016. Secondary and exploratory objectives will evaluate the changes in glycaemic and extraglycaemic efficacy parameters after initiation of dapagliflozin or after initiation of comparator glucose lowering medications (DPP-4 inhibitors, gliclazide extended release, and long-acting GLP-1 receptor agonists). An automated software will extract relevant data from the same electronic chart system at all centres, thereby minimizing data treatment and human intervention.
CONCLUSION:
The study is expected to collect an enormous dataset of information on dapagliflozin- and comparator-using patients. After study completion, the Italian Diabetes Society will launch an open crowdsourcing call on the DARWIN-T2D database, challenging diabetes researchers to apply their ideas and approaches to address new unmet needs and knowledge gaps in diabetes. We believe this will move DARWIN-T2D to the next generation of real world studies
Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: impact on cardiovascular events. A randomized controlled trial
No full textBACKGROUND AND AIMS:
Metformin is the first-line therapy in type 2 diabetes. In patients inadequately controlled with metformin, the addition of a sulfonylurea or pioglitazone are equally plausible options to improve glycemic control. However, these drugs have profound differences in their mechanism of action, side effects, and impact on cardiovascular risk factors. A formal comparison of these two therapies in terms of cardiovascular morbidity and mortality is lacking. The TOSCA.IT study was designed to explore the effects of adding pioglitazone or a sulfonylurea on cardiovascular events in type 2 diabetic patients inadequately controlled with metformin.
METHODS:
Multicentre, randomized, open label, parallel group trial of 48 month duration. Type 2 diabetic subjects, 50-75 years, BMI 20-45 Kg/m(2), on secondary failure to metformin monotherapy will be randomized to add-on a sulfonylurea or pioglitazone. The primary efficacy outcome is a composite endpoint of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned coronary revascularization. Principal secondary outcome is a composite ischemic endpoint of sudden death, fatal and non-fatal myocardial infarction and stroke, endovascular or surgical intervention on the coronary, leg or carotid arteries, major amputations. Side effects, quality of life and economic costs will also be evaluated. Efficacy, safety, tolerability, and study conduct will be monitored by an independent Data Safety Monitoring Board. End points will be adjudicated by an independent external committee.
CONCLUSIONS:
TOSCA.IT is the first on-going study investigating the head-to-head comparison of adding a sulfonylurea or pioglitazone to existing metformin treatment in terms of hard cardiovascular outcomes. Registration: Clinicaltrials.gov ID NCT00700856
Распространенность гиперурикемии у профессиональных спортсменов и ее роль в генезе различных патологических состояний и обменных нарушений
No full textIn recent decades, the prevalence of hyperuricemia (HU) is increasing worldwide; the role of uric acid (UA) in the genesis of various metabolic disorders, cardiovascular diseases, and kidney disease is being discussed. There are very few investigations of the rate of HU and its role in the development of diseases in certain social groups, including in professional athletes.Objective: to estimate the prevalence of HU and its role in the genesis of various pathological conditions and metabolic disturbances in professional athletes.Patients and methods. A retrospective comparative one-stage study was conducted, for which 2148 athletes who met inclusion criteria were selected and examined in the Federal Research and Clinical Center for Sports Medicine and Rehabilitation, Federal Biomedical Agency, in 2015. A control group consisted of 99 ageand sex-matched healthy volunteers examined at the V.A. Nasonova Research Institute of Rheumatology in 2017. The analysis included a comparison of the rate of HU and other examined parameters in professional athletes and healthy volunteers. The examined parameters were separately compared in athletes with/without HU, followed by statistical processing of results.Results. HU was detected in 306 (14.2%) of the 2148 athletes, more often in men (n=253 (20%) than in women (n=53 (6%); (p<0.001). The rate of HU in the athletes was comparable with that in the healthy population (12.1%). The athletes with HU (n=306) compared with the other athletes (n=1842) had the following statistically higher indicators: the mean serum levels of creatinine, triglycerides, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase, creatinine phosphokinase, and myoglobin, glomerular filtration rate, and body mass index (BMI) (p<0.00001 for all cases).Conclusion. HU is detected quite often in professional athletes (14.2%), which is comparable with the indicators seen in healthy volunteers (12.1%). The high prevalence of HU and its association with indicators reflecting kidney function, lipid metabolic disturbances, and BMI necessitate further investigations aimed at searching the causes of HU and methods of its prevention and treatment in professional athletes.В последние десятилетия распространенность гиперурикемии (ГУ) в мире увеличивается, обсуждается роль мочевой кислоты (МК) в генезе различных обменных нарушений, сердечно-сосудистых заболеваний, болезней почек. Исследований, посвященных изучению частоты ГУ и ее роли в развитии заболеваний в отдельных социальных группах, в том числе у профессиональных спортсменов, крайне мало.Цель исследования – оценка распространенности ГУ и ее роли в генезе различных патологических состояний, обменных нарушений у профессиональных спортсменов.Пациенты и методы. Проведено ретроспективное сравнительное одномоментное исследование, для участия в котором отобраны 2148 спортсменов, соответствующих критериям включения, обследованных на базе ФГБУ «Федеральный научно-клинический центр спортивной медицины и реабилитации Федерального медико-биологического агентства» в 2015 г. Группу контроля составили 99 здоровых добровольцев, сопоставимых по возрасту и полу, обследованных на базе ФГБНУ НИИР им. В.А. Насоновой в 2017 г. Анализ включал сравнение частоты ГУ и других исследуемых параметров у профессиональных спортсменов и здоровых добровольцев. Отдельно проводилось сопоставление исследуемых показателей у спортсменов с/без ГУ с последующей статистической обработкой результатов.Результаты. ГУ выявлена у 306 (14,2%) из 2148 спортсменов, чаще у мужчин (253, или 20%), чем у женщин (53, или 6%; p<0,001). Частота ГУ у спортсменов оказалась сопоставимой с таковой в здоровой популяции (12,1%). У спортсменов с ГУ (n=306) в сравнении с остальными спортсменами (n=1842) статистически выше были следующие показатели: средние сывороточные уровни креатинина, триглицеридов, а также аспартатаминотрансферазы, аланинаминотрансферазы, гамма-глутамилтранспептидазы, креатининфосфокиназы, миоглобина, скорости клубочковой фильтрации, индекса массы тела (ИМТ; р<0,00001 для всех случаев).Выводы. ГУ у профессиональных спортсменов выявляется достаточно часто (14,2%), что сопоставимо с показателями у здоровых добровольцев (12,1%). Высокая распространенность ГУ, ассоциация ее с показателями, отражающими функцию почек, нарушениями липидного обмена, ИМТ делают необходимыми дальнейшие исследования, направленные на поиск причин, методов профилактики и лечения ГУ у профессиональных спортсменов
