The inhibitory activity and binding characteristics of caffeic acid,
-coumaric acid, quercetin and capsaicin, four phenolic compounds found in hot pepper, against porcine pancreatic lipase activity ...were studied and compared to hot pepper extract. Quercetin was the strongest inhibitor (IC
=(6.1±2.4) µM), followed by
-coumaric acid ((170.2±20.6) µM) and caffeic acid ((401.5±32.1) µM), while capsaicin and a hot pepper extract had very low inhibitory activity. All polyphenolic compounds showed a mixed-type inhibition. Fluorescence spectroscopy studies showed that polyphenolic compounds had the ability to quench the intrinsic fluorescence of pancreatic lipase by a static mechanism. The sequence of Stern-Volmer constant was quercetin, followed by caffeic and
-coumaric acids. Molecular docking studies showed that caffeic acid, quercetin and
-coumaric acid bound near the active site, while capsaicin bound far away from the active site. Hydrogen bonds and π-stacking hydrophobic interactions are the main pancreatic lipase-polyphenolic compound interactions observed.
Aims
Tumour budding (TB), desmoplastic reaction (DR) and intraepithelial tumour infiltrating lymphocytes (iTILs) are recently recognised prognostic factors in colorectal cancer (CRC). In this study, ...we evaluated their significance and relationship to each other and their cumulative effect on survival.
Methods and results
A total of 372 stages I–III CRC cases from 2013 to 2016 were included. Low TB was identified in 302 (81%) cases, immature/myxoid DR in 67 (18%) cases and iTILs in 130 (35.0%) cases. iTILs was associated with low budding (P = 0.0247), non‐myxoid DR (P = 0.0004), poorly differentiated histology (P = 0.0015), absence of perineural invasion (P = 0.0367) and loss of mismatch repair proteins (P = 0.0002). Absence of iTILs and presence of immature/myxoid DR were associated with a worse recurrence‐free survival (RFS) hazard ratio (HR) = 2.191, 95% confidence interval (CI) = 1.232–3.895; and HR = 5.706, 95% CI = 3.632–8.964, respectively. A competing risk analysis showed statistically significant prognostic groups combining iTILs and TB (P < 0.0001). Cases with iTILs and low TB were associated with better RFS compared to cases without iTILs and with intermediate/high TB (HR = 0.214, 95% CI = 0.109–0.421). Similarly, combining iTILs and DR revealed statistically significant prognostic groups (P < 0.0001). Cases with iTILs and a non‐myxoid DR had better RFS compared to cases without iTILs and immature/myxoid DR (HR = 0.113, 95% CI = 0.056–0.230). On multivariate cause‐specific analysis, patients’ age (P = 0.0045), iTILs (P = 0.0345), DR (P < 0.0001) and pTNM prognostic groups (P < 0.0001) were associated with RFS.
Conclusions
Our study validates the association of iTILs and DR as independent prognostic finding in CRC, and propose a prognostic model using the combinations of iTILs with TB and stromal reaction in CRC.
The digestive enzymes-polyphenolic compounds (PCs) interactions behind the inhibition of these enzymes have not been completely studied. The existing studies have mainly analyzed polyphenolic ...extracts and reported inhibition percentages of catalytic activities determined by UV-Vis spectroscopy techniques. Recently, pure PCs and new methods such as isothermal titration calorimetry and circular dichroism have been applied to describe these interactions. The present review focuses on PCs structural characteristics behind the inhibition of digestive enzymes, and progress of the used methods. Some characteristics such as molecular weight, number and position of substitution, and glycosylation of flavonoids seem to be related to the inhibitory effect of PCs; also, this effect seems to be different for carbohydrate-hydrolyzing enzymes and proteases. The digestive enzyme-PCs molecular interactions have shown that non-covalent binding, mostly by van der Waals forces, hydrogen binding, hydrophobic binding, and other electrostatic forces regulate them. These interactions were mainly associated to non-competitive type inhibitions of the enzymatic activities. The present review emphasizes on the digestive enzymes such as α-glycosidase (AG), α-amylase (PA), lipase (PL), pepsin (PE), trypsin (TP), and chymotrypsin (CT). Existing studies conducted in vitro allow one to elucidate the characteristics of the structure-function relationships, where differences between the structures of PCs might be the reason for different in vivo effects.
The first probabilistic tsunami flooding maps have been developed. The methodology, called probabilistic tsunami hazard assessment (PTHA), integrates tsunami inundation modeling with methods of ...probabilistic seismic hazard assessment (PSHA). Application of the methodology to Seaside, Oregon, has yielded estimates of the spatial distribution of 100‐ and 500‐year maximum tsunami amplitudes, i.e., amplitudes with 1% and 0.2% annual probability of exceedance. The 100‐year tsunami is generated most frequently by far‐field sources in the Alaska‐Aleutian Subduction Zone and is characterized by maximum amplitudes that do not exceed 4 m, with an inland extent of less than 500 m. In contrast, the 500‐year tsunami is dominated by local sources in the Cascadia Subduction Zone and is characterized by maximum amplitudes in excess of 10 m and an inland extent of more than 1 km. The primary sources of uncertainty in these results include those associated with interevent time estimates, modeling of background sea level, and accounting for temporal changes in bathymetry and topography. Nonetheless, PTHA represents an important contribution to tsunami hazard assessment techniques; viewed in the broader context of risk analysis, PTHA provides a method for quantifying estimates of the likelihood and severity of the tsunami hazard, which can then be combined with vulnerability and exposure to yield estimates of tsunami risk.
Aim
Current international criteria provide standardized procedures to diagnose sarcopenia in older people. However, to date few data exist on patients with acute disease. The present study was ...carried out to determine the frequency of sarcopenia in acute hip fracture patients, and its association with their baseline characteristics and prognosis during hospitalization.
Methods
Data were collected from 509 consecutive patients hospitalized for hip fracture. The European Working Group on Sarcopenia in Older People Criteria for sarcopenia were applied in the first 72 h. Muscle mass was measured by electrical bioimpedance and grip strength by hydraulic dynamometer. Clinical, functional and cognitive characteristics were assessed at baseline and hospital discharge, and their association with the presence of sarcopenia was studied.
Results
A total of 479 patients (94%) met the inclusion criteria. The mean age was 85.3 (SD 6.8 years). The frequency of sarcopenia was 17.1% (12.4% in men, 18.3% in women). Sarcopenia was associated with residence in nursing homes (30.5% vs 19.6%, P = 0.030), older age (86.8, SD 6.2 vs 85.1, SD 6.9 years, P = 0.038), and lower body mass index (23.1, SD 3.6 vs 25.6, SD 4.23, P < 0.001). In the multivariate analysis, only low body mass index was predictive of sarcopenia (OR 0.85, 95% CI 0.80–0.91). Sarcopenia was associated with worse functional prognosis at discharge in the crude analysis (OR 1.88, 95% CI 1.15–3.07), but not in the multivariate analysis (OR 1.68, 95% CI 0.99–2.84).
Conclusions
Sarcopenia was detected in almost one of five acute hip fracture patients and was associated with lower body mass index, but an association with worse prognosis at discharge could not be confirmed. Geriatr Gerontol Int 2016; 16: 1021‐1027.
Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary ...treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-β, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of β-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors.
Display omitted
•Molecules from T. Crassiceps improve the 5FU activity in CAC model.•TcES down regulates proliferation and malignancy markers Ki67 and Cyclin D1.•Granzyme B1 is upregulated in TcES+5FU treatment.•Combinatory effect TcES+5FU improve apoptosis through up-regulation P53.
We analyzed chemical and kinematical properties of about 850 FGK solar neighborhood long-lived dwarfs observed with the HARPS high-resolution spectrograph. The aim of this study is to characterize ...and explore the kinematics and chemical properties of stellar populations of the Galaxy in order to understand their origins and evolution. Our results suggest that radial migration played an important role in the formation and evolution of the thin disk. For the thick disk stars it is not possible to reach a firm conclusion about their origin. Based on the eccentricity distribution of the thick disk stars only their accretion origin can be ruled out, and the heating and migration scenario could explain the positive steep gradient of V with Fe/H. Further detailed investigations would help to clarify their exact nature and origin.
•Cleavage of GABAergic proteins by calpain generates break down products identifiable in vitro and in vivo.•Calpain inhibition reduces the cleavage of GABAergic proteins in cultured neurons.•A ...calpain inhibitor partially reduces the cleavage of GABAergic proteins after status epilepticus.•Calpain inhibition might represent an alternative approach to block epileptogenesis.
Epileptogenesis is the processes by which a normal brain transforms and becomes capable of generate spontaneous seizures. In acquired epilepsy, it is thought that epileptogenesis can be triggered by a brain injury but the understanding of the cellular or molecular changes unraveling is incomplete. In the CA1 region of hippocampus less GABAergic activity precede the appearance of spontaneous seizures and calpain overactivation has been detected after chemoconvulsant-induced status epilepticus (SE). Inhibition of calpain overactivation following SE ameliorates seizure burden, suggesting a role for calpain dysregulation in epileptogenesis. The current study analyzed if GABAergic proteins (i.e., gephyrin, the vesicular GABA transporter and the potassium chloride co-transporter 2) undergo calpain-dependent cleavage during epileptogenesis. A time-dependent generation of break down products (BDPs) for these proteins was observed in the CA1 region of hippocampus after pilocarpine-induced SE. Generation of these BDPs was partially blocked by treatment with the calpain inhibitor MDL-28170. These findings suggest that calpain-dependent loss of GABAergic proteins might promote the erosion of inhibitory drive and contribute to hyperexcitability during epileptogenesis.
Natural products (NPs) have been shown to be an extraordinary source of bioactive compounds and three-dimensional complex frameworks that can be useful to produce high-value molecular collections ...that are able to address "undruggable" and difficult therapeutic targets. Bicyclic acetals are particularly relevant for these purposes, given their key role in several biological interactions and the structural and stereochemical diversity that comes from the many possible ring combinations. To investigate this topological diversity, we have systematically characterized in a systematic and detailed manner fused, spiro and bridged bicyclic acetals in a large set of NPs, highlighting the great potential of bicyclic acetals in Diversity-Oriented Synthesis (DOS). Accordingly, a summary of some recent efforts on the development of acetal-containing small molecule collections through DOS approaches is herein reported.
The chemoinformatics analysis of fused, spiro, and bridged bicyclic acetals is instrumental for the DOS of natural product-inspired molecular collections.
We present accurate force fields developed from density functional theory (DFT) calculations with periodic boundary conditions for use in molecular simulations involving M2(dobdc) (M-MOF-74; dobdc4– ...= 2,5-dioxidobenzenedicarboxylate; M = Mg, Mn, Fe, Co, Ni, Zn) and frameworks of similar topology. In these systems, conventional force fields fail to accurately model gas adsorption due to the strongly binding open-metal sites. The DFT-derived force fields predict the adsorption of CO2, H2O, and CH4 inside these frameworks much more accurately than other common force fields. We show that these force fields can also be used for M2(dobpdc) (dobpdc4– = 4,4′-dioxidobiphenyl-3,3′-dicarboxylate), an extended version of MOF-74, and thus are a promising alternative to common force fields for studying materials similar to MOF-74 for carbon capture applications. Furthermore, it is anticipated that the approach can be applied to other metal–organic framework topologies to obtain force fields for different systems. We have used this force field to study the effect of contaminants such as H2O and N2 upon these materials’ performance for the separation of CO2 from the emissions of natural gas reservoirs and coal-fired power plants. Specifically, mixture adsorption isotherms calculated with these DFT-derived force fields showed a significant reduction in the uptake of many gas components in the presence of even trace amounts of H2O vapor. The extent to which the various gases are affected by the concentration of H2O in the reservoir is quantitatively different for the different frameworks and is related to their heats of adsorption. Additionally, significant increases in CO2 selectivities over CH4 and N2 are observed as the temperature of the systems is lowered.
PDF
