Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene.

Lethal disease due to hepatic periportal fibrosis occurs in 2%-10% of subjects infected by Schistosoma mansoni in endemic regions such as Sudan. It is unknown why few infected individuals present with severe disease, and inherited factors may play a role in fibrosis development. Schistosoma mansoni infection levels have been shown to be controlled by a locus that maps to chromosome 5q31-q33. To investigate the genetic control of severe hepatic fibrosis (assessed by ultrasound examination) causing portal hypertension, a segregation analysis was performed in 65 Sudanese pedigrees from the same village. Results provide evidence for a codominant major gene, with.16 as the estimated allele A frequency predisposing to advanced periportal fibrosis. For AA males, AA females, and Aa males a 50% penetrance is reached after, respectively, 9, 14, and 19 years of residency in the area, whereas for other subjects the penetrance remains <.02 after 20 years of exposure. Linkage analysis performed in four candidate regions shows that this major locus maps to chromosome 6q22-q23 and that it is closely linked (multipoint LOD score 3.12) to the IFN-gammaR1 gene encoding the receptor of the strongly antifibrogenic cytokine interferon-gamma. These results show that infection levels and advanced hepatic fibrosis in human schistosomiasis are controlled by distinct loci; they suggest that polymorphisms within the IFN-gammaR1 gene could determine severe hepatic disease due to S. mansoni infection and that the IFN-gammaR1 gene is a strong candidate for the control of abnormal fibrosis observed in other diseases.     

Resveratrol targeting the Wnt signaling pathway: A focus on therapeutic activities

Wingless-type MMTV integration site (Wnt) signaling pathway is considered as an important pathway regulating a variety of biological processes such as tissue formation and homeostasis, cell proliferation, cell migration, cell differentiation, and embryogenesis. Impairment in the Wnt signaling pathway is associated with pathological conditions, particularly cancer. So, modulation of this pathway can be considered as a promising strategy and several drugs have been developed in line with this strategy. Resveratrol (Res) is a naturally occurring nutraceutical compound exclusively found in different fruits and nuts such as grape, peanut, and pistachio. This compound has favorable biological and therapeutic activities such as antioxidant, anti-inflammatory, antitumor, hepatoprotective, cardioprotective, and antidiabetic. At the present review, we demonstrate how Res modulates Wnt signaling pathway to exert its pharmacological effects.     

Decellularized Wharton's jelly extracellular matrix as a promising scaffold for promoting hepatic differentiation of human induced pluripotent stem cells

Liver tissue engineering as a therapeutic option for restoring of damaged liver function has a special focus on using native decellularized liver matrix, but there are limitations such as the shortage of liver donor. Therefore, an appropriate alternative scaffold is needed to circumvent the donor shortage. This study was designed to evaluate hepatic differentiation of human induced pluripotent stem cells (hiPSCs) in decellularized Wharton's jelly (WJ) matrix as an alternative for native liver matrix. WJ matrices were treated with a series of detergents for decellularization. Then hiPSCs were seeded into decellularized WJ scaffold (DWJS) for hepatic differentiation by a defined induction protocol. The DNA quantitative assay and histological evaluation showed that cellular and nuclear materials were efficiently removed and the composition of extracellular matrix was maintained. In DWJS, hiPSCs-derived hepatocyte-like cells (hiPSCs-Heps) efficiently entered into the differentiation phase (G1) and gradually took a polygonal shape, a typical shape of hepatocytes. The expression of hepatic-associated genes (albumin, TAT, Cytokeratin19, and Cyp7A1), albumin and urea secretion in hiPSCs-Heps cultured into DWJS was significantly higher than those cultured in the culture plates (2D). Altogether, our results suggest that DWJS could provide a proper microenvironment that efficiently promotes hepatic differentiation of hiPSCs.     

A panel of noncoding RNAs in non–small-cell lung cancer

Non–small-lung cancer (NSCLC) is the leading cause of cancer death. Early detection of NSCLC could pave the way for effective therapies. Analysis of molecular genetic biomarkers in biological fluids has been proposed as a useful tool for cancer diagnosis. Here, we aimed to develop a panel of noncoding RNAs (ncRNAs) in sputum for NSCLC early detection. Expression of 11 ncRNAs were analyzed by real–time polymerase chain reaction in sputum samples of 30 NSCLC patients and 30 sex- and age-matched cancer-free controls. Stability of endogenous microRNAs (miRNAs) in sputum was evaluated after 3 and 6 days at 4°C, 6 months, and 1 year at −80°C. Nine ncRNAs showed significant differences of their expression in sputum between NSCLC patients and controls. A logistic regression model with the best prediction was built based on miR-145, miR-126, and miR-7. The composite of the three miRNAs produced 90% sensitivity and specificity in distinguishing NSCLC patients from the controls. Results indicate that miRNAs could be useful biomarkers based on their stability under various storage conditions and maintain differential changes between cancer and control groups. Moreover, measurement of miRNAs in sputum could be a noninvasive approach for detection of lung cancer.     

Design,synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents

Selective PDE3 inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this research we designed, synthesized and evaluated the potential cardiotonic activity of thirteen PDE3 inhibitors (4-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]butanamide analogs) using the spontaneously beating atria model. The design strategy was based on the structure of cilostamide, a selective PDE3 inhibitor. In each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthetic compounds were assessed. All experiments were carried out in comparison with IBMX, amrinone and cilostamide as standard compounds. The results showed that, among the new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, 4j, which displayed selectivity for increasing the force of contraction (165 ± 4% change over the control) rather than the frequency rate (115 ± 7% change over the control) at 100 μM and potent inhibitory activity of PDE3 with IC₅₀ = 0.20 μM.     

Point Charges Optimally Placed to Represent the Multipole Expansion of Charge Distributions

We propose an approach for approximating electrostatic charge distributions with a small number of point charges to optimally represent the original charge distribution. By construction, the proposed optimal point charge approximation (OPCA) retains many of the useful properties of point multipole expansion, including the same far-field asymptotic behavior of the approximate potential. A general framework for numerically computing OPCA, for any given number of approximating charges, is described. We then derive a 2-charge practical point charge approximation, PPCA, which approximates the 2-charge OPCA via closed form analytical expressions, and test the PPCA on a set of charge distributions relevant to biomolecular modeling. We measure the accuracy of the new approximations as the RMS error in the electrostatic potential relative to that produced by the original charge distribution, at a distance the extent of the charge distribution–the mid-field. The error for the 2-charge PPCA is found to be on average 23% smaller than that of optimally placed point dipole approximation, and comparable to that of the point quadrupole approximation. The standard deviation in RMS error for the 2-charge PPCA is 53% lower than that of the optimal point dipole approximation, and comparable to that of the point quadrupole approximation. We also calculate the 3-charge OPCA for representing the gas phase quantum mechanical charge distribution of a water molecule. The electrostatic potential calculated by the 3-charge OPCA for water, in the mid-field (2.8 Å from the oxygen atom), is on average 33.3% more accurate than the potential due to the point multipole expansion up to the octupole order. Compared to a 3 point charge approximation in which the charges are placed on the atom centers, the 3-charge OPCA is seven times more accurate, by RMS error. The maximum error at the oxygen-Na distance (2.23 Å ) is half that of the point multipole expansion up to the octupole order.     

Conversion of arachidonic acid to lipoxygenase products by human fetal tissues

[14C]Arachidonic acid was converted to several lipoxygenase products by homogenates of human fetal tissues as determined by thin-layer chromatography. The net conversions of [14C]arachidonic acid to radiolabeled lipoxygenase products were high (greater than or equal to 5%) in the case of fetal liver and brain, and low (less than or equal to 2%) in the case of fetal adrenal, heart, and kidney.