Switchable silver-ion complexation by triazolated calix[4]semitubes.

Triazolated calix[4]semitubes comprising several binding sites were studied for complexation of Ag+ to get insight into the ability of the multitopic semi-tubular environment to host cation(s) in a structure-specific/switchable manner. For this purpose, a series of triazolated calix[4]semitubes having two or three 1,3-alternate calix[4]arene cores and crown-5-ether loops in the structures were prepared using the recently developed stepwise synthesis approach. Crown-5-ether loops were used as model receptor units which could be filled with K+ to charge positively either a specific 'end' or both 'ends' of the semi-tubular assemblies and to affect the complexation abilities of the internal binding sites of triazolated calix[4]semitubes. Comparative analysis of complexation-induced broadening in the 1H NMR spectra of three isomeric tris(calixarenes) having different mutual arrangements of the internal binding sites upon addition of Ag+ suggested intramolecular rather than intermolecular migrations of the bound cation between two bistriazole units. The study on Ag+/K+ complexation by the crowned biscalixarene semitubes revealed strong dependence of the ditopic complexation mode on the mutual arrangement of the triazole and crownether sites within the molecule, which managed either the heterodinuclear Ag+/K+ binding, or switching between two single-nuclear complexes. In crowned triscalixarene semitubular systems, the same structure/complexation mode correlation was observed, but in this case, binding of K+ by an appropriately arranged crownether loop did not destroy the initial silver complex, but stopped the above migrations of Ag+ between the internal sites of heteromultitopic ligands, thus indicating the applicability of the triscalixarene semitubular core for the design of multipositioned molecular switches.

The role of adrenergic and muscarinic receptors in stress-induced cardiac injury.

Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that fully mimics TS. It has now been documented that stress exposure (24 h) of rats induced the state which is similar TS in human: contracture damage of myofibrils, elevation of the serum creatine kinase MB level, increased 99mTc-pyrophosphate (99mTc-PYP) accumulation in the heart, QTc interval prolongation, and contractility dysfunction of the heart. Immobilization stress resulted in an increase in coronary blood flow. Emotional stress increased the serum catecholamine level. Blockade of ß1-adrenergic receptor (AR) prevented stress-induced cardiac injury (SICI). Blockade of ß2-AR aggravated stress-induced cardiac injury. Stimulation of ß2-AR increased cardiac tolerance to stress. Inhibition of ß3-AR, α1-AR had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravated SICI. Pretreatment with the selective ß1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction, but recovery of cardiac contractility is not complete. There is indirect evidence that circulating catecholamines play an important role in SICI. Consequently, the activation of ß1-AR plays a significant role in SICI. However, there are other receptors which are also involved in SICI and require further investigation.

Chiral Heteroditopic Baskets Designed from Triazolated Calixarenes and Short Peptides.

Cone calix[4]arenes and calix[6]arenes bearing two, three, and four short peptide units each having two chiral carbon atoms were prepared. The syntheses were performed by using an efficient modular approach that includes the Ugi preparation of the azido-peptide followed by its reactions with the propargylated calixarenes under CuAAC (Cu(I) -catalyzed azide-alkyne cycloaddition) conditions. The three novel multitopic hosts were probed for their ability to bind metal ions by UV titration, and showed the highest complexation efficiency towards copper(II) and lead(II). These two cations possessed quite different complexation modes with copper(II) bound predominantly by multiple-triazole sites, in contrast to lead(II), which is stabilized mainly by multiple interactions with amide groups of the peptide units. Circular dichroism data for the free chiral hosts, their equimolar mixtures with copper(II) perchlorate and lead(II) perchlorate, and for tertiary mixtures of all three compounds showed the formation of mono- and binuclear complexes, or a switching behavior, depending on the structure of the host and the addition order of the cations.

Copper(I)-Catalyzed Cycloaddition of Azides to Multiple Alkynes: A Selectivity Study Using a Calixarene Framework.

Copper(I)-catalyzed addition of limited amounts of azides to multiple alkynes, which led to statistical mixtures of triazole/acetylene derivatives or, in other cases, resulted in preferred formation of multiple triazoles, was studied at pre-organizable calixarene platforms bearing up to four propargyl groups. Depending on calixarene structures and reaction conditions, the unprecedented specific or selective formation of exhaustively triazolated calixarenes or a complete loss of the selectivity were observed. Both autocatalytic copper activation and a local copper(I) concentration increase due to copper-triazole complexation were thoroughly studied as the most expected reasons for the selectivity and both were disproved. Mixed triazolated/propargylated calixarenes and their copper(I) complexes proved not to be involved in the cascade-like process that was modeled to be driven by an intramolecular transfer of two copper(I) ions from a just-formed binuclear copper intermediate to the adjacent acetylene unit.

Preserved cardiac mitochondrial function and reduced ischaemia/reperfusion injury afforded by chronic continuous hypoxia: role of opioid receptors.

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to acute ischaemia/reperfusion injury. The objective of this study was to find out whether the cardioprotective effect of CNH mediated by opioid receptors is associated with preservation of mitochondrial function. Rats were adapted to CNH (12% oxygen) for 3 weeks. Isolated perfused hearts were subjected to 45 min of global ischaemia and 30 min of reperfusion; subgroups were pretreated with non-selective opioid receptor antagonist naloxone (300 nmol/L) for 10 min. Cardiac contractile function, creatine kinase activity in coronary effluent, mitochondrial respiration rate, and calcium retention capacity were assessed. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the post-ischaemic recovery of contractile function, mitochondrial state 3 and uncoupled respiration rates, and calcium retention capacity compared to the normoxic group. These protective effects were completely abolished by naloxone. The contractile recovery positively correlated with state 3 respiration and calcium retention capacity. The results suggest that the preserved mitochondrial function contributes to the protected cardiac phenotype afforded by adaptation to CNH and point to an important role of opioid receptor activation.

Synthesis and crystal structures of 5,17-di-bromo-26,28-dihy-droxy-25,27-dipropynyloxycalix[4]arene, 5,17-di-bromo-26,28-dipropoxy-25,27-dipropynyloxycalix[4]arene and 25,27-bis-(2-azido-eth-oxy)-5,17-di-bromo-26,28-di-hydroxy-calix[4]arene.

The calixarenes, 5,17-di-bromo-26,28-dihy-droxy-25,27-dipropynyloxycalix[4]arene (C34H26Br2O4, 1), 5,17-di-bromo-26,28-dipropoxy-25,27-dipropynyloxycalix[4]arene (C40H38Br2O4, 2) and 25,27-bis-(2-azido-eth-oxy)-5,17-di-bromo-26,28-di-hydroxy-calix[4]arene (C32H28Br2N6O4, 3) possess a pinched cone mol-ecular shape for 1 and 3, and a 1,3-alternate shape for compound 2. In calixarenes 1 and 3, the cone conformations are additionally stabilized by intra-molecular O-H⋯O hydrogen bonds, while in calixarene 2 intra-molecular Br⋯Br inter-actions consolidate the 1,3-alternate mol-ecular conformation. The dense crystal packing of the cone dialkyne 1 is a consequence of π-π, C-H⋯π and C-H⋯O inter-actions. In the crystal of the diazide 3, there are large channels extending parallel to the c axis, which are filled by highly disordered CH2Cl2 solvent mol-ecules. Their contribution to the intensity data was removed by the SQUEEZE procedure that showed an accessible void volume of 585 Å3 where there is room for 4.5 CH2Cl2 solvent mol-ecules per unit cell. Rigid mol-ecules of the 1,3-alternate calixarene 2 form a columnar head-to-tail packing parallel to [010] via van der Waals inter-actions, and the resulting columns are held together by weak C-H⋯π contacts.

Chemical composition of the White Sea sponge Halichondriа panicea.

The extract of the White Sea sponge Halichondria panicea (Pallas, 1766) exhibits cytotoxic and cytostatic effects. The main part of the extract consists of hydrophilic low molecular weight compounds: free amino acids (13.9%), glucose (19.9%), polyatomic alcohols (glycerin and others) (6.1%), carboxylic acids (0.7%) and nitrogenous heterocycles (1.2%). Of the substances specific to the metabolome, bicyclic diketopiperazines (four derivatives), pyroglutamic acid, phenylacetic acid, and two steroids (3ß,5α)cholest-7-en-3-ol and dihydrocholesterol were identified. Toxicants characteristic of the genus Halichondria were not found in the White Sea sponge.

Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart-The signaling mechanism.

BACKGROUND: The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1-7 has some promise in this regard. OBJECTIVE: The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1-7. METHODS: PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. RESULTS: Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1-7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1-7. Angiotensin 1-7 alleviates Ca2+ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1-7-triggered cardiac tolerance to I/R. Furthermore, angiotensin 1-7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1-7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1-7 possesses anti-inflammatory properties, possibly achieved through NF-kB activity inhibition. Phosphoinositide 3-kinase, Akt, and NO synthase are involved in the infarct-reducing effect of angiotensin 1-7. However, the specific end-effector of the cardioprotective impact of angiotensin 1-7 remains unknown. CONCLUSION: The molecular nature of the end-effector of the infarct-limiting effect of angiotensin 1-7 has not been elucidated. Perhaps, this end-effector is the sarcolemmal KATP channel or the mitochondrial KATP channel.

Effects of Different Therapeutic Approaches on Redox Balance in Psoriatic Patients.

Given that oxidative stress represents an important etiological factor in the pathogenesis of psoriasis, the aim of this study was to assess the effects of different therapeutic approaches, methotrexate, secukinumab, and ustekinumab on systemic oxidative stress biomarkers in psoriatic patients. This study involved 78 psoriatic patients, divided into the group treated with methotrexate (23 patients), secukinumab (28 patients), and ustekinumab (27 patients), and 15 healthy controls. Oxidative stress biomarkers (index of lipid peroxidation measured as TBARS, nitrites (NO2-), superoxide anion radical (O2-), and hydrogen peroxide (H2O2)) and antioxidative defense system (superoxide dismutase (SOD) activity, catalase (CAT) activity, and reduced glutathione (GSH)) were determined spectrophotometrically from the blood before the initiation of therapy in 16th, 28th, and 52nd week. O2- and SOD showed the most prominent changes comparing the psoriatic patients and healthy controls. CAT activity was significantly lower in psoriatic patients, and methotrexate induced a further decline in CAT activity. Ustekinumab induced a significant increase in GSH level after 52 weeks of treatment, while methotrexate reduced GSH. All applied therapeutic options induced a reduction in PASI, BSA, DLQI, and EARP. Biological drugs exert more pronounced antioxidant effects compared to methotrexate, which is most clearly observed in the values of O2- and SOD.

δ-Opioid Receptor as a Molecular Target for Increasing Cardiac Resistance to Reperfusion in Drug Development.

An analysis of published data and the results of our own studies reveal that the activation of a peripheral δ2-opioid receptor (δ2-OR) increases the cardiac tolerance to reperfusion. It has been found that this δ2-OR is localized in cardiomyocytes. Endogenous opioids are not involved in the regulation of cardiac resistance to reperfusion. The infarct-limiting effect of the δ2-OR agonist deltorphin II depends on the activation of several protein kinases, including PKCδ, ERK1/2, PI3K, and PKG. Hypothetical end-effectors of the cardioprotective effect of deltorphin II are the sarcolemmal KATP channels and the MPT pore.

Effects of Isoflavone-Rich NADES Extract of Pueraria lobata Roots and Astaxanthin-Rich Phaffia rhodozyma Extract on Prostate Carcinogenesis in Rats.

Prostate cancer (PCa) is one of the most common male malignancies worldwide. In the current study, we evaluated the effects of a natural deep eutectic solvent (NADES) extract of Pueraria lobata roots rich in isoflavones (ISF) and Phaffia rhodozyma extract rich in astaxanthin (ASX) on an N-methyl-N-nitrosourea plus testosterone PCa model in rats. ISF consisted of puerarin, daidzein, genistein, formononetin and other polyphenols, while ASX contained lipids and unsaturated species in addition to astaxanthin. Extracts were administered through a whole promotion period in daily doses shown by our group to successfully inhibit benign prostate hyperplasia (BPH) development - 200 mg/kg for ISF and 25 mg/kg for ASX. Though a similar effect was found for BPH processes accompanying PCa induction, the incidence of PCa in animals treated with placebo, ISF and ASX was 37%, 37% and 41%, respectively, showing no chemopreventive activity of ISF and ASX. PCa development was associated with a decrease in the Ca/Mg ratio in serum and an increase in prostate tissue. Treatment with both extracts produced a normalization effect on Ca balance in serum, which, combined with a decrease in the prostatic index, suggests some positive health effects of ISF and ASX.

Production of Reactive Oxygen Species by Epicardial Adipocytes Is Associated with an Increase in Postprandial Glycemia, Postprandial Insulin, and a Decrease in Serum Adiponectin in Patients with Severe Coronary Atherosclerosis.

Purpose. This work investigates the relations between the production of reactive oxygen species (ROS) by epicardial adipose tissue (EAT) adipocytes and parameters of glucose/insulin metabolism, circulating adipokines levels, and severity of coronary atherosclerosis in patients with coronary artery disease (CAD); establishing significant determinants describing changes in ROS EAT in this category of patients. Material and methods. This study included 19 patients (14 men and 5 women, 53−72 y.o., 6 patients with diabetes mellitus type 2; 5 patients with prediabetes), with CAD, who underwent coronary artery bypass graft surgery. EAT adipocytes were isolated by the enzymatic method from intraoperative explants obtained during coronary artery bypass grafting. The size of EAT adipocytes and ROS level were determined. Results. The production of ROS by EAT adipocytes demonstrated a direct correlation with the level of postprandial glycemia (rs = 0.62, p < 0.05), and an inverse correlation with serum adiponectin (rs = −0.50, p = 0.026), but not with general and abdominal obesity, EAT thickness, and dyslipidemia. Regression analysis demonstrated that the increase in ROS of EAT adipocytes occurs due to the interaction of the following factors: postprandial glycemia (ß = 0.95), postprandial insulin (ß = 0.24), and reduced serum adiponectin (ß = −0.20). EAT adipocytes in patients with diabetes and prediabetes manifested higher ROS production than in patients with normoglycemia. Although there was no correlation between the production of ROS by EAT adipocytes and Gensini score in the total group of patients, higher rates of oxidative stress were observed in EAT adipocytes from patients with a Gensini score greater than median Gensini score values (≥70.55 points, Gr.B), compared to patients with less severe coronary atherosclerosis (<70.55 points, Gr.A). Of note, the frequency of patients with diabetes and prediabetes was higher among the patients with the most severe coronary atherosclerosis (Gr.B) than in the Gr.A. Conclusions. Our data have demonstrated for the first time that systemic impairments of glucose/insulin metabolism and a decrease in serum adiponectin are significant independent determinants of oxidative stress intensity in EAT adipocytes in patients with severe coronary atherosclerosis. The possible input of the interplay between oxidative stress in EAT adipocytes and metabolic disturbances to the severity of coronary atherosclerosis requires further investigation.

Evaluation of Age-Dependent Changes in the Coloration of Male Killifish Nothobranchius Guentheri Using New Photoprocessing Methods.

Fish as model objects have found wide applications in biology and fundamental medicine and allow studies of behavioral and physiological responses to various environmental factors. Representatives of the genus Nothobranchius are one of the most convenient objects for such studies. Male fish belonging to the family Nothobranchiidae are characterized by extremely diverse coloration, which constantly changes, depending on the age of the fish, environmental factors, and social hierarchical status. These fish species are characterized by a short life cycle, which allows changes in coloration, an indicator of the ontogenesis stage, to be estimated. Existing methods of fish color assessments do not allow the intensity of coloration of particular body zones to be clearly differentiated. In the present study, we suggest a method of two-factor assessment of specific fish body zones using modified methods of photofixation and image processing software. We describe the protocol of the method and the results of its application to different-aged groups of male Nothobranchius guentheri. The coloration of selected areas (i.e., red spot on the gill cover (RSGC), black border on the caudal fin (BBCF), and white border on the dorsal fin (WBDF)) differed significantly according to the size and age of the fish (p < 0.05). The data obtained suggest that N. guentheri can be a model for studying aging by the intensity of body coloration in males.

Inherently dinuclear iridium(III) meso architectures accessed by cyclometalation of calix[4]arene-based bis(aryltriazoles).

Conventional cyclometalation of calix[4]arene bis(aryltriazoles) with iridium(III) chloride hydrate leads to unique meso architectures in which the Ir2Cl2 core is cross-bound by two (C^N)2 ligands, which allows further replacement of the chloride bridges with ancillary ligands while maintaining the dinuclear structures of the complexes having independent or coupled iridium pairs.

High carbohydrate high fat diet causes arterial hypertension and histological changes in the aortic wall in aged rats: The involvement of connective tissue growth factors and fibronectin.

BACKGROUND: Age and diabetes are risk factors for arterial hypertension. However, the relationship between age, connective tissue growth factors, vascular aging and arterial hypertension while on a the high-carbohydrate high-fat diet (HCHFD) remains poorly understood. PURPOSE: To estimate the relationship between humoral factors, the morphological changes of aorta and impaired blood pressure regulation under the influence of age and a HCHFD. METHODS: A study was carried out in male Wistar rats, which were divided into the following groups: 1st (n = 15) - naive young rats; 2nd (n = 15) - young rats, exposed to HCHFD; 3rd (n = 14) - naive old rats; 4th (n = 12) - old rats exposed to HCHFD. The age of old rats was 540 days, and young rats 150 days at the end of the diet. HCHFD contained proteins 16%, fats 21%, carbohydrates 46%, including 17% fructose, 0.125% cholesterol, 90 days. Blood pressure and body weight were measured weekly, carbohydrate metabolism, histological signs of changes in the aorta, serum transforming growth factor-ß (TGF-ß), connective tissue growth factor (CTGF), fibronectin, and endothelin-1 levels were determined one week after the onset of diet. RESULTS: The severity of arterial hypertension and its histological signs in the aortic wall was found to be most pronounced in elderly rats kept on a HCHFD. In young rats kept on a HCHFD, arterial hypertension was transient. An increase in systolic blood pressure has a positive correlation with the degree of obesity, serum fibronectin, and endothelin-1 content, and impaired carbohydrate metabolism. The rise in diastolic blood pressure has a positive correlation with the serum CTGF, endothelin-1, fibronectin levels and aortic wall thickness, and impaired carbohydrate metabolism. A rise in the serum concentration of fibronectin was also associated with increased endothelin-1, TGFß and CTGF serum levels. CONCLUSION: This study indicated that an increase in blood pressure in old rats with a high-carbohydrate high-fat diet is due to a disturbance of a structure of the vascular wall, the release of fibronectin, which can occur under the influence of carbohydrate metabolism disorders, endothelin-1, TGFß and CTGF.

A route to virtually unlimited functionalization of water-soluble p-sulfonatocalix[4]arenes.

The functionality of p-sulfonatocalix[4]arenes can be easily extended using the propargylation/CuAAC reaction sequence, which allows the introduction of up to four substituted triazole units to the narrow rims of the macrocycles while maintaining their cone shapes and water solubility and, thus, biomedical applicability.

A Review of Humoral Factors in Remote Preconditioning of the Heart.

A humoral mechanism of cardioprotection by remote ischemic preconditioning (RIP) has been clearly demonstrated in various models of ischemia-reperfusion including upper and lower extremities, liver, and the mesenteric and renal arteries. A wide range of humoral factors for RIP have been proposed including hydrophobic peptides, opioid peptides, adenosine, prostanoids, endovanilloids, endocannabinoids, calcitonin gene-related peptide, leukotrienes, noradrenaline, adrenomedullin, erythropoietin, apolipoprotein, A-I glucagon-like peptide-1, interleukin 10, stromal cell-derived factor 1, and microRNAs. Virtually, all of the components of ischemic preconditioning's signaling pathway such as nitric oxide synthase, protein kinase C, redox signaling, PI3-kinase/Akt, glycogen synthase kinase ß, ERK1/2, mitoKATP channels, Connexin 43, and STAT were all found to play a role. The signaling pattern also depends on which remote vascular bed was subjected to ischemia and on the time between applying the rip and myocardial ischemia occurs. Because there is convincing evidence for many seemingly diverse humoral components in RIP, the most likely explanation is that the overall mechanism is complex like that seen in ischemic preconditioning where multiple components are both in series and in parallel and interact with each other. Inhibition of any single component in the right circumstance may block the resulting protective effect, and selectively activating that component may trigger the protection. Identifying the humoral factors responsible for RIP might be useful in developing drugs that confer RIP's protection in a more comfortable and reliable manner.