Synthesis and anti‐inflammatory activity of diversified heterocyclic systems

In continuation with our research program on the development of novel bioactive molecules, we report herein the design and synthesis of a series of diversified heterocycles ( 4 – 22 ). The synthesized compounds were evaluated for their anti‐inflammatory activity. The chemical structures of the newly synthesized compounds have been confirmed by NMR, FTIR, and microanalysis.     

Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance

The pyruvate dehydrogenase complex (PDH) has been hypothesized to link lipid exposure to skeletal muscle insulin resistance through a glucose-fatty acid cycle in which increased fatty acid oxidation increases acetyl-CoA concentrations, thereby inactivating PDH and decreasing glucose oxidation. However, whether fatty acids induce insulin resistance by decreasing PDH flux remains unknown. To genetically examine this hypothesis we assessed relative rates of pyruvate dehydrogenase flux/mitochondrial oxidative flux and insulin-stimulated rates of muscle glucose metabolism in awake mice lacking pyruvate dehydrogenase kinase 2 and 4 [double knockout (DKO)], which results in constitutively activated PDH. Surprisingly, increased glucose oxidation in DKO muscle was accompanied by reduced insulin-stimulated muscle glucose uptake. Preferential myocellular glucose utilization in DKO mice decreased fatty acid oxidation, resulting in increased reesterification of acyl-CoAs into diacylglycerol and triacylglycerol, with subsequent activation of PKC-θ and inhibition of insulin signaling in muscle. In contrast, other putative mediators of muscle insulin resistance, including muscle acylcarnitines, ceramides, reactive oxygen species production, and oxidative stress markers, were not increased. These findings demonstrate that modulation of oxidative substrate selection to increase muscle glucose utilization surprisingly results in muscle insulin resistance, offering genetic evidence against the glucose-fatty acid cycle hypothesis of muscle insulin resistance.Lipid-induced muscle insulin resistance plays a major role in the pathogenesis of type 2 diabetes (T2D), but the cellular mechanisms remain unknown (1, 2). More than 50 y ago Randle et al. (3) postulated the glucose-fatty acid cycle to explain the impairment of insulin-stimulated glucose disposal by fatty acids in muscle. In this model, fat oxidation increases mitochondrial acetyl-CoA/CoA and NADH/NAD⁺ ratios. Acetyl-CoA and NADH allosterically inhibit pyruvate dehydrogenase complex (PDH), the mitochondrial enzyme that links glycolysis to the TCA cycle by converting pyruvate to acetyl-CoA. Additionally, fatty acid-derived acetyl-CoA produces citrate, which inhibits phosphofructokinase. This in turn increases glucose-6-phosphate (G6P), a potent allosteric inhibitor of hexokinase. By these mechanisms, increased fatty acid oxidation was hypothesized to reduce glycolytic flux and prevent further muscle glucose uptake. However, in vivo studies of human skeletal muscle metabolism have challenged the Randle hypothesis. Five hours of a lipid infusion, combined with heparin to activate lipoprotein lipase, raised plasma fatty acids and induced muscle insulin resistance in healthy individuals, yet intramyocellular G6P and glucose concentrations were reduced compared with control glycerol infusion studies, implicating defects in insulin-stimulated glucose transport activity (4, 5). An alternative hypothesis to explain the muscle insulin resistance associated with lipid exposure posits that accumulation of bioactive lipid intermediates initiates signaling cascades that impair insulin action. Lipid species implicated include diacylglycerols (DAGs) (6–10), ceramides (11, 12), and long-chain acyl-CoAs (13). DAG activation of PKC-θ in skeletal muscle has been shown to impair canonical insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation through increased IRS-1 serine phosphorylation at the 1101 position (2, 6, 7, 14).More recently, incomplete fat oxidation and subsequent accumulation of mitochondrially derived acylcarnitines has been proposed to contribute to lipid-induced muscle insulin resistance (15–17). According to this model, insulin resistance stems from increased fat oxidation, leading to increased conversion of acyl-CoA to medium- and long-chain acylcarnitines, which may mediate insulin resistance via unknown mechanisms. In contrast, short-chain acylcarnitines have been suggested to promote metabolic flexibility. The shortest acylcarnitine, acetylcarnitine, is synthesized from acetyl-CoA and carnitine by carnitine acetyltransferase (CrAT), a mitochondrial matrix enzyme, and is responsible for buffering the mitochondrial acetyl-CoA pool and mitigating acetyl-CoA inhibition of PDH (18). Consistent with the notion that CrAT regulates substrate selection by modulating PDH flux, mice with muscle-specific deletion of CrAT exhibited reduced PDH activity during the fed-to-fasted transition, resulting in glucose intolerance and metabolic inflexibility, a term coined by Kelley and Mandarino (19) to explain the impairment in the ability to adjust fuel oxidation to fuel availability.Although these studies emphasize the importance of PDH in the promotion of metabolic inflexibility, the role of PDH and mitochondrial oxidative substrate selection in the regulation of basal and insulin-stimulated muscle glucose metabolism has not been directly assessed in vivo. To examine this question, we sought to determine whether modulation of oxidative substrate selection in a genetic mouse model with constitutively active PDH activity would affect insulin sensitivity in skeletal muscle.     

Association of endothelial nitric oxide synthase gene variant (G894T) with coronary artery disease in Western Iran

There are conflicting reports about the association of endothelial nitric oxide synthase (eNOS) gene polymorphism and the risk of coronary artery disease (CAD). To determine the frequency of eNOS G894T variant and to find the possible association between this polymorphism with CAD we studied 207 unrelated patients with total CAD (with and without diabetes) and 92 controls. The eNOS variants were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The presence of GT + TT genotype was associated with 2.1-fold (P = .006), 2.29-fold (P = .006), and 1.93-fold (P = .032) increased risk of CAD in total CAD, CAD with diabetes, and in CAD without diabetes patients, respectively. The presence of T allele of eNOS increased the risk of CAD 2.15-fold (P = .001). The levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) tended to be higher in patients carrier for T allele compared to those with G allele. The results of present study revealed that eNOS G894T polymorphism is associated with increased risk of CAD in our population.     

The treatment of mandibular condyle fractures: A meta-analysis

BackgroundThe treatment for mandibular condyle fractures remains controversial. Conservative management (CM) and open reduction/internal fixation (ORIF) are both used, but the evidence to support superiority of one method over the other has not been assessed.MethodsWe performed a meta-analysis of studies comparing CM versus ORIF in patients with condyle fractures. The primary outcome was post-treatment function; we looked at the status of the post-treatment occlusion, mouth opening, protrusion, facial height, pain and the presence of postoperative ankylosis. Furthermore, in studies evaluating ORIF, adverse effects such as facial nerve weakness and scarring, were also recorded.ResultsTwenty (20) studies enrolling 1596 patients were eligible. These included four randomized controlled trials (RCTs) and 16 non-randomized case series. Only 1186 of these patients were analyzed by the studies; the reasons for exclusion were rarely clarified. All four RCTs were prospective but the majority (69%) of the remaining studies were retrospective. The inclusion criteria were described in all four RCTs; however, this was not the case in half of the remaining studies (44%). Only four (20%) studies were blinded. Across all included studies, we recorded great variation between treatment protocols, follow-up periods, and outcomes measured. This precluded any quantitative synthesis. In nine studies (45%) the superiority of ORIF over CM reached statistical significance. The incidence of facial nerve weakness following ORIF averaged 6% and it was temporary for the majority of the patients. The identified RCTs were small (160 patients) and suffered from a number of methodological shortcomings. All of them reached statistically significant conclusions favoring ORIF over CM.ConclusionThe current meta-analysis suggests that ORIF for condylar fractures may be as good or better than CM. The morbidity associated with the operation is low. However, the available evidence is of poor quality and not strong enough to change clinical practice.     

Push‐out bond strength of two root‐end filling materials in root‐end cavities prepared by Er,Cr:YSGG laser or ultrasonic technique

This study compared the push‐out bond strength of mineral trioxide aggregate (MTA) and a new endodontic cement (NEC) as root‐end filling materials in root‐end cavities prepared by ultrasonic technique (US) or Er,Cr:YSGG laser (L). Eighty single‐rooted extracted human teeth were endodontically treated, apicectomised and randomly divided into four following groups (n = 20): US/MTA, US/NEC, L/MTA and L/NEC. In US/MTA and US/NEC groups, root‐end cavities were prepared with ultrasonic retrotip and filled with MTA and NEC, respectively. In L/MTA and L/NEC groups, root‐end cavities were prepared using Er,Cr:YSGG laser and filled with MTA and NEC, respectively. Each root was cut apically to create a 2 mm‐thick root slice for measurement of bond strength using a universal testing machine. Then, all slices were examined to determine the mode of bond failure. Data were analysed using two‐way anova . Root‐end filling materials showed significantly higher bond strength in root‐end cavities prepared using ultrasonic technique (US/MTA and US/NEC) (P < 0.001). The bond strengths of MTA and NEC did not differ significantly. The failure modes were mainly adhesive for MTA, but cohesive for NEC. In conclusion, bond strengths of MTA and NEC to root‐end cavities were comparable and higher in ultrasonically prepared cavities.