scholarly journals In vivo studies demonstrate that endothelin-1 traps are a potential therapy for type I diabetes

2019 ◽  
Vol 18 (1) ◽  
pp. 133-143 ◽  
Author(s):  
Arjun Jain ◽  
Vidhi Mehrotra ◽  
Ira Jha ◽  
Ashok Jain
Keyword(s):  
Type I Diabetes ◽  
In Vivo Studies ◽  
Type I ◽  
Endothelin 1

scholarly journals Surface-Modified Poly(l-lactide-co-glycolide) Scaffolds for the Treatment of Osteochondral Critical Size Defects—In Vivo Studies on Rabbits

2020 ◽  
Vol 21 (20) ◽  
pp. 7541
Author(s):  
Małgorzata Krok-Borkowicz ◽  
Katarzyna Reczyńska ◽  
Łucja Rumian ◽  
Elżbieta Menaszek ◽  
Maciej Orzelski ◽  
...  
Keyword(s):  
Bone Tissue ◽  
Tissue Regeneration ◽  
Photoelectron Spectroscopy ◽  
Sessile Drop ◽  
Bone Tissue Regeneration ◽  
In Vivo Studies ◽  
In Vivo Model ◽  
Type I ◽  
X Ray

Poly(l-lactide-co-glycolide) (PLGA) porous scaffolds were modified with collagen type I (PLGA/coll) or hydroxyapatite (PLGA/HAp) and implanted in rabbits osteochondral defects to check their biocompatibility and bone tissue regeneration potential. The scaffolds were fabricated using solvent casting/particulate leaching method. Their total porosity was 85% and the pore size was in the range of 250–320 µm. The physico-chemical properties of the scaffolds were evaluated using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), sessile drop, and compression tests. Three types of the scaffolds (unmodified PLGA, PLGA/coll, and PLGA/HAp) were implanted into the defects created in New Zealand rabbit femoral trochlears; empty defect acted as control. Samples were extracted after 1, 4, 12, and 26 weeks from the implantation, evaluated using micro-computed tomography (µCT), and stained by Masson–Goldner and hematoxylin-eosin. The results showed that the proposed method is suitable for fabrication of highly porous PLGA scaffolds. Effective deposition of both coll and HAp was confirmed on all surfaces of the pores through the entire scaffold volume. In the in vivo model, PLGA and PLGA/HAp scaffolds enhanced tissue ingrowth as shown by histological and morphometric analyses. Bone formation was the highest for PLGA/HAp scaffolds as evidenced by µCT. Neo-tissue formation in the defect site was well correlated with degradation kinetics of the scaffold material. Interestingly, around PLGA/coll extensive inflammation and inhibited tissue healing were detected, presumably due to immunological response of the host towards collagen of bovine origin. To summarize, PLGA scaffolds modified with HAp are the most promising materials for bone tissue regeneration.

scholarly journals Angiostatic activity of the antitumor cytokine interleukin-21

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4940-4947 ◽  
Author(s):  
Karolien Castermans ◽  
Sebastien P. Tabruyn ◽  
Rong Zeng ◽  
Judy R. van Beijnum ◽  
Cheryl Eppolito ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Angiogenesis ◽  
Chorioallantoic Membrane ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Type I ◽  
Stat3 Phosphorylation ◽  
Interleukin 21

Abstract Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.

scholarly journals Isopsoralen Enhanced Osteogenesis by Targeting AhR/ERα

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2600 ◽  
Author(s):  
Luna Ge ◽  
Yazhou Cui ◽  
Kai Cheng ◽  
Jinxiang Han
Keyword(s):  
Osteoblast Differentiation ◽  
Estrogen Receptor Alpha ◽  
Biological Effects ◽  
Hormone Deficiency ◽  
In Vivo Studies ◽  
Osteogenic Potential ◽  
Type I ◽  
Dependent Manner

Isopsoralen (IPRN), one of the main effective ingredients in Psoralea corylifolia Linn, has a variety of biological effects, including antiosteoporotic effects. In vivo studies show that IPRN can increase bone strength and trabecular bone microstructure in a sex hormone deficiency-induced osteoporosis model. However, the mechanism underlying this osteogenic potential has not been investigated in detail. In the present study, we investigated the molecular mechanism of IPRN-induced osteogenesis in MC3T3-E1 cells. Isopsoralen promoted osteoblast differentiation and mineralization, increased calcium nodule levels and alkaline phosphatase (ALP) activity and upregulated osteoblast markers, including ALP, runt-related transcription factor 2 (RUNX2), and collagen type I alpha 1 chain (COL1A1). Furthermore, IPRN limited the nucleocytoplasmic shuttling of aryl hydrocarbon receptor (AhR) by directly binding to AhR. The AhR target gene cytochrome P450 family 1 subfamily A member 1 (CYP1A1) was also inhibited in vitro and in vivo. This effect was inhibited by the AhR agonists indole-3-carbinol (I3C) and 3-methylcholanthrene (3MC). Moreover, IPRN also increased estrogen receptor alpha (ERα) expression in an AhR-dependent manner. Taken together, these results suggest that IPRN acts as an AhR antagonist and promotes osteoblast differentiation via the AhR/ERα axis.

scholarly journals Exchangeable Chaperone Modules Contribute to Specification of Type I and Type II Hsp40 Cellular Function

2004 ◽  
Vol 15 (2) ◽  
pp. 761-773 ◽  
Author(s):  
Chun-Yang Fan ◽  
Soojin Lee ◽  
Hong-Yu Ren ◽  
Douglas M. Cyr
Keyword(s):  
In Vivo Studies ◽  
Cell Physiology ◽  
Type I ◽  
Type Ii ◽  
Cellular Functions ◽  
Chaperone Function ◽  
Sequence Identity ◽  
Carboxyl Terminal ◽  
High Degree

Hsp40 family members regulate Hsp70s ability to bind nonnative polypeptides and thereby play an essential role in cell physiology. Type I and type II Hsp40s, such as yeast Ydj1 and Sis1, form chaperone pairs with cytosolic Hsp70 Ssa1 that fold proteins with different efficiencies and carry out specific cellular functions. The mechanism by which Ydj1 and Sis1 specify Hsp70 functions is not clear. Ydj1 and Sis1 share a high degree of sequence identity in their amino and carboxyl terminal ends, but each contains a structurally unique and centrally located protein module that is implicated in chaperone function. To test whether the chaperone modules of Ydj1 and Sis1 function in the specification of Hsp70 action, we constructed a set of chimeric Hsp40s in which the chaperone domains of Ydj1 and Sis1 were swapped to form YSY and SYS. Purified SYS and YSY exhibited protein-folding activity and substrate specificity that mimicked that of Ydj1 and Sis1, respectively. In in vivo studies, YSY exhibited a gain of function and, unlike Ydj1, could complement the lethal phenotype of sis1Δ and facilitate maintenance of the prion [RNQ+]. Ydj1 and Sis1 contain exchangeable chaperone modules that assist in specification of Hsp70 function.

Design of proteolytically stable RI-anchoring disruptor peptidomimetics for in vivo studies of anchored type I protein kinase A-mediated signalling

2009 ◽  
Vol 424 (1) ◽  
pp. 69-78 ◽  
Author(s):  
Eirik A. Torheim ◽  
Elisabeth Jarnæss ◽  
Birgitte Lygren ◽  
Kjetil Taskén
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Immunological Synapse ◽  
In Vivo Studies ◽  
Immune Reactivity ◽  
Type I ◽  
Improved Stability ◽  
Natural Amino Acids ◽  
Kinase A

We have reported previously the design of a RIAD (RI-anchoring disruptor) peptide that specifically displaces PKA (protein kinase A) type I from the AKAP (A-kinase-anchoring protein) ezrin, which is present in the immunological synapse of T-cells. This increases immune reactivity by reducing the threshold for activation and may prove a feasible approach for improving immune function in patients with cAMP-mediated T-cell dysfunction. However, the use of RIAD in biological systems is restricted by its susceptibility to enzymatic cleavage and, consequently, its short half-life in presence of the ubiquitous serum peptidases. In the present study, carefully selected non-natural amino acids were employed in the design of RIAD analogues with improved stability. The resulting peptidomimetics demonstrated up to 50-fold increased half-lives in serum compared with RIAD, while maintaining similar or improved specificity and potency with respect to disruption of PKA type I–AKAP interactions.

scholarly journals The Repertoire of Newly Developing Regulatory T Cells in the Type I Diabetes-Prone NOD Mouse is Very Diverse

2021 ◽  
Author(s):  
Ariel Galindo-Albarrán ◽  
Sarah Castan ◽  
Jérémy C. Santamaria ◽  
Olivier P. Joffre ◽  
Bart Haegeman ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Nod Mice ◽  
Vital Role ◽  
Nod Mouse ◽  
Type I ◽  
Antigen Specificity ◽  
Regulatory T Lymphocytes ◽  
Winged Helix Transcription Factor ◽  
Complementarity Determining Region

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their <i>in vivo</i> activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCRa and TCRb variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRa and TCRb chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

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.

Multi-scale Modeling and Sensitivity Analysis in Biological Systems

2021 ◽  
Author(s):  
◽  
An Do Dela
Keyword(s):  
Sensitivity Analysis ◽  
Computational Model ◽  
Type I Diabetes ◽  
Model Fitting ◽  
Type I ◽  
Stochastic Fluctuations ◽  
Highly Nonlinear ◽  
Critical Issues ◽  
The Face

We develop a multi-method sensitivity framework, which incorporates two variance-based methods, namely Sobol's method, eFAST and Derivative-based global measures to identify which parameters are most influential to the model outputs. A new implementation version of eFAST, namely DeFAST, was developed to address some critical issues in an existing published algorithm. Sensitivity analysis is a powerful tool in the modeling process that can be leveraged in various ways including model reduction and model fitting to data. There are two novel models that have been developed in this work where sensitivity analysis was applied. A stochastic computational model was constructed to understand mechanistic division event in Caulobacter crecentus bacterium in order to investigate how precise measurements can be made at the micron scale in the face of stochastic fluctuations. In this context, sensitivity analysis is used to derive a minimal PDE model in a minimal intermittent-search framework that could capture key results of the computational model closely. In addition, a new single compartment mathematical model for type I diabetes was analyzed to understand which parameters are the main driver of the blood glucose dynamics with the intention to understand the curative potential of dendritic-cell-based vaccine therapies. In this case, the sensitivity analysis was used to rank parameters and reduce the parameter space so that we can calibrate the model with in-vivo data in the future. The novelty of this work is that we validate our sensitivity analysis approach on highly nonlinear and stochastic models. These complex models present significant challenges for the application of sensitivity analysis algorithms as compared to the simpler case-study models that are typically used for testing sensitivity analysis methods.

Type I diabetes suppresses intracellular calcium ion increase normally evoked by heat stress in rat skeletal muscle

2021 ◽  
Author(s):  
Ryo Ikegami ◽  
Hiroaki Eshima ◽  
Toshiaki Nakajima ◽  
Shigeru Toyoda ◽  
David C. Poole ◽  
...  
Keyword(s):  
Heat Stress ◽  
Protein Expression ◽  
Type I Diabetes ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Type I ◽  
Male Wistar Rats ◽  
Intracellular Calcium Ion ◽  
And Function

Heat stress, via its effects on muscle intracellular Ca2+ concentrations ([Ca2+]i), has been invoked as a putative therapeutic countermeasure to Type 1 diabetes-induced muscle atrophy. Using in vivo muscle preparation we tested the hypothesis that impaired muscle Ca2+ homeostasis in type I diabetic rats is due to attenuated heat stress tolerance mediated via TRPV1. Male Wistar rats were assigned to 1 of 4 groups: 1.control 30oC (CONT 30oC), 2.CONT 40oC, 3.diabetes 30oC (DIA 30oC), 4.DIA 40oC. 40oC was selected because it just exceeds the TRPV1 activation threshold. Spinotrapezius muscles were exteriorized in vivo and loaded with the fluorescent Ca2+ probe Fura-2AM. [Ca2+]i was estimated over 20min using fluorescence microscopy in quiescent muscle held at the required temperature using calibrated heat source applied to the ventral muscle surface. Western blotting was performed to determine the protein expression levels of TRPV1 in spinotrapezius muscle. After 20min of heat stress, the CONT 40oC condition induced a 12.3% [Ca2+]i elevation that was absent from the DIA 40oC or other conditions. Thus, no significant differences were found among DIA 40oC, DIA 30oC and CONT 30oC. TRPV1 protein expression was decreased by 42.0% in DIA compared with CONT (P<0.05) and, unlike CONT, heat stress did not increase TRPV1 phosphorylation. In conclusion, diabetes suppresses TRPV1 protein expression and function and inhibits the elevated myocyte [Ca2+]i evoked normally by heat stress. These results suggest that capsaicin or other therapeutic strategies to increase Ca2+ accumulation via TRPV1 might be more effective than hyperthermic therapy for Type I diabetic patients.

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