Roles for the long non-coding RNA / in pancreatic beta cell function.

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell function. Here, we show that an lncRNA-transcribed antisense to Pax6, annotated as Pax6os1/PAX6-AS1, was upregulated by high glucose concentrations in human as well as murine beta cell lines and islets. Elevated expression was also observed in islets from mice on a high-fat diet and patients with type 2 diabetes.

LRH-1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype.

Background: The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross-talk between the immune system and insulin-producing beta cells, has hindered the development of effective disease-modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH-1/NR5A2 activation and improve islet survival.

Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells.

BCAS1 defines a heterogeneous cell population in diffuse gliomas.

Oligodendrocyte precursor markers have become of great interest to identify new diagnostic and therapeutic targets for diffuse gliomas, since state-of-the-art studies point towards immature oligodendrocytes as a possible source of gliomagenesis. Brain enriched myelin associated protein 1 (BCAS1) is a novel marker of immature oligodendrocytes and was proposed to contribute to tumorigenesis in non-central nervous system tumors. However, BCAS1 role in diffuse glioma is still underexplored.

The PTGS2/COX2-PGE signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus.

Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling.

Enzyme-Responsive Zr-Based Metal-Organic Frameworks for Controlled Drug Delivery: Taking Advantage of Clickable PEG-Phosphate Ligands.

We report for the first time the controlled drug release from a nanoscale Zr-based metal-organic framework (MOF), UiO-66, in the presence of the enzyme alkaline phosphatase (ALP). This unprecedented reactivity was possible thanks to the prior functionalization of the MOF with N-PEG-PO ligands, which were designed for three specific aims: (1) to impart colloidal stability in phosphate-containing media; (2) to endow the MOF with multifunctionality thanks to azide groups for the covalent attachment of an imaging agent by click-chemistry; and (3) to confer stimuli-responsive properties, specifically the selective release of doxorubicin triggered by the enzymatic activity of ALP. Cell studies revealed that the functionalization of the MOF with N-(PEG)-PO ligands improved their intracellular stability and led to a sustained drug release compared to the bare MOF.

Chromosomal Instability in Genome Evolution: From Cancer to Macroevolution.

The integrity of the genome is crucial for the survival of all living organisms. However, genomes need to adapt to survive certain pressures, and for this purpose use several mechanisms to diversify. Chromosomal instability (CIN) is one of the main mechanisms leading to the creation of genomic heterogeneity by altering the number of chromosomes and changing their structures.

Membrane Vesicles of Toxigenic Affect the Metabolism of Liver HepG2 Cells.

infection (CDI) appears to be associated with different liver diseases. secretes membrane vesicles (MVs), which may be involved in the development of nonalcoholic fatty liver disease (NALFD) and drug-induced liver injury (DILI). In this study, we investigated the presence of -derived MVs in patients with and without CDI, and analyzed their effects on pathways related to NAFLD and DILI in HepG2 cells.

Umbilical cord mesenchymal stromal cells transplantation delays the onset of hyperglycemia in the RIP-B7.1 mouse model of experimental autoimmune diabetes through multiple immunosuppressive and anti-inflammatory responses.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder specifically targeting pancreatic islet beta cells. Despite many efforts focused on identifying new therapies able to counteract this autoimmune attack and/or stimulate beta cells regeneration, TD1M remains without effective clinical treatments providing no clear advantages over the conventional treatment with insulin. We previously postulated that both the inflammatory and immune responses and beta cell survival/regeneration must be simultaneously targeted to blunt the progression of disease.

Human Omental Mesothelial Cells Impart an Immunomodulatory Landscape Impeding B- and T-Cell Activation.

Mesothelial cells form the mesothelium, a simple epithelium lining the walls of serous cavities and the surface of visceral organs. Although mesothelial cells are phenotypically well characterized, their immunoregulatory properties remain largely unknown, with only two studies reporting their capacity to inhibit T cells through TGF-β and their consumption of L-arginine by arginase-1. Whether human mesothelial cells can suppress other immune cells and possess additional leukosuppressive mechanisms, remain to be addressed to better delineate their therapeutic potential for cell therapy.

NR5A2/LRH-1 regulates the PTGS2-PGE-PTGER1 pathway contributing to pancreatic islet survival and function.

LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection.

Is Transcriptionally Regulated by EGR-1 during Nitric Oxide-Induced Endoderm Differentiation of Mouse Embryonic Stem Cells.

The transcription factor, early growth response-1 (EGR-1), is involved in the regulation of cell differentiation, proliferation, and apoptosis in response to different stimuli. EGR-1 is described to be involved in pancreatic endoderm differentiation, but the regulatory mechanisms controlling its action are not fully elucidated. Our previous investigation reported that exposure of mouse embryonic stem cells (mESCs) to the chemical nitric oxide (NO) donor diethylenetriamine nitric oxide adduct (DETA-NO) induces the expression of early differentiation genes such as pancreatic and duodenal homeobox 1 ().

The Role of Nitric Oxide in Stem Cell Biology.

Nitric oxide (NO) is a gaseous biomolecule endogenously synthesized with an essential role in embryonic development and several physiological functions, such as regulating mitochondrial respiration and modulation of the immune response. The dual role of NO in embryonic stem cells (ESCs) has been previously reported, preserving pluripotency and cell survival or inducing differentiation with a dose-dependent pattern. In this line, high doses of NO have been used in vitro cultures to induce focused differentiation toward different cell lineages being a key molecule in the regenerative medicine field.

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase.

Stemness of Human Pluripotent Cells: Hypoxia-Like Response Induced by Low Nitric Oxide.

The optimization of conditions to promote the stemness of pluripotent cells in vitro is instrumental for their use in advanced therapies. We show here that exposure of human iPSCs and human ESCs to low concentrations of the chemical NO donor DETA/NO leads to stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α) under normoxia, with this effect being dependent on diminished Pro 402 hydroxylation and decreased degradation by the proteasome. Moreover, the master genes of pluripotency, NANOG and OCT-4, were upregulated.

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation.

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer.

Human prefoldin modulates co-transcriptional pre-mRNA splicing.

Prefoldin is a heterohexameric complex conserved from archaea to humans that plays a cochaperone role during the co-translational folding of actin and tubulin monomers. Additional functions of prefoldin have been described, including a positive contribution to transcription elongation and chromatin dynamics in yeast. Here we show that prefoldin perturbations provoked transcriptional alterations across the human genome.

The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity.

We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues.

Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?

Diabetes is a chronic metabolic disease caused by an absolute or relative deficiency in functional pancreatic β-cells that leads to defective control of blood glucose. Current treatments for diabetes, despite their great beneficial effects on clinical symptoms, are not curative treatments, leading to a chronic dependence on insulin throughout life that does not prevent the secondary complications associated with diabetes. The overwhelming increase in DM incidence has led to a search for novel antidiabetic therapies aiming at the regeneration of the lost functional β-cells to allow the re-establishment of the endogenous glucose homeostasis.

A new hypothetical model for pancreatic development based on change in the cell division orientation.

Although lifelong renewal and additional compensatory growth in response to demand are undeniable facts, so far, no specific stem cells have been found for pancreatic cells. According to the consensus model, the development of pancreas results from the hierarchical differentiation of pluripotent stem cells towards the appearance of the first endocrine and exocrine cells at approximately 7.5 to 8th gestation week (GW) of human embryo.

Thyroid hormones in diabetes, cancer, and aging.

Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid hormones modulate cellular processes relevant for aging and for the majority of age-related diseases. While several studies have associated mild reductions on thyroid hormone function with exceptional longevity in animals and humans, alterations in thyroid hormones are serious medical conditions associated with unhealthy aging and premature death.

Corrigendum: Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus.

[This corrects the article DOI: 10.3389/fimmu.2019.

Role of non-coding RNAs as novel biomarkers for detection of colorectal cancer progression through interaction with the cell signaling pathways.

Colorectal cancer (CRC) is one of the most common types of cancer which affects the colon and the rectum. Approximately one third of annual CRC mortality occurs due to the late detection of this type of cancer. Therefore, there is an urgent need for more powerful diagnostic and prognostic tools for identification and treatment of colorectal tumorigenesis.

Overexpression of Canonical Prefoldin Associates with the Risk of Mortality and Metastasis in Non-Small Cell Lung Cancer.

Canonical prefoldin is a protein cochaperone composed of six different subunits (PFDN1 to 6). PFDN1 overexpression promotes epithelial-mesenchymal transition (EMT) and increases the growth of xenograft lung cancer (LC) cell lines. We investigated whether this putative involvement of canonical PFDN in LC translates into the clinic.