Synthesis, Docking and Biological Activities of Novel Hybrids Celecoxib and Anthraquinone Analogs as Potent Cytotoxic Agents

Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src)

Intrauterine diabetic milieu instigates dysregulated adipocytokines production in F1 offspring

Abstract Background Intrauterine environment plays a pivotal role in the origin of fatal diseases such as the metabolic syndrome. Diabetes is associated with low-grade inflammatory state and dysregulated adipokines production. The aim of this study is to investigate the effect of maternal diabetes on adipocytokines (adiponectin, leptin and TNF-\u3b1) production in F1 offspring in rats. Methods The offspring groups were as follows: F1 offspring of control mothers under control diet (CD) ( CF1-CD ), F1 offspring of control mothers under high caloric diet (HCD) ( CF1-HCD ), F1 offspring of diabetic mothers under CD ( DF1-CD ), and F1 offspring of diabetic mothers under HCD ( DF1-HCD ). Every 5\ua0weeks post-natal, 10 pups of each subgroup were culled to obtain blood samples for biochemical analysis. Results The results indicate that DF1-CD and DF1-HCD groups exhibited hyperinsulinemia, dyslipidemia, insulin resistance and impaired glucose homeostasis compared to CF1-CD ( p\u2009>\u20090.05 ). DF1-CD and DF1-HCD groups had high hepatic and muscular depositions of TGs. The significant elevated NEFA level only appeared in offspring of diabetic mothers that was fed HCD. DF1-CD and DF1-HCD groups demonstrated low serum levels of adiponectin, high levels of leptin, and elevated levels of TNF-\u3b1 compared to CF1-CD ( p\u2009>\u20090.05 ). These results reveal the disturbed metabolic lipid profile of offspring of diabetic mothers and could guide further characterization of the mechanisms involved. Conclusion Dysregulated adipocytokines production could be a possible mechanism for the transgenerational transmittance of diabetes, especially following a postnatal diabetogenic environment. Moreover, the exacerbating effects of postnatal HCD on NEFA in rats might be prone to adipcytokine dysregulation. Furthermore, dysregulation of serum adipokines is a prevalent consequence of maternal diabetes and could guide further investigations to predict the development of metabolic disturbances

Maternal diabetes impairs oxidative and inflammatory response in murine placenta

Placenta is the major exchange surface between mother and fetus and plays a pivotal role in fetal development. A better understanding of the mechanisms by which diabetes alters placental function may allow better management of diabetes pregnancies. In this study, we attempt to investigate the effect of diabetic milieu with and without malformation on placental function. In order to investigate the impact of diabetic pregnancy on oxidative stress, endothelial and vascular functions of placental tissue, we mated diabetic and non-diabetic female rats with normal male rats. At gestational day 17, we terminated pregnancy, assessed fetuses for malformations and isolated placenta for measurement of various parameters of placental function. Our results show that maternal diabetes induced a state of oxidative stress in placenta, which disrupts normal signaling, activating apoptosis, as well as perturbing endothelial and vascular placental functions. The coalescence of these insults on various levels of placental function could contribute to the pleiotropic nature of diabetes-induced placental stress

The effect of histidine-tryptophan-ketoglutarate cardioplegia alone or combined with preoperative infusion of levosimendan on vasoactive inotropic score in patients with poor cardiac function undergoing coronary artery bypass grafting

Background: Patients with poor left ventricular function undergoing cardiac surgery frequently require inotropic drug support immediately after cardiopulmonary bypass. Levosimendan is an effective agent that acts via two complementary mechanisms. It enhances cardiac contractility and reduces cardiac workload. Aim: to assess the effect of histidine-tryptophan-ketoglutarate cardioplegia (HTK cardioplegia) alone or combined with preoperative infusion of levosimendan on the vasoactive inotropic score in patients with poor left ventricular function undergoing coronary artery bypass grafting. Material and method: this double-blinded randomized controlled trial was carried on 100 patients, divided into two groups; Levosimendan group (n = 49): patients received 0.1ug/kg/min levosimendan without loading, 12 hours preoperatively and continued for a total of 24 hours. Control group (n = 51): patients received a placebo 12 hours before surgery and continued for a total 24 hours. Both groups received HTK cardioplegia after cross-clamping of the aorta approximately 20 ml/kg into the ascending aorta over 6–8 minutes at a temperature of 4−10°C. Results: Levosimendan group was superior to control group with statistical significance regarding the need of intraaortic balloon pump (IABP), vasoactive inotropic score over the first 24 hours, troponin levels over the first 72 hours, ICU stays, hospital stay, and cumulative hospital costs. Although the incidence of postoperative low Cardiac output syndrome (LCOS), atrial fibrillation (AF), acute kidney injury (AKI), and overall mortality was lower in levosimendan group, but all were not statistically significant. Conclusion: Preoperative infusion of levosimendan combined with HTK cardioplegia in patients with poor cardiac function decreased vasoactive inotropic score and lowered the costs of hospital stay.</p

Synthesis, Molecular Docking and Preliminary in-Vitro Cytotoxic Evaluation of Some Substituted Tetrahydro-naphthalene (2&#039;,3&#039;,4&#039;,6&#039;-Tetra-O-Acetyl-β-D-Gluco/-Galactopyranosyl) Derivatives

A facile, convenient and high yielding synthesis of novel &lt;em&gt;S&lt;/em&gt;-glycosides and &lt;em&gt;N&lt;/em&gt;-glycosides incorporating 1,2,3,4-tetrahydronaphthalene and or 1,2-dihydropyridines moieties has been described. The aglycons &lt;strong&gt;2&lt;/strong&gt;, &lt;strong&gt;4&lt;/strong&gt;, and &lt;strong&gt;7&lt;/strong&gt; were coupled with different activated halosugars in the presence of basic and acidic medium. The preliminary &lt;em&gt;in-vitro&lt;/em&gt; cytotoxic evaluation&lt;strong&gt; &lt;/strong&gt;revealed that compounds &lt;strong&gt;3c&lt;/strong&gt;, &lt;strong&gt;3f&lt;/strong&gt;, &lt;strong&gt;5c&lt;/strong&gt; and &lt;strong&gt;7b&lt;/strong&gt; show promising activity. A molecular docking study was performed against tyrosine kinase (TK) (PDB code: 1t46) by Autodock Vina. The docking output was analyzed and some compounds have shown hydrogen bond (H-B) formation with reasonable distances ranged from 2.06 A° to 3.06 A° with Thr 670 and Cys 673 residues found in the specified pocket. No hydrogen bond was observed with either Glu 640 nor Asp 810 residues, as was expected from pdbsum

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)