A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- MeSH
- Apoptosis * drug effects MeSH
- Cell Cycle drug effects MeSH
- Histone Deacetylases metabolism MeSH
- Histone Deacetylase Inhibitors * pharmacology chemical synthesis chemistry MeSH
- Hydroxamic Acids * pharmacology chemical synthesis chemistry MeSH
- Coumaric Acids * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemical synthesis chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- THP-1 Cells MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The regulation of the pyrimidine biosynthetic pathway by pyrimidines was investigated in the biological control agent Pseudomonas aureofaciens ATCC 17418. Using succinate as a carbon source, orotic acid or uracil supplementation had a repressive effect in ATCC 17418 cells on dihydroorotate dehydrogenase or orotidine 5'- monophosphate decarboxylase activity but only orotic acid supplementation appeared to repress the level of orotate phosphoribosyltransferase activity. In glucose-grown ATCC 17418 cells, orotic acid supplementation appeared to repress the level of phosphoribosyltransferase or decarboxylase while uracil supplementation depressed the dihydroorotase, dehydrogenase, and decarboxylase activities. The pyrimidine auxotrophic mutant strain GW-2, isolated from ATCC 17418 using chemical mutagenesis and resistance to 5-fluoroorotic acid, was found to be deficient for orotidine 5'-monophosphate decarboxylase activity. Pyrimidine limitation of the succinate-grown mutant strain cells resulted in only a slight derepression of transcarbamoylase activity while pyrimidine limitation of glucose-grown mutant cells caused a derepression of the four active pyrimidine biosynthetic enzyme activities relative to their activities in the mutant cells grown with excess uracil. The control of the known regulatory enzyme aspartate transcarbamoylase was examined in P. aureofaciens ATCC 17418. Transcarbamoylase activity was shown to be inhibited by pyrophosphate, ATP, UTP, and ADP. It was concluded that the pyrimidine biosynthetic pathway in P. aureofaciens ATCC 17418 was subject to regulation at the transcriptional level and at the level of aspartate transcarbamoylase activity, which could be valuable in comprehending its nucleic acid metabolism as well as its taxonomic assignment to the Pseudomonas chlororaphis homology group.
- MeSH
- Aspartate Carbamoyltransferase metabolism MeSH
- Bacterial Proteins metabolism genetics MeSH
- Biosynthetic Pathways MeSH
- Dihydroorotate Dehydrogenase MeSH
- Glucose metabolism MeSH
- Succinic Acid metabolism MeSH
- Orotic Acid metabolism MeSH
- Orotate Phosphoribosyltransferase metabolism MeSH
- Orotidine-5'-Phosphate Decarboxylase metabolism genetics MeSH
- Oxidoreductases Acting on CH-CH Group Donors metabolism MeSH
- Pseudomonas * metabolism genetics enzymology MeSH
- Pyrimidines * biosynthesis MeSH
- Gene Expression Regulation, Bacterial * MeSH
- Uracil metabolism MeSH
- Publication type
- Journal Article MeSH
AIMS: Retinoids participate in multiple key processes in the human body e.g., vision, cell differentiation and embryonic development. There is growing evidence of the relationship between retinol, its active metabolite- all-trans retinoic acid (ATRA) - and several pancreatic disorders. Although low levels of ATRA in pancreatic ductal adenocarcinoma (PDAC) tissue have been reported, data on serum levels of ATRA in PDAC is still limited. The aim of our work was to determine serum concentrations of retinol and ATRA in patients with PDAC, type-2 diabetes mellitus (T2DM), chronic pancreatitis (CHP) and healthy controls. METHODS: High performance liquid chromatography with UV detection (HPLC) was used to measure serum levels of retinol and ATRA in 246 patients with different stages of PDAC, T2DM, CHP and healthy controls. RESULTS: We found a significant decrease in the retinol concentration in PDAC (0.44+/-0.18 mg/L) compared to T2DM (0.65+/-0.19 mg/L, P<0.001), CHP (0.60+/-0.18 mg/L, P< 0.001) and healthy controls (0.61+/-0.15 mg/L, P<0.001), significant decrease of ATRA levels in PDAC (1.14+/-0.49 ug/L) compared to T2DM (1.37+/-0.56 ug/L, P<0.001) and healthy controls(1.43+/-0.55 ug/L, P<0.001). Differences between early stages (I+II) of PDAC and non-carcinoma groups were not significant. We describe correlations between retinol, prealbumin and transferrin, and correlation of ATRA and IGFBP-2. CONCLUSION: Significant decrease in retinol and ATRA levels in PDAC compared to T2DM, healthy individuals and/or CHP supports existing evidence of the role of retinoids in PDAC. However, neither ATRA nor retinol are suitable for detection of early PDAC. Correlation of ATRA levels and IGFBP-2 provides new information about a possible IGF and retinol relationship.
- MeSH
- Pancreatitis, Chronic * metabolism blood MeSH
- Diabetes Mellitus, Type 2 * metabolism MeSH
- Adult MeSH
- Carcinoma, Pancreatic Ductal metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Pancreatic Neoplasms * metabolism blood MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Tretinoin * metabolism blood MeSH
- Vitamin A * blood metabolism MeSH
- Chromatography, High Pressure Liquid MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
The spectrum averaged cross sections (SACS) in standard neutron field, e.g. 252Cf(s.f.), is a preferable tool for cross section evaluation and validation. A set of reaction measurements with high energy thresholds was previously performed. The presented work focuses on lower energy threshold reactions, namely on the inelastic scattering of the tin foil, more specifically the reaction 117Sn(n,n')117mSn, and the zinc foil reaction, namely 67Zn(n,p)67Cu. These reactions are of special interest due to their intermediate energy range, which is essential in classical reactor dosimetry and fast reactor dosimetry. The experiments were carried out in a standard neutron field formed by 252Cf(s.f.) source in Řež. The experimental results were compared with calculations using MCNP6.2, ENDF/B-VII.1 transport library, and ENDF/B-VIII.0 and IRDFF-II cross section data library. Additionally, the calculations using CEA code DARWIN/PEPIN2 using JEFF-3.0/A were executed. The obtained experimental SACS of previously measured reactions were in good agreement with the SACS calculated using the IRDFF-II library. Additionally, the calculational reaction rate of 67Zn(n,p)67Cu was in accordance with the experimental data in case of ENDF/B-VIII.0 nuclear data library. Moreover, the calculational results of 117Sn(n,n')117mSn obtained by DARWIN/PEPIN2 code (using JEFF-3.0/A nuclear data library) are closest to the experimental results.
- Publication type
- Journal Article MeSH
This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.
- MeSH
- Acetylcysteine analogs & derivatives MeSH
- Aldosterone MeSH
- Aminobutyrates * MeSH
- Biphenyl Compounds pharmacology MeSH
- Fibrosis MeSH
- Drug Combinations MeSH
- Hypertension * drug therapy MeSH
- Hypertrophy, Left Ventricular MeSH
- Rats MeSH
- Rats, Wistar MeSH
- Prehypertension * MeSH
- Renin-Angiotensin System MeSH
- Renin MeSH
- Heart Failure * MeSH
- Stroke Volume MeSH
- Tetrazoles pharmacology therapeutic use MeSH
- Valsartan pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Tick saliva injected into the vertebrate host contains bioactive anti-proteolytic proteins from the cystatin family; however, the molecular basis of their unusual biochemical and physiological properties, distinct from those of host homologs, is unknown. Here, we present Ricistatin, a novel secreted cystatin identified in the salivary gland transcriptome of Ixodes ricinus ticks. Recombinant Ricistatin inhibited host-derived cysteine cathepsins and preferentially targeted endopeptidases, while having only limited impact on proteolysis driven by exopeptidases. Determination of the crystal structure of Ricistatin in complex with a cysteine cathepsin together with characterization of structural determinants in the Ricistatin binding site explained its restricted specificity. Furthermore, Ricistatin was potently immunosuppressive and anti-inflammatory, reducing levels of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α and nitric oxide in macrophages; IL-2 and IL-9 levels in Th9 cells; and OVA antigen-induced CD4+ T cell proliferation and neutrophil migration. This work highlights the immunotherapeutic potential of Ricistatin and, for the first time, provides structural insights into the unique narrow selectivity of tick salivary cystatins determining their bioactivity.
- MeSH
- Cystatins * pharmacology MeSH
- Cysteine metabolism MeSH
- Endopeptidases metabolism MeSH
- Cathepsins metabolism MeSH
- Ixodes * chemistry MeSH
- Vertebrates MeSH
- Peptide Hydrolases metabolism MeSH
- Salivary Cystatins chemistry MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
Článok prezentuje výsledky štúdie hypoglykemických vlastností medzi 1,2,4-triazolovými derivátmi syntetizovanými na Katedre fyzikálnej a koloidnej chémie Štátnej lekárskej univerzity v Zaporizhzhia. V súčasnosti má veľké množstvo ľudí sedavý spôsob života, aj väčšina ich stravy obsahuje často používané produkty, ktoré zvyšujú hladinu glukózy v krvi, čo môže vyvolať rozvoj závažných ochorení. Preto do dnešného dňa zostáva vytvorenie liekov, ktoré vykazujú hypoglykemickú aktivitu a majú nízku úroveň toxicity, naliehavou úlohou pre lekárne. V prvej fáze nášho výskumu bola vykonaná predpoveď akútnej toxicity. Hypoglykemická aktivita syntetizovaných zlúčenín bola hodnotená vykonaním intraperitoneálneho glukózového tolerančného testu (IPGTT) so zmenou koncentrácie glukózy v krvi zvieraťa po jeho jednorazovom intraperitoneálnom podaní vo forme 40 % roztoku v dávke 2 g/kg telesnej hmotnosti potkana. Zlúčeniny (38) rôznych tried boli študované na hypoglykemickú aktivitu. 2-{5-[(3,4-dimetoxyfenyl)-3H-1,2,4-triazol-3-yl]sulfanyl}acetát zinočnatý (3.18) vykazoval najvyššiu účinnosť z hľadiska schopnosti znižovať krv hladiny glukózy, a to o 27,3 % (približne 1,3-krát).
This article presents the study results of the hypoglycemic properties among 1,2,4-triazole derivatives synthesized at the Department of Physical and Colloidal Chemistry of the Zaporizhzhia State Medical University. Today, many people have a sedentary way of life, also most of their diet contains products that they frequently use, which increase the level of glucose in the blood, which can provoke the development of serious diseases. Therefore, to date, the creation of drugs that exhibit hypoglycemic activity and have a low level of toxicity remains an urgent task for medicine and pharmacy. In the first stage of our research, acute toxicity prediction was performed. The hypoglycemic activity of the synthesized compounds was assessed by performing an intraperitoneal glucose tolerance test (IPGTT) with a change in the blood glucose concentration of the animal after its single intraperitoneal administration in the form of a 40% solution at a dose of 2 g/kg of rat body weight. Thirty-eight compounds of the different classes were studied for hypoglycemic activity. Zinc (II) 2-{5-[(3,4-methoxyphenyl)-3H-1,2,4-triazole-3-yl]thio} acetate (3.18) showed the highest efficiency in terms of the ability to lower blood glucose levels, namely, by 27.3% (approximately 1.3 times).
Background: Overconsumption of fructose may cause metabolic syndrome (MetS). MetS pathogenesis is caused by oxidative stress, cellular malfunction, and systemic inflammation caused by hereditary and environmental factors. N-acetylcysteine (NAC) has become associated with the phrase "antioxidant." Most researchers use and test NAC with the goal of preventing or reducing oxidative stress.Aim: To determine the positive effects of NAC on blood glucose, lipid profile, and body weight in fructose-induced metabolic syndrome in albino rats.Materials and Methods: Forty male albino rats, 10-12 weeks old, were haphazardly divided into five groups of identical size. Group I (negative control) received tap water for 12 weeks. Group II (positive control) received a 60% w/w fructose solution (60% FS) instead of tap water for 12 weeks. Group III (NAC) received tap water and an intra-peritoneal (IP) injection of NAC (150 mg/kg/day) for 12 weeks. Group IV (protection) co-administered 60% FS orally and NAC IP injection (150 mg/kg/day) for 12 weeks. Group V (treatment) received 60% FS for 8 weeks followed by 4 weeks of drinking tap water with NAC IP injection (150 mg/kg/day). Blood samples were taken at weeks 0, 8, and 12 and were tested for serum glucose and lipid profile. All animals of each group were weighted at weeks 0, 8 and 12 of the study.Results: Concerning serum glucose, group II showed increased glycaemia at week 8 and further elevation during week 12. Group III displayed normal glycaemia at weeks 8 and 12. In group IV, glycaemia showed elevation at week 8 followed by almost complete restoration at week 12. In group V, there was an increased glycaemia at week 8 followed by a partial restoration at week 12. Regarding lipid profile parameters, group II demonstrated a deterioration during week 8 and more worsening during week 12. There were no significant changes in group III's parameters during weeks 8 and 12. Group IV displayed a worsening in lipid profile during week 8 followed by a nearly complete improvement during week 12. During week 8, group V deteriorated, followed by a partial recovery during week 12. Concerning body weight, group II showed a weight gain at week 8 and further elevation during week 12. Group III displayed normal glycaemia at weeks 8 and 12. In group IV, glycaemia showed elevation at week 8 followed by almost complete restoration at week 12. In group V, there was an increased glycaemia at week 8 followed by a partial restoration at week 12. At week 8, there was a significant elevation in body weights in groups II and V compared to group I. Moreover, a significant reduction in body weight was recorded in group IV compared to group II during week 8. At week 12, a significant elevation in body weight was noticed in groups II and V compared to group I. Moreover, there was a significant reduction in body weight in group III compared to group I. On the other hand, there was a significant fall in body weight in groups IV and V compared to group II during week 12.Conclusion: MetS was caused by a high-fructose diet, which has been shown to have a negative impact on serum glucose, lipid profiles, and body weight. Moreover, NAC has been shown to enhance these parameters in a time-dependent manner.
- MeSH
- Acetylcysteine * administration & dosage pharmacology MeSH
- Fructose administration & dosage adverse effects MeSH
- Blood Glucose drug effects MeSH
- Rats MeSH
- Metabolic Syndrome * chemically induced drug therapy blood MeSH
- Disease Models, Animal MeSH
- Body Weight drug effects MeSH
- Treatment Outcome MeSH
- Check Tag
- Rats MeSH
- Male MeSH
Cysteine is one of the least abundant but most conserved amino acid residues in proteins, playing a role in their structure, metal binding, catalysis, and redox chemistry. Thiols present in cysteines can be modified by post-translational modifications like sulfenylation, acylation, or glutathionylation, regulating protein activity and function and serving as signals. Their modification depends on their position in the structure, surrounding amino acids, solvent accessibility, pH, etc. The most studied modifications are the redox modifications by reactive oxygen, nitrogen, and sulfur species, leading to reversible changes that serve as cell signals or irreversible changes indicating oxidative stress and cell damage. Selected antioxidants undergoing reversible oxidative modifications like peroxiredoxin-thioredoxin system are involved in a redox-relay signaling that can propagate to target proteins. Cysteine thiols can also be modified by acyl moieties' addition (derived from lipid metabolism), resulting in protein functional modification or changes in protein anchoring in the membrane. In this review, we update the current knowledge on cysteine modifications and their consequences in pancreatic β-cells. Because β-cells exhibit well-balanced redox homeostasis, the redox modifications of cysteines here serve primarily for signaling purposes. Similarly, lipid metabolism provides regulatory intermediates that have been shown to be necessary in addition to redox modifications for proper β-cell function and, in particular, for efficient insulin secretion. On the contrary, the excess of reactive oxygen, nitrogen, and sulfur species and the imbalance of lipids under pathological conditions cause irreversible changes and contribute to oxidative stress leading to cell failure and the development of type 2 diabetes.
