Synthesis of n-alkylated derivatives of 1-(4-methoxyphenyl)-1,5-dihydro-4h-pyrazolo[3,4-d]pyrimidin-4-ones as potential anticonvulsants

High psychotropic activity of pyrimidine derivatives attracts attention and directs the creation of new pyrimidine drugs which affect the central nervous system. As psychotropic agents a special attention deserve azolopyrimidine derivatives, including pyrazolopyrimidines.Thus, among the pyrazolopyrimidine derivatives had been found compounds with antiepileptic, anticonvulsant, sedative, anxiolytic activity [1, 2], ligands of benzodiazepine site of GABA receptors [3]. In addition, the ligands of 5HT-6 receptors were identified that are promising for the treatment of central nervous system, muscle relaxants [4].The purpose of this research was a synthesis of alkylated derivatives of 1-(4-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-ones

The role of advanced glycation end products in patogenesis of diabetic nephropathy

Diabetes mellitus (DM) and chronic kidney disease are the diseases that have exceeded epidemic thresholds in terms of prevalence all over the world. That made it possible to classify them as non-communicable epidemics of the XXI century. Diabetic nephropathy (DN) is implicated with high levels of disablement and mortality. Advanced glycation end products (AGE) play a key role in the progression of DN. Increased formation of AGE occurs due to hyperglycemia under the conditions of diabetes. Moreover, there are additional factors in DN that increase the elaboration of AGE, such as high levels of oxidative stress and decreased renal clearance which slows down the AGE excretion. Both immediate effects of AGE and interaction of AGE with its cell-bound receptor (RAGE) result in a сascade of events that lead to further progression of DN. Thus, the research of the new therapeutic approaches targeted on the AGE-RAGE system is of great interest to slow progression of DN and improve the prognosis

Технико-экономический прогноз при выборе оптимальной технологии использования биомассы и местных ископаемых топлив для производства тепловой и электрической энергии

The paper provides a technical and economic analysis pertaining to selection of optimum biomass and local fossil fuel application technology for thermal electric energy generation while using a matrix of costs and a method of minimum value. Calculation results give grounds to assert that it is expedient to burn in the boiling layer – 69 % and 31 % of wood pellets and wastes, respectively and 54 % of peat and 46 % of slate stones. A steam and gas unit (SGU) can fully operate on peat. Taking into account reorientation on decentralized power supply and increase of small power plants up to 3–5 MW the paper specifies variants of the most efficient technologies for burning biomass and local fossil fuels. Проведен технико-экономический анализ выбора оптимальной технологии использования биомассы и местных ископаемых топлив для производства тепловой и электрической энергии с использованием матрицы затрат и метода минимальной стоимости. Результаты расчетов дают основание утверждать, что в кипящем слое целесообразно сжигать 69 % древесных гранул и 31 % древесных отходов, а также 54 % торфа, 46 % сланцев. ПГУ может полностью работать на торфе.С учетом переориентации на децентрализованное энергоснабжение и увеличение количества малых энергетических установок до 3–5 МВт отмечены варианты наиболее эффективных технологий сжигания биомассы и местных ископаемых топлив

Синтез, протимікробна активність та докінгові дослідження 6-(1H-бензімідазол-2- іл)-5-метилтієно[2,3-d]піримідин-4(3H)-онів з ацетамідними та 1,2,4-оксадіазол-5- ілметильними замісниками

Aim. To synthesize, study the antimicrobial activity and suggest antimicrobial activity mechanism for the novel derivatives of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one. Results and discussion. As the result of the targeted modification of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]-pyrimidin-4(3H)-one in position 3 with acetamide and 1,2,4-oxadiazol-5-ylmethyl substituents, the compounds, which demonstrated better antimicrobial activity in the agar well diffusion assay than the reference drug Streptomycin, were obtained. To elucidate the mechanism of action of the novel compounds, the docking studies were con-ducted to the active site of the 16S subunit of ribosomal RNA, the proven target for aminoglycoside antibiotics, as well as tRNA (Guanine37-N1)-methyltransferase (TrmD), which inhibitors were considered as a new potential class of antibiotics. Experimental part. By the interaction of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one with a series of N-arylchloroacetamides and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles in DMF in the presence of K2CO3 the target compounds were obtained. The antimicrobial activity was assessed by the agar well diffusion method. The concentration of microbial cells was determined by the McFarland standard; the value was 107 cells in 1 mL of the media. The 18 – 24 hour culture of microorganisms was used for tests. For the bacteria cultivation, Müller-Hinton agar was used, Sabouraud agar was applied for C. albicans cultivation. The compounds were tested as the DMSO solution with the concentration of 100 µg/mL; the volume of the solution was 0.3 mL, the same volume was used for Streptomycin (the concentration 30 µg/mL). The docking studies were performed using Autodock Vina. Crystallographic data for the complexes of Streptomycin with the 16S subunit of ribosomal RNA (1NTB) and its active site, as well as for tRNA (Guanine37-N1)-methyltransferase (EC 2.1.1.228; TrmD) (5ZHN) and its active site were obtained from the Protein Data Bank.Conclusions. It has been determined that 2-[6-(1H-benzimidazol-2-yl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl]-N-[4-(ethoxy)phenyl]acetamide, which is the most active as an antimicrobial agent among the compounds tested, also shows the best binding activity towards the active site of tRNA (guanine37-N1)-methyltransferase.Мета. Синтезувати й дослідити протимікробну активність нових похідних 6-(1H-бензімідазол-2-іл)-5-метилтієно[2,3-d]піримідин-4(3H)-онів та запропонувати механізм протимікробної активності.Результати та їх обговорення. У результаті цілеспрямованої модифікації положення 3 6-(1H-бензімідазол-2-іл)-5-метилтієно[2,3-d]піримідин-4(3H)-ону ацетамідним та 1,2,4-оксадіазол-5-ілметильним замісниками було одержано сполуки з визначеною методом дифузії в агар протимікробною активністю, що є більшою за активність препарату порівняння Стрептоміцину. З метою з’ясування механізму дії синтезованих сполук було проведено докінгові дослідження щодо активного сайту субодиниці 16S рибосомальної РНК, яка є підтвердженою мішенню для аміноглікозидних антибіотиків, а також тРНК (Гуанін-37-N1)-метилтрансферази (TrmD), інгібітори якої розглядаються як новий потенційний клас антибіотиків. Експериментальна частина. Шляхом взаємодії 6-(1H-бензімідазол-2-іл)-5-метилтієно[2,3-d]піримідин-4(3H)-ону з рядом N-арилхлороацетамідів та 3-арил-5-(хлорометил)-1,2,4-оксадіазолів в умовах ДМФА-K2CO3 було одержано цільові сполуки. Антимікробну активність визначали методом дифузії в агар. Концентрацію мікробних клітин визначали за МакФарландом; мікробне навантаження склало 107 мікробних одиниць в 1 мл середовища. Для тестів використовували 18 – 24 годинну культуру мікроорганізмів. Для культивування бактерій використовували агар Мюллера-Гінтона; для культивування C. albicans використовували агар Сабуро. Сполуки вводили методом дифузії в агар (лунками) у вигляді розчину у ДМСО в концентрації 100 мкг/мл в об’ємі 0,3 мл; аналогічний об’єм використовували для Стрептоміцину (конц. 30 мкг/мл). Докінгові дослідження проводили за допомогою програми Autodock Vina. Кристалографічні дані для комплексів стрептоміцину з 16S субодиницею рибосомальної РНК (1NTB) та її активного сайту і для тРНК (Гуанін-37-N1)-метилтрансферази (EC 2.1.1.228; TrmD) (5ZHN) та її активного сайту було отримано з Protein Data Bank.Висновки. Виявлено, що сполука 2-[6-(1H-бензімідазол-2-іл)-5-метил-4-оксотієно[2,3-d]піримідин-3(4H)-іл]-N-[4-(етокси)феніл]ацетамід, яка характеризується найбільшою протимікробною активністю, у докінгових розрахунках є також найбільш ефективним інгібітором тРНК (Гуанін-37-N1)-метилтрансферази

Therapeutic Effects of Butyrate on Pediatric Obesity: A Randomized Clinical Trial

Importance: The pediatric obesity disease burden imposes the necessity of new effective strategies. Objective: To determine whether oral butyrate supplementation as an adjunct to standard care is effective in the treatment of pediatric obesity. Design, Setting, and Participants: A randomized, quadruple-blind, placebo-controlled trial was performed from November 1, 2020, to December 31, 2021, at the Tertiary Center for Pediatric Nutrition, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy. Participants included children aged 5 to 17 years with body mass index (BMI) greater than the 95th percentile. Interventions: Standard care for pediatric obesity supplemented with oral sodium butyrate, 20 mg/kg body weight per day, or placebo for 6 months was administered. Main Outcomes and Measures: The main outcome was the decrease of at least 0.25 BMI SD scores at 6 months. The secondary outcomes were changes in waist circumference; fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, ghrelin, microRNA-221, and interleukin-6 levels; homeostatic model assessment of insulin resistance (HOMA-IR); dietary and lifestyle habits; and gut microbiome structure. Intention-to-treat analysis was conducted. Results: Fifty-four children with obesity (31 girls [57%], mean [SD] age, 11 [2.91] years) were randomized into the butyrate and placebo groups; 4 were lost to follow-up after receiving the intervention in the butyrate group and 2 in the placebo group. At intention-to-treat analysis (n = 54), children treated with butyrate had a higher rate of BMI decrease greater than or equal to 0.25 SD scores at 6 months (96% vs 56%, absolute benefit increase, 40%; 95% CI, 21% to 61%; P < .01). At per-protocol analysis (n = 48), the butyrate group showed the following changes as compared with the placebo group: waist circumference, -5.07 cm (95% CI, -7.68 to -2.46 cm; P < .001); insulin level, -5.41 μU/mL (95% CI, -10.49 to -0.34 μU/mL; P = .03); HOMA-IR, -1.14 (95% CI, -2.13 to -0.15; P = .02); ghrelin level, -47.89 μg/mL (95% CI, -91.80 to -3.98 μg/mL; P < .001); microRNA221 relative expression, -2.17 (95% CI, -3.35 to -0.99; P < .001); and IL-6 level, -4.81 pg/mL (95% CI, -7.74 to -1.88 pg/mL; P < .001). Similar patterns of adherence to standard care were observed in the 2 groups. Baseline gut microbiome signatures predictable of the therapeutic response were identified. Adverse effects included transient mild nausea and headache reported by 2 patients during the first month of butyrate intervention. Conclusions and Relevance: Oral butyrate supplementation may be effective in the treatment of pediatric obesity. Trial Registration: ClinicalTrials.gov Identifier: NCT04620057

Simultaneous pancreas‐kidney transplantation in type 1 diabetes mellitus. Clinical options

Simultaneous pancreas-kidney transplantation (SPKT) is the most promising treatment option for patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease (ESRD) due to diabetic nephropathy (DN). Successful SPKT eliminates uremic intoxication and hyperglycemia – the leading trigger of vascular diabetic complications. Therefore, euglycemia is an important metabolic change in patients after surgery and remains only one of the factors for the saved renal allograft functioning. In the case of resuming renal replacement therapy by dialysis after SPKT, the management and monitoring of the pancreatic graft remains open. Special attention to the pancreatic graft’s function is due to both the potential risk of surgical complications, and some probability of T1DM relapse with the need to resume insulin therapy. In patients with saved function of both transplants, the assessment of the dynamics of diabetic complications in general becomes more important. The results of few studies in this regard remain contradictory. Thus, clinical options can be unpredictably diverse and require not only search for the root cause, but also optimization of rehabilitation tactics, even if the expected results are achieved

A simultaneous pancreas-kidney transplantation for type 1 diabetes mellitus after a long-term of receiving hemodialysis renal replacement therapy. Clinical сase

At the present time, a simultaneous pancreas-kidney transplantation (SPKT) is an effective method of treatment for patients on renal replacement therapy by hemodialysis program in the outcome of the terminal stage of diabetic nephropathy. This method of treatment solves several problems: it reduces the severity of intoxication syndrome, contributes to the achievement of euglycemia in most cases, which certainly allows to slow the progression of micro- and macrovascular complications of diabetes. Despite of positive effect of euglycaemia and kidney function normalization, the accumulated metabolic memory legacy of long-term uncompensated diabetes mellitus is realized, which makes a posttransplantational rehabilitation of patients difficult. A duration of hemodialysis therapy is known as a cardiovascular events risk factor, which affects the surgery result and favorable posttransplant period. More often after successful SPKT microvascular diabetic complications are stabilized, but macrovascular diabetic complications, diabetic neuroosteoarthropathy and mineral and bone disease are progressed. That’s why is necessary to perform regular examination after SPKT by a team of specialists, including nephrologist, endocrinologist, cardiologist, ophthalmologist with correction of ongoing therapy. Therefore both the preparation of  the patient for transplantation with the earliest possible placement on the waiting list and the post-transplant rehabilitation afterwards are extremely important

The structure of mineral and bone disorders in patients with сhronic kidney disease of the 5th dialysis stage, taking into account the presence or absence of a diagnosis of type 1 diabetes mellitus

BACKGROUND: In patients with end-stage CKD, receiving renal replacement therapy (RRT) with programmed hemodialysis (HD), the severity of complications is associated with metabolic disturbances: accumulation of uremic toxins, nephrogenic anemia, secondary hyperparathyroidism (SHPT), extraskeletal calcification, impaired clearance and rhythm of hormone secretion.AIM: To evaluate the main biochemical and hormonal parameters, and manifestations of mineral bone disease (MBD) in patients receiving RRT with HD, before and after hemodialysis, taking into account the presence or absence of diabetes mellitus.MATERIALS AND METHODS: We divided all patients receiving RRT with HD in two groups: #1 (n=24) — patients with DM, #2 (n=16) — patients without DM. All of them had their blood analyzed before and immediately after the HD. Data analysis was performed with the Statistica 13 (StatSoft, USA). A prognostically significant model was considered at p<0.05.RESULTS: The level of iPTH, both at baseline and after HD, was lower in group #1 (p<0.001). The level of alkaline phosphatase (AP) was significantly higher in group #2 (p=0.012). In both groups before HD, a high incidence of hypocalcemia was detected (according to albumin-corrected calcium in group #1 in 58.3%, in group #2 in 43.7% of cases, p = 0.366) and hyperphosphatemia (in 66.7% and in 43 .7% of cases, respectively, p=0.151). Hypocalcemia after HD in group #1 persisted in 14%, in group #2 — in 20% of cases (p>0.05); hyperphosphatemia in group #1 was completely leveled, in group #2 it persisted in 7% of cases (p=0.417). Prior to the HD session, group #1 had significantly higher levels of RAGE, glucagon, immunoreactive insulin (IRI), cortisol, and glucose than after the HD session (p<0.05). In group #2, after HD, the levels of glucagon, IRI and cortisol significantly decreased (p<0.05), and the level of 3-nitrotyrosine (3-HT) increased significantly (p=0.026). In group #1, fibrocalcinosis of the heart valves according to ECHO and calcification of the arteries of the lower extremities according to ultrasonic doplerography were more common than in group #2 (42% vs 25%, p<0.001 and 75% vs 37.5%, p=0.018, respectively). (χ2)). Compression fractures occurred with the same frequency in both groups (60%). A decrease in bone mineral density (BMD) to the level of osteopenia was noted more often in group #1 (50% vs 18.8%), and osteoporosis was more common in group #2 (68.8% vs 33.3%) (p<0.001, χ2).CONCLUSION: The low level of PTH in group #1 may reflect the effect of diabetes on calcium-phosphorus metabolism. Patients with DM have an increased risk of renal osteodystrophy with a low bone turnover because of a number of metabolic factors inherent in diabetes. At the same time, the dynamics of phosphorus and calcium indicators during the HD procedure were similar