Preventive potential of andrographis paniculata-derived compounds in metabolic syndrome-associated prostate cancer: a narrative review on the mechanism of action

Metabolic syndrome (MetS) and prostate cancer (PCa) are among the diseases with a concerning prevalence. The reported cases for both medical dilemmas have been steady with no sign of abating at the moment. More worrying is that researchers have started to discover that some of the components of MetS associatively worsen the prognosis of PCa. Even though the relationship is not fully known, its manifestation could cause extra burden to the currently implemented treatment approaches. The use of plant bioactive compounds as an alternative treatment has gained recognition, provided that its mechanisms of action, tolerability, efficacy, safety, and cost-effectiveness are well understood. Therefore, the current review intended to highlight the potential of bioactive compounds derived from plants to simultaneously target MetS, PCa, and MetS-PCa codisease. Additionally, emphasis on the potential of Andrographispaniculata (AP) as a candidate for the treatment of MetS-PCa is also highlighted

Design and physicochemical evaluation of nanostructured lipid carrier encapsulated zingiber zerumbet oil by D-optimal mixture design

The D-optimal mixture design was employed to evaluate the effect of different composition variables on particle size, polydispersity index, zeta potential and encapsulation efficiency for optimization of Zingiber zerumbet oil loaded nanostructured lipid carrier (NLC). The glyceryl monostearate were used as solid lipid, virgin coconut oil as liquid lipid, and Tween 80 as well as soy lecithin were used as surfactant to achieve stable NLC formulation. The hot homogenization and ultrasonication techniques were employed in preparation of NLC. The statistical evaluations by ANOVA revealed that optimum NLC formulation generated as 3.7% Zingiber zerumbet oil, 5% liquid lipid and 1.3% solid lipid. The optimal NLC formulation had an average diameter of 91.002 nm, PDI of 0.172, zeta-potential of -40.88 mV, and encapsulation efficiency of 94.45%. The transmission electron microscopy (TEM) observations exhibited spherical morphology of Zingiber zerumbet oil loaded NLC. Penetration through Strat-M® membrane shown an excellent diffusion coefficient of NLC-Zingiber zerumbet oil. Therefore, D-optimal mixture design has succeeded in generating optimum NLC formulation for encapsulation of Zingiber zerumbet oil. The stable formulation of NLC for encapsulating essential oil give promising future in various applications such as drug delivery, food, textile and cosmetics

DIANA Scheduling Hierarchies for Optimizing Bulk Job Scheduling

The use of meta-schedulers for resource management in large-scale distributed systems often leads to a hierarchy of schedulers. In this paper, we discuss why existing meta-scheduling hierarchies are sometimes not sufficient for Grid systems due to their inability to re-organise jobs already scheduled locally. Such a job re-organisation is required to adapt to evolving loads which are common in heavily used Grid infrastructures. We propose a peer-to-peer scheduling model and evaluate it using case studies and mathematical modelling. We detail the DIANA (Data Intensive and Network Aware) scheduling algorithm and its queue management system for coping with the load distribution and for supporting bulk job scheduling. We demonstrate that such a system is beneficial for dynamic, distributed and self-organizing resource management and can assist in optimizing load or job distribution in complex Grid infrastructures.Comment: 8 pages, 9 figures. Presented at the 2nd IEEE Int Conference on eScience & Grid Computing. Amsterdam Netherlands, December 200

Targeted delivery of bromelain using dual mode nanoparticles: Synthesis, physicochemical characterization,: In vitro and in vivo evaluation

The engineering, characterization, and application of dual-functional delivery vehicle "SPIONs-Br-FA" are reported. In this study, a citrate-coated SPIONs (superparamagnetic iron oxide nanoparticles) drug-delivery vehicle was conjugated with Br (bromelain), a phytotherapeutic anticancer agent, and finally immobilized with FA (folic acid), as a targeting moiety to the FAR+, folate receptor positive, cancer cells. Then, in vitro compatibility tests were performed to confirm the biocompatibility of the engineered system. A cytotoxicity study was carried out, which showed a significant dose advantage with SPIONs-Br-FA in reducing the IC50 values of FAR+ cancer cells compared with neat Br. Through morphological alternation studies, it was disclosed that the SPIONs-Br-FA-treated cells had undergone apoptosis, since shrinkage as well as apoptotic bodies were obviously observed. We demonstrated that SPIONs-Br-FA was a good candidate to suppress the migration of the FAR+ cancer cells as well as to inhibit colony formation of the FAR+ cancer cells compared to SPIONs-Br. We found that the apoptosis percentage was sharply increased in the FAR+ cancer cells treated by SPIONs-Br-FA compared to those treated by neat Br. Moreover, the qualitative and quantitative biodistribution study performed on the vital organs and tumor indicated a significant tumor targetability of the SPIONs-FA. Next, we demonstrated the administration of SPIONs-Br-FA through the tail vein could reduce the tumor burden in 4T1-bearing mice and also increased their lifespan when compared with SPIONs-Br and neat Br at the same concentration of bromelain. In conclusion, the results indicated that the synthesized SPIONs-Br-FA is a promising tool in the field of biomedicine, particularly in cancer therapy

Reproducibility of scientific workflows execution using cloud-aware provenance (ReCAP)

© 2018, Springer-Verlag GmbH Austria, part of Springer Nature. Provenance of scientific workflows has been considered a mean to provide workflow reproducibility. However, the provenance approaches adopted so far are not applicable in the context of Cloud because the provenance trace lacks the Cloud information. This paper presents a novel approach that collects the Cloud-aware provenance and represents it as a graph. The workflow execution reproducibility on the Cloud is determined by comparing the workflow provenance at three levels i.e., workflow structure, execution infrastructure and workflow outputs. The experimental evaluation shows that the implemented approach can detect changes in the provenance traces and the outputs produced by the workflow

Enhancing the efficacy of glycolytic blockade in cancer cells via RAD51 inhibition.

Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor. Next, we tested the cancer-cell specificity of a therapeutic compound using the MEC1 cell line, a chronic lymphocytic leukemia (CLL) cell line that expresses activation induced cytidine deaminase (AID). We show that MEC1 cells, are susceptible to 4,4\u27-Diisothiocyano-2,2\u27-stilbenedisulfonic acid (DIDS), a specific RAD51 inhibitor. We then combine 2DG and DIDS, each at a lower dose and demonstrate that this combination is more efficacious than fludarabine, the current standard- of- care treatment for CLL. This suggests that the therapeutic blockade of glycolysis together with the therapeutic inhibition of RAD51-dependent homologous recombination can be a potentially beneficial combination for targeting AID positive cancer cells with minimal adverse effects on normal tissue. IMPLICATIONS: Combination therapy targeting glycolysis and specific RAD51 function shows increased efficacy as compared to standard of care treatments in leukemias

Gene Expression Signature in Peripheral Blood Detects Thoracic Aortic Aneurysm

BACKGROUND: Thoracic aortic aneurysm (TAA) is usually asymptomatic and associated with high mortality. Adverse clinical outcome of TAA is preventable by elective surgical repair; however, identifying at-risk individuals is difficult. We hypothesized that gene expression patterns in peripheral blood cells may correlate with TAA disease status. Our goal was to identify a distinct gene expression signature in peripheral blood that may identify individuals at risk for TAA. METHODS AND FINDINGS: Whole genome gene expression profiles from 94 peripheral blood samples (collected from 58 individuals with TAA and 36 controls) were analyzed. Significance Analysis of Microarray (SAM) identified potential signature genes characterizing TAA vs. normal, ascending vs. descending TAA, and sporadic vs. familial TAA. Using a training set containing 36 TAA patients and 25 controls, a 41-gene classification model was constructed for detecting TAA status and an overall accuracy of 78+/-6% was achieved. Testing this classifier on an independent validation set containing 22 TAA samples and 11 controls yielded an overall classification accuracy of 78%. These 41 classifier genes were further validated by TaqMan real-time PCR assays. Classification based on the TaqMan data replicated the microarray results and achieved 80% classification accuracy on the testing set. CONCLUSIONS: This study identified informative gene expression signatures in peripheral blood cells that can characterize TAA status and subtypes of TAA. Moreover, a 41-gene classifier based on expression signature can identify TAA patients with high accuracy. The transcriptional programs in peripheral blood leading to the identification of these markers also provide insights into the mechanism of development of aortic aneurysms and highlight potential targets for therapeutic intervention. The classifier genes identified in this study, and validated by TaqMan real-time PCR, define a set of promising potential diagnostic markers, setting the stage for a blood-based gene expression test to facilitate early detection of TAA

Mineralocorticoid receptor antagonism of vamorolone: Evidence from LIONHEART and VISION-DMD clinical trials

The effect of vamorolone, the first dissociative corticosteroid for Duchenne muscular dystrophy (DMD), at the mineralocorticoid receptor (MR) was investigated in the Phase 1 mechanistic LIONHEART study and using serum samples from boys with DMD in the pivotal VISION-DMD trial. In LIONHEART, 30 healthy adult males were randomized 1:1:1 to vamorolone 20 mg/kg, eplerenone 200 mg, or no treatment arms. A fludrocortisone challenge was administered between –9 h and 24 h after treatment. The LIONHEART primary outcome was urinary Na+/K+ ratio; additional outcomes were pharmacokinetics, urine Na+ and K+ concentrations, and safety. In VISION-DMD, boys with DMD aged 4–7 years were treated with vamorolone 2 or 6 mg/kg/d for 48 weeks or with prednisone 0.75 mg/kg/d or placebo for 24 weeks followed by vamorolone 2 or 6 mg/kg/d for 20 weeks following a 4-week washout. Serum sample analysis from VISION-DMD used the SomaScan® 7 K assay. In LIONHEART, vamorolone reversed the decrease in urinary Na+/K+ ratio induced by fludrocortisone, confirming vamorolone MR antagonism. The maximum MRA effect of vamorolone was observed at 4–6 h post dose and was detectable until approximately 10 h post dose. Vamorolone reversed fludrocortisone induced Na+ retention with no evidence of decreased potassium excretion. Vamorolone 20 mg/kg was well tolerated, and results were consistent with known PK parameters. The VISION-DMD results showed vamorolone-specific increases in renin serum levels, as well as klotho, and calcium carrier proteins fetuin A and B, consistent with an MR antagonist effect. The available data confirm the MR antagonistic effect of vamorolone in humans. LIONHEART: NCT06649409; VISION-DMD: NCT03439670

Generating and repairing genetically programmed DNA breaks during immunoglobulin class switch recombination

Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR. Within the Ig locus, DNA repair pathways are diverted from their canonical role in maintaining genomic integrity to permit AID-directed mutation and deletion of gene coding segments. Recently identified proteins, genes, and regulatory networks have provided new insights into the temporally and spatially coordinated molecular interactions that control the formation and repair of DSBs within the Ig locus. Unravelling the genetic program that allows B cells to selectively alter the Ig coding regions while protecting non-Ig genes from DNA damage advances our understanding of the molecular processes that maintain genomic integrity as well as humoral immunity