Structurally Minimalized and Druglike TGase2 Inhibitors Based on 7-Aminoquinoline-5,8-dione Scaffolds for the Treatment of Diabetic Retinopathy.

Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives.

Wafer-Scale Atomic Assembly for 2D Multinary Transition Metal Dichalcogenides for Visible and NIR Photodetection.

The tunable properties of 2D transition-metal dichalcogenide (TMDs) materials are extensively investigated for high-performance and wavelength-tunable optoelectronic applications. However, the precise modification of large-scale systems for practical optoelectronic applications remains a challenge. In this study, a wafer-scale atomic assembly process to produce 2D multinary (binary, ternary, and quaternary) TMDs for broadband photodetection is demonstrated.

Proinsulin C-peptide inhibits high glucose-induced migration and invasion of ovarian cancer cells.

Proinsulin C-peptide, a biologically active polypeptide released from pancreatic β-cells, is known to prevent hyperglycemia-induced microvascular leakage; however, the role of C-peptide in migration and invasion of cancer cells is unknown. Here, we investigated high glucose-induced migration and invasion of ovarian cancer cells and the inhibitory effects of human C-peptide on metastatic cellular responses. In SKOV3 human ovarian cancer cells, high glucose conditions activated a vicious cycle of reactive oxygen species (ROS) generation and transglutaminase 2 (TGase2) activation through elevation of intracellular Ca levels.

Therapeutic effect of ultra-long-lasting human C-peptide delivery against hyperglycemia-induced neovascularization in diabetic retinopathy.

Neovascularization is a hallmark of the late stages of diabetic retinopathy (DR) leading to blindness. The current anti-DR drugs have clinical disadvantages including short circulation half-lives and the need for frequent intraocular administration. New therapies with long-lasting drug release and minimal side effects are therefore needed.

Simultaneous attenuation of hyperglycemic memory-induced retinal, pulmonary, and glomerular dysfunctions by proinsulin C-peptide in diabetes.

Background: Hyperglycemic memory (HGM) is a pivotal phenomenon in the development of diabetic complications. Although coincident diabetic complications are reported, research on their development and treatment is limited. Thus, we investigated whether C-peptide can simultaneously inhibit HGM-induced retinal, pulmonary, and glomerular dysfunctions in diabetic mice supplemented with insulin.

Systemic C-peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF-induced pathological events in diabetes.

Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C-peptide has been shown to be beneficial against hyperglycemia-induced microvascular leakage in the retina of diabetes; however, the effect of C-peptide on diabetes-induced retinal neurodegeneration remains unknown. Moreover, extraocular C-peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied.

Dopamine ameliorates hyperglycemic memory-induced microvascular dysfunction in diabetic retinopathy.

Dopamine is a neurotransmitter that mediates visual function in the retina and diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of blindness; however, the role of dopamine in retinal vascular dysfunction in DR remains unclear. Here, we report a mechanism of hyperglycemic memory (HGM)-induced retinal microvascular dysfunction and the protective effect of dopamine against the HGM-induced retinal microvascular leakage and abnormalities. We found that HGM induced persistent oxidative stress, mitochondrial membrane potential collapse and fission, and adherens junction disassembly and subsequent vascular leakage after blood glucose normalization in the mouse retinas.

C-peptide attenuates hyperglycemia-induced pulmonary fibrosis by inhibiting transglutaminase 2.

Proinsulin C-peptide has a protective effect against diabetic complications; however, its role in hyperglycemia-induced pulmonary fibrosis is unknown. In this study, we investigated the inhibitory effect of C-peptide on hyperglycemia-induced pulmonary fibrosis and the molecular mechanism of C-peptide action in the lungs of diabetic mice and in human pulmonary microvascular endothelial cells (HPMVECs). We found that, in the lungs of diabetic mice, C-peptide supplementation using osmotic pumps attenuated hyperglycemia-induced pulmonary fibrosis and expression of fibrosis-related proteins.

Midazolam Ameliorates Hyperglycemia-Induced Glomerular Endothelial Dysfunction by Inhibiting Transglutaminase 2 in Diabetes.

Midazolam is an anesthetic widely used for anxiolysis and sedation; however, to date, a possible role for midazolam in diabetic kidney disease remains unknown. Here, we investigated the effect of midazolam on hyperglycemia-induced glomerular endothelial dysfunction and elucidated its mechanism of action in kidneys of diabetic mice and human glomerular microvascular endothelial cells (HGECs). We found that, in diabetic mice, subcutaneous midazolam treatment for 6 weeks attenuated hyperglycemia-induced elevation in urine albumin/creatinine ratios.

Anti-metastatic effect of midazolam on melanoma B16F10 cells in the lungs of diabetic mice.

Midazolam is an anesthetic agent commonly used for anesthesia and sedation in surgery. However, there is no information on the role of midazolam in hyperglycemia-induced cancer metastasis to date. In this study, we investigated the effects of midazolam on inhibiting metastases in the lungs of diabetic mice and on human pulmonary microvascular endothelial cells (HPMVECs).

Activity-expression profiling of glucose-6-phosphate dehydrogenase in tissues of normal and diabetic mice.

Glucose-6-phosphate dehydrogenase (G6PD) plays a principal role in the regulation of oxidative stress by modulating the nicotinamide adenine dinucleotide phosphate pool and is expected to be associated with metabolic diseases such as diabetes mellitus (DM). However, it is unclear whether hyperglycemia increases G6PD activity levels in DM because suitable assays for quantifying the activity in a high-throughput manner are lacking. Using liquid droplet arrays tailored to analyze tissue lysates, we performed G6PD activity profiling in eight tissues of normal and diabetic mice: brain, heart, kidney, liver, lung, muscle, spleen, and thyroid.

The vicious cycle between transglutaminase 2 and reactive oxygen species in hyperglycemic memory-induced endothelial dysfunction.

Clinical trials suggested that the vascular system can remember episodes of poor glycemic control through a phenomenon known as hyperglycemic memory (HGM). HGM is associated with long-term diabetic vascular complications in type 1 and type 2 diabetes, although the molecular mechanism of that association is not clearly understood. We hypothesized that transglutaminase 2 (TGase2) and intracellular reactive oxygen species (ROS) play a key role in HGM-induced vascular dysfunction.

Insulin prevents pulmonary vascular leakage by inhibiting transglutaminase 2 in diabetic mice.

Aims: Insulin is a central peptide hormone required for carbohydrate metabolism; however, its role in diabetes-associated pulmonary disease is unknown. Here, we investigated the preventative effect of insulin against hyperglycemia-induced pulmonary vascular leakage and its molecular mechanism of action in the lungs of diabetic mice.

Main Methods: Vascular endothelial growth factor (VEGF) activated transglutaminase 2 (TGase2) by sequentially elevating intracellular Ca and reactive oxygen species (ROS) levels in primary human pulmonary microvascular endothelial cells (HPMVECs).

Inhibition of parasite invasion by monoclonal antibody against epidermal growth factor-like domain of Plasmodium vivax merozoite surface protein 1 paralog.

The Plasmodium vivax merozoite surface protein 1 paralog (PvMSP1P), which has epidermal growth factor (EGF)-like domains, was identified as a novel erythrocyte adhesive molecule. This EGF-like domain (PvMSP1P-19) elicited high level of acquired immune response in patients. Antibodies against PvMSP1P significantly reduced erythrocyte adhesion activity to its unknown receptor.

Proinsulin C-peptide prevents hyperglycemia-induced vascular leakage and metastasis of melanoma cells in the lungs of diabetic mice.

C-peptide has a beneficial effect against diabetic complications, but its role in hyperglycemia-induced metastasis is unknown. We investigated hyperglycemia-mediated pulmonary vascular leakage and metastasis and C-peptide inhibition of these molecular events using human pulmonary microvascular endothelial cells (HPMVECs) and streptozotocin-induced diabetic mice. VEGF, which is elevated in the lungs of diabetic mice, activated transglutaminase 2 (TGase2) in HPMVECs by sequential elevation of intracellular Ca and reactive oxygen species (ROS) levels.

On-chip dual enzyme activity assay to investigate regulation of the transamidase and kinase activities of transglutaminase 2.

Transglutaminase 2 (TGase2), a multifunctional enzyme exhibiting both transamidase and kinase activity, is involved in a variety of cellular processes and diseases. However, details of the regulation of TGase2 have not been reported due to the lack of a suitable assay to examine both activities on the same platform under near-physiologic conditions. Thus, we developed an on-chip dual enzyme activity assay for TGase2 to simultaneously monitor the transamidase and kinase activities.

The benzodiazepine anesthetic midazolam prevents hyperglycemia-induced microvascular leakage in the retinas of diabetic mice.

We investigated the beneficial effects of midazolam against vascular endothelial growth factor (VEGF)-induced vascular leakage and its molecular mechanism of action in human retinal endothelial cells (HRECs) and the retinas of diabetic mice. Midazolam inhibited VEGF-induced elevation of intracellular Ca, generation of reactive oxygen species (ROS), and transglutaminase activation in HRECs; these effects were reversed by the GABA, type A (GABA) receptor antagonist flumazenil but not by the translocator protein antagonist PK11195. Midazolam also prevented VEGF-induced disassembly of adherens junctions and in vitro permeability.

Identification of a novel merozoite surface antigen of Plasmodium vivax, PvMSA180.

Background: Although a number of Plasmodium vivax proteins have been identified, few have been investigated as potential vaccine candidates. This study characterized the Plasmodium vivax merozoite surface antigen 180 (PvMSA180, PVX_094920), a novel P. vivax antigenic protein.

Array-Based High-Throughput Analysis of Silk-Elastinlike Protein Polymer Degradation and C-Peptide Release by Proteases.

The objective of this study was to utilize an on-chip degradation assay to evaluate polymer depots and the predicted drug release from the depots. We conjugated four silk-elastinlike protein (SELP) polymers including SELP-815K, SELP-815K-RS1, SELP-815K-RS2, and SELP-815K-RS5 with a Cy5-NHS ester and fabricated SELP arrays by immobilizing the conjugated polymers onto well-type amine arrays. SELP polymer degradation rates were investigated by calculating the half-maximal effective concentration (EC50).

Identification of transglutaminase 2 kinase substrates using a novel on-chip activity assay.

Transglutaminase 2 (TG2) is an enzyme that plays a critical role in a wide variety of cellular processes through its multifunctional activities. TG2 kinase has emerged as an important regulator of apoptosis, as well as of chromatin structure and function. However, systematic investigation of TG2 kinase substrates is limited due to a lack of a suitable TG2 kinase activity assays.

Dammarenediol-II Prevents VEGF-Mediated Microvascular Permeability in Diabetic Mice.

Diabetic retinopathy is a major diabetic complication predominantly caused by vascular endothelial growth factor (VEGF)-induced vascular permeability in the retina; however, treatments targeting glycemic control have not been successful. Here, we investigated the protective effect of dammarenediol-II, a precursor of triterpenoid saponin biosynthesis, on VEGF-induced vascular leakage using human umbilical vein endothelial cells (HUVECs) and diabetic mice. We overproduced the compound in transgenic tobacco expressing Panax ginseng dammarenediol-II synthase gene and purified using column chromatography.