PAX4 gene delivery improves β-cell function in human islets of Type II diabetes.

Type II diabetes (T2D) stems from insulin resistance, with β-cell dysfunction as a hallmark in its progression. Studies reveal that β cells undergo apoptosis or dedifferentiation during T2D development. The transcription factor PAX4 is vital for β differentiation and survival, thus may be a potential enhancer of β-cell function in T2D islets.

Nickel selenide/g-CN heterojunction photocatalyst promotes CC coupling for photocatalytic CO reduction to ethane.

Photocatalytic CO reduction to generate high value-added and renewable chemicals is of great potential in facilitating the realization of closed-loop and carbon-neutral hydrogen economy. Stabilizing and accelerating the formation of COCO* intermediate is crucial to achieve high-selectivity ethane production. Herein, a novel 3D/2D NiSe/g-CN heterostructure that mesoscale hedgehog nickel selenide (NiSe) grown on the ultrathin g-CN nanosheets were synthesized via a successively high temperature calcination process and in-situ thermal injection method for the first time.

Pax4 in Health and Diabetes.

Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting β cell lineage. Knockout of Pax4 in animal models leads to the absence of β cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth.

Pax4 Gene Delivery Improves Islet Transplantation Efficacy by Promoting β Cell Survival and α-to-β Cell Transdifferentiation.

The transcription factor Pax4 plays an essential role in the development of insulin-producing β cells in pancreatic islets. Ectopic Pax4 expression not only promotes β cell survival but also induces α-to-β cell transdifferentiation. This dual functionality of Pax4 makes it an appealing therapeutic target for the treatment of insulin-deficient type 1 diabetes (T1D).

Intracrine Testosterone Activation in Human Pancreatic β-Cells Stimulates Insulin Secretion.

Testosterone (T) affects β-cell function in men and women. T is a prohormone that undergoes intracrine conversion in target tissues to the potent androgen dihydrotestosterone (DHT) via the enzyme 5α-reductase (5α-R) or to the active estrogen 17β-estradiol (E2) via the aromatase enzyme. Using male and female human pancreas sections, we show that the 5α-R type 1 isoform (SRD5A1) and aromatase are expressed in male and female β-cells.

Improved Dielectric Properties of Thermoplastic Polyurethane Elastomer Filled with Core-Shell Structured PDA@TiC Particles.

Insulating interlayer between nanoparticles and polymer matrix is crucial for suppressing the dielectric loss of polymer composites. In this study, titanium carbide (TiC) particles were surface modified by polydopamine (PDA), and the obtained PDA@TiC powders were used to reinforce thermoplastic polyurethane (TPU). The results indicate that the PDA@TiC were homogenously dispersed in the matrix compared with the pristine TiC, and that the PDA@TiC/TPU composites show improved dielectric and mechanical properties, i.

Genetic strategy to decrease complement activation with adenoviral therapies.

Background: A major obstacle to using recombinant adenoviral vectors in gene therapy is the natural ability of human adenovirus to activate the classical and alternate complement pathways. These innate immune responses contribute to hepatic adenoviral uptake following systemic delivery and enhance the humoral immune responses associated with adenoviral infection.

Methods: A recombinant Ad5 vector was genetically modified to display a peptide sequence ("rH17d'"), a known inhibitor of the classical complement pathway.

Development of insulin resistance in Nischarin mutant female mice.

Background/objectives: NISCH-STAB1 is a newly identified locus correlated to human waist-hip ratio (WHR), which is a risk indicator of developing obesity-associated diabetes. Our previous studies have shown that Nisch mutant male mice increased glucose tolerance in chow-fed conditions. Thus we hypothesized that Nisch mutant mice will have changes in insulin resistance, adipocytes, hepatic steatosis when mice are fed with high-fat diet (HFD).

GLP-1 Receptor in Pancreatic α-Cells Regulates Glucagon Secretion in a Glucose-Dependent Bidirectional Manner.

Glucagon-like peptide 1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1 receptor (GLP-1R) expression in α-cells using both antibody-dependent and antibody-independent strategies. A novel α-cell-specific GLP-1R knockout (αGLP-1R) mouse model was created and used to investigate its effects on glucagon secretion and glucose metabolism.

GRP94 Is an Essential Regulator of Pancreatic β-Cell Development, Mass, and Function in Male Mice.

Deficiencies in pancreatic β-cell mass contribute to both type 1 and type 2 diabetes. We investigated the role of the glucose-regulated protein (GRP) 94, an endoplasmic reticulum protein abundantly expressed in the pancreatic acini and islets, in β-cell development, survival, and function. We used a conditional knockout (KO) mouse in which the GRP94 gene, Hsp90b1, was specifically deleted in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells.

Effects of Linagliptin on Pancreatic Cells of Type 1 Diabetic Mice.

The dipeptidyl peptidase-4 inhibitor linagliptin promotes -cell survival and insulin secretion by prolonging endogenous glucagon-like peptide 1 (GLP-1) action and therefore helps to maintain normoglycemia in diabetic patients. The effect of linagliptin on glucagon-producing cells, however, was not clear. In this study, we investigated whether linagliptin had any effects on cells with regard to their proliferation and hormonal production using type 1 diabetes mouse models, including streptozotocin-induced and nonobese diabetes mice.

Regenerating β cells of the pancreas - potential developments in diabetes treatment.

Introduction: The etiology of diabetes is mainly attributed to insulin deficiency due to the lack of β cells (type 1), or to insulin resistance that eventually results in β cell dysfunction (type 2). Therefore, an ultimate cure for diabetes requires the ability to replace the lost insulin-secreting β cells. Strategies for regenerating β cells are under extensive investigation.

Carbon Monoxide Inhibits Islet Apoptosis via Induction of Autophagy.

Aim: Carbon monoxide (CO) functions as a therapeutic molecule in various disease models because of its anti-inflammatory and antiapoptotic properties. We investigated the capacity of CO to reduce hypoxia-induced islet cell death and dysfunction in human and mouse models.

Results: Culturing islets in CO-saturated medium protected them from hypoxia-induced apoptosis and preserved β cell function by suppressing expression of proapoptotic (Bim, PARP, Cas-3), proinflammatory (TNF-α), and endoplasmic reticulum (ER) stress (glucose-regulated protein 94, grp94, CHOP) proteins.

Differential Effects of Linagliptin on the Function of Human Islets Isolated from Non-diabetic and Diabetic Donors.

Linagliptin is a dipeptidyl Peptidase-4 (DPP-4) inhibitor that inhibits the degradation of glucagon-like peptide 1 (GLP-1), and has been approved for the treatment of type 2 diabetes (T2D) in clinic. Previous studies have shown linagliptin improves β cell function using animal models and isolated islets from normal subjects. Since β cell dysfunction occurs during diabetes development, it was not clear how human islets of T2D patients would respond to linagliptin treatment.

Intra-islet glucagon-like peptide 1.

Purpose: Glucagon-like peptide-1 (GLP-1) is originally identified in the gut as an incretin hormone, and it is potent in stimulating insulin secretion in the pancreas. However, increasing evidence suggests that GLP-1 is also produced locally within pancreatic islets. This review focuses on the past and current discoveries regarding intra-islet GLP-1 production and its functions.

Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.

Although men with testosterone deficiency are at increased risk for type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β cells. We show that male mice lacking AR in β cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS), leading to glucose intolerance. The AR agonist dihydrotestosterone (DHT) enhances GSIS in cultured male islets, an effect that is abolished in βARKO(-/y) islets and human islets treated with an AR antagonist.

Cell-Permeable Peptide Blocks TLR4 Signaling and Improves Islet Allograft Survival.

Toll-like receptor 4 (TLR4) activation in pancreatic β cells activates aberrant islet graft cellular pathways and contributes to immune rejection in allogeneic islet transplantation. As an approach to overcoming this problem, we determined the capacity of a 33-amino acid peptide consisting of a protein transduction domain (PTD) from the Hph-1 virus and a fragment of the intracellular domain of TLR4 from the C3H mice (PTD-dnTLR4) to block TLR4 signaling and improve allogeneic islet survival in vitro and after transplantation. The efficacy of PTD-dnTLR4 in blocking TLR4 signaling was assessed in the Raw264.

PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment.

The transcription factor Pax4 plays a critical role in the determination of α- versus β-cell lineage during endocrine pancreas development. In this study, we explored whether Pax4 gene transfer into α-cells could convert them into functional β-cells and thus provide therapeutic benefits for insulin-deficient diabetes. We found that Pax4 delivered by adenoviral vector, Ad5.

Progressive change of intra-islet GLP-1 production during diabetes development.

Background: Glucagon-like peptide 1 (GLP-1) and glucagon share the same precursor molecule proglucagon, but each arises from a distinct posttranslational process in a tissue-specific manner. Recently, it has been shown that GLP-1 is co-expressed with glucagon in pancreatic islet cells. This study was aimed to investigate the progressive changes of GLP-1 versus glucagon production in pancreatic islets during the course of diabetes development.

Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation.

Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis in the liver, and eventually leads to insulin resistance and type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of bilirubin, a powerful antioxidant, reduces hyperglycemia and ameliorates obesity in leptin-receptor-deficient (db/db) and diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with bilirubin or vehicle ip.

X-ray repair cross-complementing 1 polymorphism and prognosis of platinum-based chemotherapy in gastric and colorectal cancer: a meta-analysis.

Background And Aim: The relationships between the X-ray repair cross-complementing 1 (XRCC1) Arg399Gln polymorphism (rs25487, G > A) and responses to platinum-based chemotherapy of gastric and colorectal cancer patients are controversial. Therefore, we performed a meta-analysis to assess the relationships.

Methods: We retrieved the relevant articles from MEDLINE and EMBASE databases.

Using multivalent adenoviral vectors for HIV vaccination.

Adenoviral vectors have been used for a variety of vaccine applications including cancer and infectious diseases. Traditionally, Ad-based vaccines are designed to express antigens through transgene expression of a given antigen. For effective vaccine development it is often necessary to express or present multiple antigens to the immune system to elicit an optimal vaccine as observed preclinically with mosaic/polyvalent HIV vaccines or malaria vaccines.

FAK-related nonkinase is a multifunctional negative regulator of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease whose underlying molecular mechanisms are largely unknown. Herein, we show that focal adhesion kinase-related nonkinase (FRNK) plays a key role in limiting the development of lung fibrosis. Loss of FRNK function in vivo leads to increased lung fibrosis in an experimental mouse model.