The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the P-glycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells.
Natural polyphenols are a large class of phytochemicals with neuroprotective effects. Four polyphenolic compounds: hesperidin, icariin, dihydromyricetin and baicalin were selected to evaluate their effects on Alzheimer’s disease (AD). We analyzed by an inverse docking procedure (INVDOCK) the potential protein targets of these polyphenols within the KEGG AD pathway. Consequently, their therapeutic effects were evaluated and compared in a transgenic APP/PS1 mouse model of AD. These polyphenols were docked to several targets, including APP, BACE, PSEN, IDE, CASP, calpain and TNF-α, suggesting potential in vivo activities. Five month old transgenic mice were treated with these polyphenols. Icariin and hesperidin restored behavioral deficits and ameliorated Aβ deposits in both the cortex and hippocampus while baicalin and dihydromyricetin showed no substantial effects. Our findings suggest that hesperidin and icariin could be considered potential therapeutic candidates of human AD.
Despite their potential applications in future regenerative medicine, periodontal ligament stem cells (PDLSCs) are difficult to obtain in large amounts from patients. Therefore, maintaining stemness while expanding the cell numbers for medical use is the key to transitioning PDLSCs from the bench to the clinic. Lysophosphatidic acid (LPA), which is present in the human body and saliva, is a signaling molecule derived from phospholipids. In this study, we examined the effects of LPA on stemness maintenance in human PDLSCs. Several spindle-shaped and fibroblast-like periodontal ligament stem-like cell lines were established from PDLSC isolation. Among these cell lines, the most morphologically appropriate cell line was characterized. The expression levels of OCT4, NANOG (a stem cell marker), and CD90 (a mesenchymal stem cell marker) were high. However, CD73 (a negative marker of mesenchymal stem cells) expression was not observed. Notably, immunofluorescence analysis identified the expression of STRO-1, CD146 (a mesenchymal stem cell marker), and sex determining region Y-box 2 at the protein level. In addition, lipid droplets were stained by Oil red O after the induction of adipogenesis for 21 days, and mineralized nodules were stained by Alizarin Red S after the induction of osteogenesis for 14 days. Alkaline phosphate staining also demonstrated the occurrence of osteogenesis. In summary, we established a human PDLSC line, which could be applied as a cell source for tissue regeneration in dental patients. However, further studies are needed to determine the detailed effects of LPA on PDLSCs.
This study was designed to compare the impact of post and core systems on resistance to fracture of endodontically treated anterior teeth with flared root canals and to assess their fracture pattern. Sixty central incisors were cut horizontally 2 mm coronal to the cementoenamel junction (CEJ). After root canal therapy, teeth were assigned into 6 groups (n=10 each) based on a post system and used as follows: Group C, non-flared root received size #1 glass fiber posts (Control); Group AP, flared root restored with anatomical post; Group RC, flared root restored with size #1 fiber post and cemented with thick layer of resin cement; Group CR, flared root restored with size #1 and reinforced with composite resin; Group CM, cast post-core; Group CP, CAD̸/CAM polymer-infiltrated ceramic post and core. Following post cementation, core build-up and crown insertion, the specimens were thermo-cycled up to 10,000 cycles (5C/55C; 30 seconds dwell time, 6 seconds transition time) and then statically loaded at 1 mm/minute crosshead speed using a universal testing machine. One-way ANOVA and Tukey HSD post hoc test (α=0.05) were used for data analysis. Group C recorded significantly higher resistance to fracture values [(826.9±39.1) N] followed by group CP [(793.8±55.6) N] while group RC yielded the lowest fracture resistance values [(586.7±51.4) N]. The resistance to fracture of wide root canals can be enhanced by using one-piece CAM/CAM post and core as an alternative to the use of either glass fiber post, relined with composite resin increasing the thickness of luting cement or the use of cast post and core system. However, this was an in vitro investigation and further in vivo studies are necessary.
This study was conducted to investigate the maxillary denture bases and occlusal discrepancies using the Vertex Thermosens in comparison with the conventional polymethyl-methacrylate materials. Twenty maxillary denture bases were prepared from the Vertex ThermoSens and a conventional heat-cured denture base materials. Acrylic maxillary second molars were arranged in their respective positions on the ridge. After curing of both types of denture bases, they were deflasked with their respective master casts. Reference points were prepared for measurements of the antero-posterior and cross-arch dimensions at the denture borders using caliper device. Furthermore, the teeth discrepancies were measured between reference points in the ligual aspect of the second maxillary molars. The recorded data was analyzed using SPSS statistical software version 20. The results showed initial shrinkage of both denture bases in the antero-posterior and cross-arch dimensions immediately after decasting. This contraction was compensated gradually during storage in water up to 2 weeks. Regarding the variable time, there was a significant difference between the tested materials. Moreover, the results revealed occlusal discrepancies and shifting of teeth inward immediately after decasting, followed by outward movement after storage in water for 2 weeks. Regarding the variables time and materials, there were significant differences. Both materials exhibited inward shrinkage in the antero-posterior and cross-arch dimensions immediately after decasting. Both denture bases showed inward shifting of teeth immediately after decasting, followed by outward movement after storage in water up to 2 weeks.
Three members of the angiopoietin-like (ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8- are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function (LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia (FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.
The study aimed to explore the prophylactic effect of melatonin, rowatinex; a naturally occurring renal drug, and its combination on diabetic nephropathy in type 2 diabetic rats. Diabetes was induced by intraperitoneal injection of a single dose of streptozotocin (50 mg/g body weight). Three days before diabetes induction, rats were daily treated with melatonin, rowatinex and their combination continuously for 8 weeks. Evaluation was done through measuring blood urea nitrogen (BUN), serum uric acid, serum creatinine, urine creatinine, creatinine clearance, nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), total antioxidant capacity (TAC), kidney injury molecule-1 (KIM-1), heat shock protein-70 (HSP-70), caspase-3, transforming growth factor β1 (TGFβ1), DNA degradation by the comet assay and total protein contents. Histopathologic study was also done for the kidney and the pancreas. Drastic changes in all measured parameters of the diabetic rats were observed. Treatment with melatonin and rowatinex showed amelioration to variable degrees. In conclusion, melatonin showed the most potent effect on protecting rats from deleterious action of diabetic nephropathy followed by its combination with rowatinex.