Silencing the FABP3 gene in insulin-secreting cells reduces fatty acid uptake and protects against lipotoxicity.

BACKGROUND: Long-term exposure of pancreatic islets to fatty acids (FAs), common in obesity, metabolic syndrome, and type 2 diabetes, leads to a compensatory hyperactivity followed by inflammation, apoptosis, dysfunctional beta cells, and results in insulin dependence of the patient. Restriction of fatty uptake by islet beta cells may protect them from lipotoxicity. PURPOSE: Pancreatic islet beta cells express the fatty acid binding protein 3 (FABP3) to bind FAs and to orchestrate lipid signals. Based on this, we investigated whether downregulation of FABP3, by Fabp3 silencing, might slow lipid metabolism and protect against lipotoxicity in insulin-secreting cells. RESULTS: Neither Fabp3 silencing, nor overexpression affected the glucose-stimulated insulin secretion in absence of FAs. Fabp3 silencing decreased FA-uptake, lipid droplets formation, and the expression of the lipid accumulation-regulating gene Dgat1 in Ins1E cells. It reduced FA-induced inflammation by deactivation of NF-κB, which was associated with upregulation of IκBα and deactivation of the NF-κB p65 nuclear translocation, and the downregulation of the cytokines ILl-6, IL-1ß, and TNFα. Ins1E cells were protected from the FA-induced apoptosis as assessed by different parameters including DNA degradation and cleaved caspase-3 immunoblotting. Furthermore, FABP3 silencing improved the viability, Pdx1 gene expression, and the insulin-secreting function in cells long-term cultured with palmitic acid. All results were confirmed by the opposite action rendered by FABP3 overexpression. CONCLUSION: The present data reveals that pancreatic beta cells can be protected from lipotoxicity by inhibition of FA-uptake, intracellular utilization and accumulation. FABP3 inhibition, hence, may be a useful pharmaceutical approach in obesity, metabolic syndrome, and type 2 diabetes.

Constitutive immunity is influenced by avian influenza virus-induced modification of gut microbiota in Eurasian teal (Anas crecca).

Understanding the dynamics of migrant birds' gut microbial communities is essential for evaluating their ecological interactions, since these birds act as vectors for zoonotic viruses and their gut microbiome may have exceptional relationship with zoonotic viral infection. The Eurasian teal duck Anas crecca traverses continents during migration, combining and providing intercontinental links for avian influenza viruses (AIV) of different origins. The present study aimed to investigate how the AIV infection affects gut microbial composition and evaluate the consequent physiological stress and constitutive immunity of teal birds. Samples were collected from 2 flocks during their migratory stopover in northern Egypt. An important shift in gut microbiota of AIV-infected individuals has been detected by RT-PCR. In healthy teal, firmicutes dominated followed by proteobacteria, while the structure was reversed in infected birds. Infection with AIV significantly increased the stress hormone corticosterone, accompanied by a significant increase in both oxidative stress markers and antioxidants. Constitutive immunity, measured by plasma bactericidal effect against E. coli, the nonspecific natural antibodies, and the mediated complement activation, was reduced in AIV-infected teal birds. Constitutive immunity parameters were proportionally correlated to the firmicutes and inversely to the proteobacteria abundances, but not to the viral positivity. In conclusion, the present study provides initial evidence of the alteration of the gut microbiome in the Eurasian teal Anas crecca by AIV infection and demonstrates that the AIV-induced reduction in constitutive immunity is a consequence of the shift in microbiome composition rather than the virus infection itself or its induced stress.

Naturally-occurring carboxylic acids from traditional antidiabetic plants as potential pancreatic islet FABP3 inhibitors. A molecular docking-aided study.

The antidiabetic action of traditional plants is mostly attributed to their antioxidant and anti-inflammatory properties. These plants are still having some secrets, making them an attractive source that allows for investigating new drugs or uncovering precise pharmacologic antidiabetic functions of their constituents. In diabetes, which is a lipid disease, long-term exposure of pancreatic islet beta cells to fatty acids (FAs) increases basal insulin release, reduces glucose-stimulated insulin secretion, causes islet beta cell inflammation, failure and apoptosis. Pancreatic islet beta cells express fatty acid binding protein 3 (FABP3) that receives long-chain FAs and traffics them throughout different cellular compartments to be metabolized and render their effects. Inhibition of this FABP3 may retard FA metabolism and protect islet beta cells. Since FAs interact with FABPs by their carboxylic group, some traditionally-known antidiabetic plants were reviewed in the present study, searching for their components that have common features of FABP ligands, namely carboxylic group and hydrophobic tail. Many of these carboxylic acids were computationally introduced into the ligand-binding pocket of FABP3 and some of them exhibited FABP3 ligand possibilities. Among others, the naturally occurring ferulic, cleomaldeic, caffeic, sinapic, hydroxycinnamic, 4-p-coumaroylquinic, quinoline-2-carboxylic, chlorogenic, 6-hydroxykynurenic, and rosmarinic acids in many plants are promising candidates for being FABP3-specific inhibitors. The study shed light on repurposing these phyto-carboxylic acids to function as FABP inhibitors. However, more in-depth biological and pharmacological studies to broaden the understanding of this function are needed.

Anti-liver fibrosis activity of curcumin/chitosan-coated green silver nanoparticles.

Liver fibrosis results from the hepatic accumulation of the extracellular matrix accompanied by a failure of the mechanisms responsible for matrix dissolution. Pathogenesis of liver fibrosis is associated with many proteins from different cell types. In the present study, in silico molecular docking analysis revealed that curcumin may inhibit the fibrosis-mediating proteins PDGF, PDGFRB, TIMP-1, and TLR-9 by direct binding. Nano-formulation can overcome curcumin problems, increasing the efficacy of curcumin as a drug by maximizing its solubility and bioavailability, enhancing its membrane permeability, and improving its pharmacokinetics, pharmacodynamics and biodistribution. Therefore, green silver nanoparticles (AgNPs) were synthesized in the presence of sunlight by means of the metabolite of Streptomyces malachiticus, and coated with curcumin-chitosan mixture to serve as a drug delivery tool for curcumin to target CCl4-induced liver fibrosis mouse model. Fibrosis induction significantly increased hepatic gene expression of COL1A1, α-SMA, PDGFRB, and TIMP1, elevated hepatic enzymes, increased histopathological findings, and increased collagen deposition as determined by Mason's trichrome staining. Treatment with naked AgNPs tended to increase these inflammatory effects, while their coating with chitosan, similar to treatment with curcumin only, did not prevent the fibrogenic effect of CCl4. The induction of liver fibrosis was reversed by concurrent treatment with curcumin/chitosan-coated AgNPs. In this nano form, curcumin was found to be efficient as anti-liver fibrosis drug, maintaining the hepatic architecture and function during fibrosis development. This efficacy can be attributed to its inhibitory role through a direct binding to fibrosis-mediating proteins such as PDGFRB, TIMP-1, TLR-9 and TGF-ß.

Utility of BMI-1 and NANOG expression levels in survival prediction of pediatric acute lymphoblastic leukemia

ABSTRACT Background Acute lymphoblastic leukemia (ALL) is the most common malignancy in children characterized by the overproduction and accumulation of immature lymphoid cells in the bone marrow and peripheral blood. The BMI-1 is an important component of the Polycomb Repressive Complex-1 (PRC1). It is an important molecule for the self-renewal of hematopoietic stem cells (HSCs). The BMI-1 expression is generally high in HSCs and decreases after cell differentiation. The BMI-1 is required for the maintenance of normal and cancer stem cells and has been reported as an oncogene in various tumors. The NANOG is a homeodomain transcription factor responsible for maintaining the stem cell compartment at the blastocyst stage of developing embryos. The NANOG gene has been proven to be transcribed in CD34+ cells and different leukemic cells. Methods The ribonucleic acid (RNA) was extracted from the peripheral blood mononuclear cells (PBMNCs) of 30 pediatric ALL patients (16 B-ALL and 14 T-ALL) and 14 healthy controls. The Bmi-1 and NANOG expression levels were determined using the quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Results Compared to normal controls, patients with ALL exhibited upregulated levels of Bmi-1 (p = 0.03). Patients who overexpressed Bmi-1 and NANOG displayed a significantly worse survival than low-expressing patients (hazard ratio (HR) 5.74, 95% confidence interval (CI):1.48-22, p = 0.012 and HR 3.8, 95% CI:1.009-14.3, p = 0.048, respectively). Conclusions Taken together, these data suggest that the Bmi-1 and NANOG might serve as a novel survival predictor in ALL patients. Our observation also suggests that the Bmi-1 and NANOG could serve as new therapeutic targets for treatment of pediatric ALL.

Utility of BMI-1 and NANOG expression levels in survival prediction of pediatric acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children characterized by the overproduction and accumulation of immature lymphoid cells in the bone marrow and peripheral blood. The BMI-1 is an important component of the Polycomb Repressive Complex-1 (PRC1). It is an important molecule for the self-renewal of hematopoietic stem cells (HSCs). The BMI-1 expression is generally high in HSCs and decreases after cell differentiation. The BMI-1 is required for the maintenance of normal and cancer stem cells and has been reported as an oncogene in various tumors. The NANOG is a homeodomain transcription factor responsible for maintaining the stem cell compartment at the blastocyst stage of developing embryos. The NANOG gene has been proven to be transcribed in CD34+ cells and different leukemic cells. METHODS: The ribonucleic acid (RNA) was extracted from the peripheral blood mononuclear cells (PBMNCs) of 30 pediatric ALL patients (16 B-ALL and 14 T-ALL) and 14 healthy controls. The Bmi-1 and NANOG expression levels were determined using the quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Compared to normal controls, patients with ALL exhibited upregulated levels of Bmi-1 (p=0.03). Patients who overexpressed Bmi-1 and NANOG displayed a significantly worse survival than low-expressing patients (hazard ratio (HR) 5.74, 95% confidence interval (CI):1.48-22, p=0.012 and HR 3.8, 95% CI:1.009-14.3, p=0.048, respectively). CONCLUSIONS: Taken together, these data suggest that the Bmi-1 and NANOG might serve as a novel survival predictor in ALL patients. Our observation also suggests that the Bmi-1 and NANOG could serve as new therapeutic targets for treatment of pediatric ALL.

In vivo toxicity and antitumor activity of newly green synthesized reduced graphene oxide/silver nanocomposites.

A novel biosynthesis of dual reduced graphene oxide/silver nanocomposites (rGO/AgNC) using the crude metabolite of Escherichia coli D8 (MF06257) strain and sunlight is introduced in this work. Physicochemical analysis of these rGO/AgNC revealed that they are sheet-like structures having spherically shaped silver nanoparticles (AgNPs) with an average particle size of 8 to 17 nm, and their absorption peak ranged from 350 to 450 nm. The biosynthesized rGO/AgNC were characterized by UV-vis and FT-IR spectra, X-ray diffraction, Zeta potential and transmission electron microscopy. After the injection of these nanocomposites to mice, their uptake by the kidney and liver has been proven by the ultrastructural observation and estimation of the hepatic and renal silver content. These nanocomposites caused a moderate toxicity for both organs. Changes in the liver and kidney functions and histopathological effects had been observed. The rGO/AgNC revealed a remarkable antitumor effect. They showed a dose-dependent cytotoxic effect on Ehrlich ascites carcinoma (EAC) cells in vitro. Treatment of mice bearing EAC tumors intraperitoneally with 10 mg/kg rGO/AgNC showed an antiproliferative effect on EAC cells, reduced ascites volume, and maintained mice survival. The results indicate that this green synergy of silver nanoparticles with reduced graphene oxide may have a promising potential in cancer therapy.

The nucleolar-related protein Dyskerin pseudouridine synthase 1 (DKC1) predicts poor prognosis in breast cancer.

BACKGROUND: Hypertrophy of the nucleolus is a distinctive cytological feature of malignant cells and corresponds to aggressive behaviour. This study aimed to identify the key gene associated with nucleolar prominence (NP) in breast cancer (BC) and determine its prognostic significance. METHODS: From The Cancer Genome Atlas (TCGA) cohort, digital whole slide images identified cancers having NP served as label and an information theory algorithm was applied to find which mRNA gene best explained NP. Dyskerin Pseudouridine Synthase 1 (DKC1) was identified. DKC1 expression was assessed using mRNA data of Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1980) and TCGA (n = 855). DKC1 protein expression was assessed using immunohistochemistry in Nottingham BC cohort (n = 943). RESULTS: Nuclear and nucleolar expressions of DKC1 protein were significantly associated with higher tumour grade (p < 0.0001), high nucleolar score (p < 0.001) and poor Nottingham Prognostic Index (p < 0.0001). High DKC1 expression was associated with shorter BC-specific survival (BCSS). In multivariate analysis, DKC1 mRNA and protein expressions were independent risk factors for BCSS (p < 0.01). CONCLUSION: DKC1 expression is strongly correlated with NP and its overexpression in BC is associated with unfavourable clinicopathological characteristics and poor outcome. This has been a detailed example in the correlation of phenotype with genotype.

RETRACTED: Dietary oligosaccharides attenuate DSS-induced colitis in mice, induce PGlyRP3 expression, and inhibit NF-κB and MEK/ERK signaling.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editors. The Editors of Cellular Immunology have been informed by Elsevier that the article had been submitted to another journal while under consideration at "Cellular Immunology", which is a case of double submission. Based on the above infringement and its deleterious impact on the mutual trust necessary for the evaluation of scientific work - the corresponding authors had stated that the article was not submitted to another journal - it was decided to retract this article.