Glycation of HDL blunts its anti-inflammatory and cholesterol efflux capacities in vitro, but has no effect in poorly controlled type 1 diabetes subjects

Type 1 diabetes (T1D), an autoimmune inflammatory disorder, develops as a consequence of pancreatic β-cell destruction and results in hyperglycaemia. Since current T1D therapy mainly involves insulin replacement, the aim of the present study was to evaluate the therapeutic potential of Origanum vulgare L. ssp. hirtum (Greek oregano) leaf extract rich in biophenols for the treatment of T1D. The phytochemical profile of methanolic oregano extract (MOE) and aqueous oregano extract (AOE) was determined by liquid chromatography/electrospray ion-trap tandem MS (LC/DAD/ESI-MSn), while their main compounds were quantified by HPLC with diode array detection. After establishing their potent in vitro antioxidant activity, the extracts were administered to C57BL/6 mice treated with multiple low doses of streptozotocin for diabetes induction. While prophylactic AOE therapy had no impact on diabetes induction, MOE reduced diabetes incidence and preserved normal insulin secretion. In addition, MOE scavenged reactive oxygen and nitrogen species and, therefore, alleviated the need for the up-regulation of antioxidant enzymes. MOE treatment specifically attenuated the pro-inflammatory response mediated by T helper 17 cells and enhanced anti-inflammatory T helper 2 and T regulatory cells through the impact on specific signalling pathways and transcription factors. Importantly, MOE preserved β-cells from in vitro apoptosis via blockade of caspase 3. Finally, rosmarinic acid, a predominant compound in MOE, exhibited only partial protection from diabetes induction. In conclusion, acting as an antioxidant, immunomodulator and in an anti-apoptotic manner, MOE protected mice from diabetes development. Seemingly, there is more than one compound responsible for the beneficial effect of MOE.

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Effect of Different Cereal Peptides on the Development of Type 1 Diabetes is Associated with Their Anti‐inflammatory Ability: In Vitro and In Vivo Studies

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201800987 ◽

2019 ◽

Vol 63 (11) ◽

pp. 1800987 ◽

Cited By ~ 1

Author(s):

Suling Sun ◽

Hao Zhang ◽

Kai Shan ◽

Tianjun Sun ◽

Mengyuan Lin ◽

...

Keyword(s):

Type 1 Diabetes ◽

In Vivo Studies ◽

Anti Inflammatory

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Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

Microorganisms ◽

10.3390/microorganisms9061177 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1177

Author(s):

Abdulaziz Alhazmi ◽

Magloire Pandoua Nekoua ◽

Hélène Michaux ◽

Famara Sane ◽

Aymen Halouani ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Viral Infections ◽

Lymphoid Organ ◽

Thymic Epithelial Cells ◽

Central Tolerance ◽

Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

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Development of a Bioartificial Vascular Pancreas

Journal of Tissue Engineering ◽

10.1177/20417314211027714 ◽

2021 ◽

Vol 12 ◽

pp. 204173142110277

Author(s):

Edward X Han ◽

Juan Wang ◽

Mehmet Kural ◽

Bo Jiang ◽

Katherine L Leiby ◽

...

Keyword(s):

Type 1 Diabetes ◽

Pancreatic Islets ◽

Vascular Graft ◽

Term Treatment ◽

Diffusion Limitations ◽

Human Scale ◽

Arterial Blood ◽

Long Term Treatment

Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.

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Anti-inflammatory effects of C-peptide on kidney of type 1 diabetes mellitus animal model

Molecular Biology Reports ◽

10.1007/s11033-019-05152-4 ◽

2019 ◽

Vol 47 (1) ◽

pp. 721-726 ◽

Cited By ~ 2

Author(s):

Michelle T. Alves ◽

Amanda C. S. Chaves ◽

Ana Paula M. Almeida ◽

Ana Cristina Simões e Silva ◽

Stanley de A. Araújo ◽

...

Keyword(s):

Diabetes Mellitus ◽

Animal Model ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

C Peptide ◽

Anti Inflammatory

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Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

Frontiers in Endocrinology ◽

10.3389/fendo.2021.635662 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kriti Joshi ◽

Fergus Cameron ◽

Swasti Tiwari ◽

Stuart I. Mannering ◽

Andrew G. Elefanty ◽

...

Keyword(s):

Type 1 Diabetes ◽

Stem Cell ◽

Genetic Variants ◽

Genetic Background ◽

Pluripotent Stem Cell ◽

Cell Types ◽

Polygenic Inheritance

Induced pluripotent stem cell (iPSC) technology is increasingly being used to create in vitro models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an in vitro model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from in vitro and in vivo sources. In this review we imagine what an ideal in vitro model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.

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Glycosylation of CaV3.2 Channels Contributes to the Hyperalgesia in Peripheral Neuropathy of Type 1 Diabetes

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.605312 ◽

2020 ◽

Vol 14 ◽

Author(s):

Sonja Lj. Joksimovic ◽

J. Grayson Evans ◽

William E. McIntire ◽

Peihan Orestes ◽

Paula Q. Barrett ◽

...

Keyword(s):

Type 1 Diabetes ◽

Adult Female ◽

Molecular Mechanisms ◽

Sprague Dawley ◽

Knock Out ◽

Peripheral Diabetic Neuropathy ◽

Novel Treatments

Our previous studies implicated glycosylation of the CaV3.2 isoform of T-type Ca2+ channels (T-channels) in the development of Type 2 painful peripheral diabetic neuropathy (PDN). Here we investigated biophysical mechanisms underlying the modulation of recombinant CaV3.2 channel by de-glycosylation enzymes such as neuraminidase (NEU) and PNGase-F (PNG), as well as their behavioral and biochemical effects in painful PDN Type 1. In our in vitro study we used whole-cell recordings of current-voltage relationships to confirm that CaV3.2 current densities were decreased ~2-fold after de-glycosylation. Furthermore, de-glycosylation induced a significant depolarizing shift in the steady-state relationships for activation and inactivation while producing little effects on the kinetics of current deactivation and recovery from inactivation. PDN was induced in vivo by injections of streptozotocin (STZ) in adult female C57Bl/6j wild type (WT) mice, adult female Sprague Dawley rats and CaV3.2 knock-out (KO mice). Either NEU or vehicle (saline) were locally injected into the right hind paws or intrathecally. We found that injections of NEU, but not vehicle, completely reversed thermal and mechanical hyperalgesia in diabetic WT rats and mice. In contrast, NEU did not alter baseline thermal and mechanical sensitivity in the CaV3.2 KO mice which also failed to develop painful PDN. Finally, we used biochemical methods with gel-shift analysis to directly demonstrate that N-terminal fragments of native CaV3.2 channels in the dorsal root ganglia (DRG) are glycosylated in both healthy and diabetic animals. Our results demonstrate that in sensory neurons glycosylation-induced alterations in CaV3.2 channels in vivo directly enhance diabetic hyperalgesia, and that glycosylation inhibitors can be used to ameliorate painful symptoms in Type 1 diabetes. We expect that our studies may lead to a better understanding of the molecular mechanisms underlying painful PDN in an effort to facilitate the discovery of novel treatments for this intractable disease.

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Type 1 Diabetes Mellitus Donor Mesenchymal Stromal Cells Exhibit Comparable Potency to Healthy Controls In Vitro

Stem Cells Translational Medicine ◽

10.5966/sctm.2015-0272 ◽

2016 ◽

Vol 5 (11) ◽

pp. 1485-1495 ◽

Cited By ~ 23

Author(s):

Lindsay C. Davies ◽

Jessica J. Alm ◽

Nina Heldring ◽

Guido Moll ◽

Caroline Gavin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Healthy Controls

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Evaluation In Vivo and In Vitro of the Antioxidant, Antinociceptive, and Anti-Inflammatory Activities of Biflavonoids From Ouratea hexasperma and O. ferruginea

Natural Product Communications ◽

10.1177/1934578x19856802 ◽

2019 ◽

Vol 14 (6) ◽

pp. 1934578X1985680 ◽

Cited By ~ 1

Author(s):

Poliana de Araujo Oliveira ◽

Queli Cristina Fidelis ◽

Thayane Ferreira da Costa Fernandes ◽

Milene Conceição de Souza ◽

Dayane Magalhães Coutinho ◽

...

Keyword(s):

Type I Collagen ◽

In Vivo Model ◽

Type I ◽

Anti Inflammatory ◽

Vitro Model ◽

Factor Α ◽

Necrosis Factor

Ouratea species are used for the treatment of inflammation-related diseases such as rheumatism and arthritic disorders. The Ouratea genus is a rich source of flavonoids and bioflavonoids and for this reason we evaluated the effects of the biflavonoid fractions from the leaves of O. hexasperma (OHME) and O. ferruginea (OFME) in the in vivo model of complete Freund’s adjuvant (CFA)-induced arthritis and in the in vitro model of oxidative stress and cellular viability. The CFA-induced arthritis model in rats was followed by paw volume, articular incapacitation and Randall-selitto models, as well as quantification of cytokines and serum C-terminal telopeptide of type I collagen levels. OHME and OFME demonstrated antinociceptive and anti-inflammatory activities, as well as improvement in articular incapacity and reduction in levels of interleukin 1β (IL-1β), IL-6, tumor necrosis factor α, and type 1 collagen, and increased cell viability. No adverse effects were observed. The results suggest that OHME and OFME can reduce inflammation and bone resorption besides their antioxidant action.

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