Association of interleukin-18 gene variants with susceptibility to visceral leishmaniasis in Iranian population

Host resistance to Leishmania infection is mediated by cellular immune responses leading to macrophage activation and parasite killing. Interleukin-18 (IL-18) known as interferon-γ (IFN-γ) inducing factor, stimulates IFN-γ production by T cells. Taking into account the important role of IL-18 in the defense against visceral leishmaniasis (VL) and the known effect of IL-18 gene polymorphisms on its production, the aim of this study was to investigate the probable relationship between IL-18 gene polymorphisms and the susceptibility to VL. The study groups included 118 pediatric patients who suffered from VL and 156 non-relative healthy people as the controls from the same endemic area. IL-18 gene polymorphisms at the positions ?656 G/T, ?137 G/C and +105A/C (codon 35/3) were analyzed by polymerase chain reaction-restricted fragment length polymorphism (PCR–RFLP). The results showed that the frequency of T allele at the position -656 was significantly higher in the controls, compared with that in the patients (P = 0.047), but it couldn’t tolerate Bonferroni correction. Regarding the IL-18 genotypes, there was no significant difference between the patients and controls. Although the frequencies of ATG single haplotype and AGG/ATG double haplotype were significantly higher in the controls (P = 0.043) and the patients (P = 0.044), respectively, the two P values couldn’t tolerate Bonferroni correction. Furthermore, a strong linkage disequilibrium was observed among the ?656, ?137 and +105 single nucleotide polymorphisms of IL-18 gene (all Ps < 0.001). In conclusion, this study suggests that the inheritance of T allele at the position ?656 may be considered as a genetic factor for resistance to VL.     

Nanotherapeutic approaches targeting angiogenesis and immune dysfunction in tumor microenvironment

Tumor microenvironment (TME) comprising cellular and non-cellular components is a major source of cancer hallmarks. Notably, angiogenesis responsible for normal physiological remodeling process can otherwise harness vessel abnormalities during tumorigenesis eliciting severe therapeutic inefficiency. Currently, FDA approved antiangiogenic drugs have only shown modest clinical success owing to tumor hypoxia, antiangiogenic therapeutic resistance, and limited knowledge in understanding TME. In order to overcome these limitations, targeting angiogenesis combined with immunosuppressive TME could offer potential therapeutic opportunities. Indeed, these therapeutic approaches can be further revisited with the advent of nanotechnology that can target the key cellular components of TME and tumor cells more precisely. Synergetic targeting without eliciting systemic toxicity achieved by integration of antiangiogenic and immunotherapy in a single nanoplatform is vital for therapeutic success. In this review, we will discuss the most promising nanotechnological advancements oriented to modulate the immunosuppressive TME in association with antiangiogenic therapy that has gained immense popularity in cancer treatment.     

AI-supported modified risk staging for multiple myeloma cancer useful in real-world scenario

Introduction: An efficient readily employable risk prognostication method is desirable for MM in settings where genomics tests cannot be performed owing to geographical/economical constraints. In this work, a new Modified Risk Staging (MRS) has been proposed for newly diagnosed Multiple Myeloma (NDMM) that exploits six easy-to-acquire clinical parameters i.e. age, albumin, β2-microglobulin (β2M), calcium, estimated glomerular filtration rate (eGFR) and hemoglobin.Materials and Methods: MRS was designed using a training cohort of 716 NDMM patients of our inhouse MM Indian (MMIn) cohort and validated on MMIn (n=354) cohort and MMRF (n=900) cohort. K-adaptive partitioning (KAP) was used to find new thresholds for the parameters. Risk staging rules, obtained via training a J48 classifier, were used to build MRS.Results: New thresholds were identified for albumin (3.6 g/dL), β2M (4.8 mg/L), calcium (11.13 mg/dL), eGFR (48.1 mL/min), and hemoglobin (12.3 g/dL) using KAP on the MMIn dataset. On the MMIn dataset, MRS outperformed ISS for OS prediction in terms of C-index, hazard ratios, and its corresponding p-values, but performs comparable in prediction of PFS. On both MMIn and MMRF datasets, MRS performed better than RISS in terms of C-index and p-values. A simple online tool was also designed to allow automated calculation of MRS based on the values of the parameters.Discussion: Our proposed ML-derived yet simple staging system, MRS, although does not employ genetic features, outperforms RISS as confirmed by better separability in KM survival curves and higher values of C-index on both MMIn and MMRF datasets.Funding: Grant: BT/MED/30/SP11006/2015 (Department of Biotechnology, Govt. of India), Grant: DST/ICPS/CPS-Individual/2018/279(G) (Department of Science and Technology, Govt. of India), UGC-Senior Research Fellowship.     

Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus

To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na(+)-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.     

Glucocorticoid-mediated inhibition of angiogenic changes in human endothelial cells is not caused by reductions in cell proliferation or migration

Background

Glucocorticoid-mediated inhibition of angiogenesis is important in physiology, pathophysiology and therapy. However, the mechanisms through which glucocorticoids inhibit growth of new blood vessels have not been established. This study addresses the hypothesis that physiological levels of glucocorticoids inhibit angiogenesis by directly preventing tube formation by endothelial cells.

Methodology/Principal Findings

Cultured human umbilical vein (HUVEC) and aortic (HAoEC) endothelial cells were used to determine the influence of glucocorticoids on tube-like structure (TLS) formation, and on cellular proliferation (5-bromo-2′-deoxyuridine (BrdU) incorporation), viability (ATP production) and migration (Boyden chambers). Dexamethasone or cortisol (at physiological concentrations) inhibited both basal and prostaglandin F_2α (PGF_2α)-induced and vascular endothelial growth factor (VEGF) stimulated TLS formation in endothelial cells (ECs) cultured on Matrigel, effects which were blocked with the glucocorticoid receptor antagonist RU38486. Glucocorticoids had no effect on EC viability, migration or proliferation. Time-lapse imaging showed that cortisol blocked VEGF-stimulated cytoskeletal reorganisation and initialisation of tube formation. Real time PCR suggested that increased expression of thrombospodin-1 contributed to glucocorticoid-mediated inhibition of TLS formation.

Conclusions/Significance

We conclude that glucocorticoids interact directly with glucocorticoid receptors on vascular ECs to inhibit TLS formation. This action, which was conserved in ECs from two distinct vascular territories, was due to alterations in cell morphology rather than inhibition of EC viability, migration or proliferation and may be mediated in part by induction of thrombospodin-1. These findings provide important insights into the anti-angiogenic action of endogenous glucocorticoids in health and disease.     

Necessity of enzymatic hydrolysis for production and functionalization of nanocelluloses

Nanocellulose (NC) from cellulosic biomass has recently gained attention owing to their biodegradable nature, low density, high mechanical properties, economic value and renewability. They still suffer, however, some drawbacks. The challenges are the exploration of raw materials, scaling, recovery of chemicals utilized for the production or functionalization and most important is toxic behavior that hinders them from implementing in medical/pharmaceutical field. This review emphasizes the structural behavior of cellulosic biomass and biological barriers for enzyme interactions, which are pertinent to understand the enzymatic hydrolysis of cellulose for the production of NCs. Additionally, the enzymatic catalysis for the modification of solid and NC is discussed. The utility of various classes of enzymes for introducing desired functional groups on the surface of NC has been further examined. Thereafter, a green mechanistic approach is applied for understanding at molecular level.     

Induction of growth and antioxidant defense mechanisms in Matricaria chamomilla L. callus by vibration

In Vitro Cellular & Developmental Biology - Plant - Effect of sinusoidal vibration on the activity of some antioxidative enzymes, pigments, membrane stability, and total phenolic was...