scholarly journals A bioinspired scaffold for rapid oxygenation of cell encapsulation systems

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Long-Hai Wang ◽  
Alexander Ulrich Ernst ◽  
Duo An ◽  
Ashim Kumar Datta ◽  
Boris Epel ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Type I Diabetes ◽  
Cell Encapsulation ◽  
Type I ◽  
Encapsulated Cells ◽  
Biomimetic Scaffold ◽  
Immunocompetent Mice ◽  
Air Channels ◽  
Vitro Analysis

AbstractInadequate oxygenation is a major challenge in cell encapsulation, a therapy which holds potential to treat many diseases including type I diabetes. In such systems, cellular oxygen (O2) delivery is limited to slow passive diffusion from transplantation sites through the poorly O2-soluble encapsulating matrix, usually a hydrogel. This constrains the maximum permitted distance between the encapsulated cells and host site to within a few hundred micrometers to ensure cellular function. Inspired by the natural gas-phase tracheal O2 delivery system of insects, we present herein the design of a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O2 diffusivity than hydrogels. We incorporate the scaffold into a bulk hydrogel containing cells, which facilitates rapid O2 transport through the whole system to cells several millimeters away from the device-host boundary. A computational model, validated by in vitro analysis, predicts that cells and islets maintain high viability even in a thick (6.6 mm) device. Finally, the therapeutic potential of the device is demonstrated through the correction of diabetes in immunocompetent mice using rat islets for over 6 months.

scholarly journals Development of Small-Molecule STING Activators for Cancer Immunotherapy

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Hee Ra Jung ◽  
Seongman Jo ◽  
Min Jae Jeon ◽  
Hyelim Lee ◽  
Yeonjeong Chu ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cyclic Gmp ◽  
Therapeutic Potential ◽  
Interferon Response ◽  
Type I ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Sting Pathway

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

DISTINCTIVE FEATURES OF PROCOAGULANT RESPONSE OF MONOCYTES FROM DIABETIC PATIENTS

1987 ◽  
Author(s):  
B JUDE ◽  
A WATEL ◽  
D FONTAINE ◽  
P FONTAINE ◽  
A COSSON
Keyword(s):  
Type I Diabetes ◽  
Vascular Complications ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Diabetic Patients ◽  
Type I ◽  
Factor X ◽  
Female Ratio ◽  
Male Female Ratio

Hypercoagulability is one of the possible factors reported in genesis or aggravation of vascular complications in diabetes mellitus. We therefore examined procoagulant activity (PCA) of disrupted monocytes frcm 26 patients with Type I diabetes and 6 with Type II, versus 32 control subjects (male/ female ratio = 1 in each group).Diabetes monocytes exhibited a slight but detectable PCA before any incubation or in vitro stimulation, whereas control monocytes did not. Data obtained with coagulation factor deficient plasmas or phospholipase C indicated that PCA was tissue factor (TF) alone in 22 cases and TF associated with a significant amount of factor VII/VIIa activity in 10 cases.Incubation in serum free medium led to significant raise of PCA in diabetes cells when stimulated with endotoxin or not, and in control cells only after stimulation. Furthermore, PCA appeared earlier in diabetes monocytes than in control ones, (4 hours, versus 20 hours). PCA frcm control cells was FT-like. PCA frcm diabetes cells was FT-like when no VII/VIIa activity was present on non-stimulated cells, and prothrombinase-like when VII/VIIa activity was early associated with the cells. In the latter case, trace amounts of factor X activity were also detectable. Whether factor VII and factor X activities were of plasmatic origin and associated to the cells, or synthesized in vitro by the cells remains unclear. The characteristics of PCA were net correlated with clinical features (age, diabetic complications) nor with the type of diabetes.Our data suggest that in diabetes patients, monocytes exhibit an increased PCA, possibly corresponding to a baseline stimulation, or at least a higher responsiveness to undergoing stimuli in vitro.

scholarly journals The tyrosine kinase FRK/RAK participates in cytokine-induced islet cell cytotoxicity

2004 ◽  
Vol 382 (1) ◽  
pp. 261-268 ◽  
Author(s):  
Michael WELSH ◽  
Charlotte WELSH ◽  
Maria EKMAN ◽  
Johan DIXELIUS ◽  
Robert HÄGERKVIST ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Type I Diabetes ◽  
Type I ◽  
Β Cell ◽  
Main Site

Hallmarks of the inflammatory process in Type I diabetes are macrophage activation, local release of β-cell-toxic cytokines and infiltration of cytotoxic T lymphocytes. We have observed recently that mice overexpressing active FRK (fyn-related kinase)/RAK (previously named GTK/Bsk/IYK, where GTK stands for gut tyrosine kinase, Bsk for β-cell Src-homology kinase and IYK for intestinal tyrosine kinase) in β-cells exhibit increased susceptibility to β-cell-toxic events, and therefore, we now attempt to find a more precise role for FRK/RAK in these processes. Phosphopeptide mapping of baculovirus-produced mouse FRK/RAK revealed an autophosphorylation pattern compatible with Tyr-394 being the main site. No evidence for in vitro phosphorylation of the C-terminal regulatory sites Tyr-497 and Tyr-504 was obtained, nor was there any indication of in vitro regulation of FRK/RAK kinase activity. Screening a panel of known tyrosine kinase inhibitors for their ability to inhibit FRK/RAK revealed several compounds that inhibited FRK/RAK, with a potency similar to that reported for their ability to inhibit other tyrosine kinases. Cytokine-induced islet toxicity was reduced in islets isolated from FRK/RAK knockout mice and this occurred without effects on the production of nitric oxide. Addition of the nitric oxide inhibitor nitroarginine to FRK/RAK knockout islets exposed to cytokines decreased cell death to a basal level. In normal islets, cytokine-induced cell death was inhibited by the addition of two FRK/RAK inhibitors, SU4984 and D-65495, or by transfection with short interfering RNA against FRK/RAK. It is concluded that FRK/RAK contributes to cytokine-induced β-cell death, and inhibition of this kinase could provide means to suppress β-cell destruction in Type I diabetes.

scholarly journals A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates

2021 ◽  
Author(s):  
Simon Ströbel ◽  
Radina Kostadinova ◽  
Katia Fiaschetti-Egli ◽  
Jana Rupp ◽  
Manuela Bieri ◽  
...  
Keyword(s):  
Complex Disease ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Therapeutic Interventions ◽  
Type I ◽  
Drug Candidates ◽  
Procollagen Type ◽  
Alcoholic Steatohepatitis ◽  
Inflammatory Stimuli

Abstract Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.

scholarly journals Lipin1 Is Involved in the Pathogenesis of Diabetic Encephalopathy through the PKD/Limk/Cofilin Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Min Xie ◽  
Meijian Wang ◽  
Wei Liu ◽  
Min Xu ◽  
Pan Shang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Rat Model ◽  
Type I Diabetes ◽  
Type I ◽  
Protective Effects ◽  
Diabetic Encephalopathy ◽  
Neuroprotective Effects ◽  
Lim Kinase ◽  
Ca1 Region

Diabetic encephalopathy is a type of central diabetic neuropathy resulting from diabetes mainly manifested as cognitive impairments. However, its underlying pathogenesis and effective treatment strategies remain unclear. In the present study, we investigated the effect of Lipin1, a phosphatidic acid phosphatase enzyme, on the pathogenesis of diabetic encephalopathy. We found that in vitro, Lipin1 exerts protective effects on high glucose-induced reductions of PC12 cell viability, while in vivo, Lipin1 is downregulated within the CA1 hippocampal region in a type I diabetes rat model. Increased levels of Lipin1 within the CA1 region are accompanied with protective effects including amelioration of dendritic spine and synaptic deficiencies, phosphorylation of the synaptic plasticity-related proteins, LIM kinase 1 (p-limk1) and cofilin, as well as increases in the synthesis of diacylglycerol (DAG), and the expression of phosphorylated protein kinase D (p-PKD). These effects are associated with the rescue of cognitive disorders as shown in this rat model of diabetes. In contrast, knockdown of Lipin1 within the CA1 region enhanced neuronal abnormalities and the genesis of cognitive impairment in rats. These results suggest that Lipin1 may exert neuroprotective effects involving the PKD/Limk/Cofilin signaling pathway and may serve as a potential therapeutic target for diabetic encephalopathy.

Towards the Development of a Bioartificial Pancreas: Effects of Poly-l-Lysine on Alginate Beads with BTC3 Cells

1997 ◽  
Vol 6 (4) ◽  
pp. 395-402 ◽  
Author(s):  
J.P. Benson ◽  
K.K. Papas ◽  
I. Constantinidis ◽  
A. Sambanis
Keyword(s):  
Type I Diabetes ◽  
Alginate Beads ◽  
Transformed Cells ◽  
Type I ◽  
Cell Aggregates ◽  
Bioartificial Pancreas ◽  
Insulin Secreting Cells ◽  
Tissue Construct

A bioartificial tissue construct that consists of insulin-secreting cells entrapped in an alginate/poly-l-lysine (PLL) matrix offers a promising approach for the treatment of type I diabetes. Use of transformed cells has been proposed as a solution to the cell availability problem posed by islets. The growth characteristics of transformed cells in their sequestered environment and the effects of PLL on their metabolic and secretory activities have not yet been characterized. Our data demonstrate that mouse insulinoma βTC3 cells proliferate while they are entrapped in both PLL-free and PLL-coated alginate beads. During this process, cell aggregates develop in the bead periphery, which increase in number and size with time. PLL is crucial for the long-term in vitro structural stability of beads, and it does not appear to affect the metabolic and secretory activities of entrapped βTC3 cells. The implications of these findings in the development of a bioartificial pancreatic construct based on transformed cells are discussed.

scholarly journals SENP3 regulates high glucose-induced endothelial dysfunction via ROS dependent signaling

2020 ◽  
Vol 17 (6) ◽  
pp. 147916412097089
Author(s):  
Fuheng Chen ◽  
Dongdong Ma ◽  
Aizhong Li
Keyword(s):  
Endothelial Dysfunction ◽  
High Glucose ◽  
Type I Diabetes ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Type I ◽  
Dependent Manner ◽  
Glucose Levels ◽  
And Migration

Background: The current study aimed to explore the role of SENP3 in endothelial cell dysfunction in a high-glucose setting. Methods: The gene and protein expressions of SENP3 in high-glucose cultured HAECs were examined using quantitative PCR and western blotting. The effects of SENP3 on HAEC viability, apoptosis, migration, and endothelial–monocyte adhesion were evaluated in vitro by knockdown. Moreover, a mouse streptozotocin-induced type I diabetes model was established for SENP3 expression assessment. In addition, the effects of SENP3 on ROS-related signaling pathways were investigated in high-glucose cultured HAECs. Results: Significantly increased levels of SENP3 mRNA and protein were found in high-glucose cultured HAECs in a time-dependent manner. SENP3 knockdown reversed high glucose-induced HAEC viability, apoptosis, and migration reduction. SENP3 knockdown attenuated the high glucose-induced intercellular adhesion of THP-1 monocytic cells and HAECs via downregulation of ICAM-1 and VCAM-1 expression. Increased levels of SENP3, ICAM-1, and VCAM-1 expression were observed in the aorta tissue of mice with type I diabetes. Downregulation of SENP3 expression was observed in HAECs cultured with high glucose levels using the free radical scavenger N-acetyl-L-cysteine or NOX4 siRNA. Conclusions: SENP3 was involved in high glucose-induced endothelial dysfunction, and ROS-dependent signaling served as the mechanism.

Erectile dysfunction in the type II diabetic db/db mouse: impaired venoocclusion with altered cavernosal vasoreactivity and matrix

2008 ◽  
Vol 294 (5) ◽  
pp. H2204-H2211 ◽  
Author(s):  
Ian P. Luttrell ◽  
Mei Swee ◽  
Barry Starcher ◽  
William C. Parks ◽  
Kanchan Chitaley
Keyword(s):  
Erectile Dysfunction ◽  
Erectile Function ◽  
Leptin Receptor ◽  
Science Studies ◽  
Type I Diabetes ◽  
Type I ◽  
Mrna Levels ◽  
Type Ii

The number of men with type II diabetes-associated erectile dysfunction (ED) continues to grow rapidly; however, the majority of basic science studies has examined mechanisms of ED in animal models of type I diabetes. In this study, we first establish an in vivo mouse model of type II diabetic ED using the leptin receptor mutated db/ db and wild-type control BKS mouse. Furthermore, we hypothesized that dual mechanistic impairments contribute to the impaired erectile function in the type II diabetic mouse, altered vasoreactivity, and venoocclusive disorder. In vivo erectile function was measured as intracavernosal pressure (ICP) normalized to mean arterial pressure (MAP) following electrical stimulation of the cavernosal nerve. Venoocclusion was assessed by the maintenance of elevated in vivo ICP following intracorporal saline infusion. Vasoreactivity of isolated cavernosum in response to contractile and dilatory stimulation was examined in vitro by myography. Collagen and elastin content were evaluated by quantification of hydroxyproline and desmosine, respectively, as well as by quantitative PCR and histological analysis of isolated cavernosum. Erectile function was significantly decreased in db/ db vs. BKS mice in a manner consistent with impairments in venoocclusive ability and decreased inflow. Heightened vasoconstriction and attenuated dilation in cavernosum of db/ db vs. BKS mice suggest an overall lowered relaxation ability and thus impaired filling of the cavernosal spaces. A decrease in desmosine and hydroxyproline as well as lowered mRNA levels for tropoelastin, fibrillin-1, and α1(I) collagen were detected. These vasoreactive and sinusoidal matrix alterations may alter tissue compliance dispensability, preventing the normal expansion necessary for erection.

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