scholarly journals β-Cells Different Vulnerability to the Parkinsonian Neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP+) and 6-Hydroxydopamine (6-OHDA)

2021 ◽  
Vol 14 (8) ◽  
pp. 767
Author(s):  
Marco Carli ◽  
Francesca Vaglini ◽  
Eleonora Risaliti ◽  
Gianluca Citi ◽  
Matilde Masini ◽  
...  
Keyword(s):  
Cell Lines ◽  
Dopaminergic Neurons ◽  
Cell Types ◽  
Population Based ◽  
Β Cells ◽  
Pharmacological Agents ◽  
Develop Type ◽  
6 Hydroxydopamine ◽  
Nanomolar Range

Neurotoxins such as rotenone, 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) are well known for their high toxicity on dopaminergic neurons and are associated with Parkinson’s disease (PD) in murine models and humans. In addition, PD patients often have glucose intolerance and may develop type 2 diabetes (T2D), whereas T2D patients have higher risk of PD compared to general population. Based on these premises, we evaluated the toxicity of these three toxins on pancreatic β-cell lines (INS-1 832/13 and MIN6) and we showed that rotenone is the most potent for reducing β-cells viability and altering mitochondrial structure and bioenergetics in the low nanomolar range, similar to that found in dopaminergic cell lines. MPP+ and 6-OHDA show similar effects but at higher concentration. Importantly, rotenone-induced toxicity was counteracted by α-tocopherol and partially by metformin, which are endowed with strong antioxidative and cytoprotective properties. These data show similarities between dopaminergic neurons and β-cells in terms of vulnerability to toxins and pharmacological agents capable to protect both cell types.

scholarly journals Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

2021 ◽  
Vol 22 (3) ◽  
pp. 1059
Author(s):  
Bodo C. Melnik
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Dopaminergic Neurons ◽  
Vagal Nerve ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

scholarly journals Increased vimentin in human α- and β-cells in type 2 diabetes

2017 ◽  
Vol 233 (3) ◽  
pp. 217-227 ◽  
Author(s):  
Maaike M Roefs ◽  
Françoise Carlotti ◽  
Katherine Jones ◽  
Hannah Wills ◽  
Alexander Hamilton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epithelial To Mesenchymal Transition ◽  
Islet Cells ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Cell Expression

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

Long-term dietary administration of diethyl phthalate triggers loss of insulin sensitivity in two key insulin target tissues of mice

2020 ◽  
Vol 39 (7) ◽  
pp. 984-993
Author(s):  
S Mondal ◽  
S Mukherjee
Keyword(s):  
Close Association ◽  
Phthalate Esters ◽  
Cell Types ◽  
Population Based ◽  
Environmental Chemicals ◽  
Diethyl Phthalate ◽  
The Past ◽  
Impaired Insulin

Over the past years, a growing body of work has linked numerous pervasive environmental chemicals with a multitude of adverse reproductive, developmental, behavioral, and metabolic changes in humans and animal models. Plasticizers include a wide variety of phthalate esters that are extensively used in a host of personal day care and cosmetic products. Many population-based studies have indicated a close association between diethyl phthalate (DEP) and diabetes albeit the mechanisms remain much unexplored. Presently, we report that long-term dietary administration of DEP to adult male Swiss albino mice at two different concentrations mirroring the recommended tolerable doses, severely impaired insulin signaling in hepatocytes and adipocytes. This was concomitant with sustained oxidative stress from the overactivation of NADPH oxidase 2, a major intracellular source of reactive oxygen species, in both the cell types. The present study provides evidences of the onset of insulin resistance in mice after chronic exposure to DEP in diet even at lower levels. This, in turn, can have serious pathological consequences with ultimate manifestations of type 2 diabetes and metabolic syndrome (MetS). Thus, by disrupting the central metabolic function of liver and adipose tissue, the key insulin target tissues, daily exposure to phthalates in plastics can potentially contribute to the alarming prevalence of MetS in recent times.

Regeneration of dopaminergic neurons in goldfish retina

Development ◽  
1992 ◽  
Vol 114 (4) ◽  
pp. 913-919 ◽  
Author(s):  
J.E. Braisted ◽  
P.A. Raymond
Keyword(s):  
Dopaminergic Neurons ◽  
Developmental Process ◽  
Ganglion Cells ◽  
Outer Nuclear Layer ◽  
Cell Loss ◽  
Cell Types ◽  
High Dose ◽  
Double Labeling ◽  
6 Hydroxydopamine ◽  
Goldfish Retina

The conditions necessary to trigger regeneration of dopaminergic neurons were investigated in the goldfish retina. Intraocular injection of 6-hydroxydopamine (6-OHDA) was used to destroy dopaminergic neurons, and neuronal regeneration was monitored by injections of the thymidine analog bromodeoxyuridine (BUdR). Regenerated dopaminergic neurons, (identified by double-labeling with anti-tyrosine hydroxylase and anti-BUdR antibodies) were found within 3 weeks after 2 injections of 0.6 mg/ml 6-OHDA (estimated intraocular concentration), but not after injection of lower doses. All retinas with regenerated dopaminergic neurons also contained other types of regenerated neurons, including cones and ganglion cells, consistent with nuclear counts which revealed non-selective cell loss (34–36%) in both the outer and inner nuclear layers after exposure to the high dose, but not lower doses of 6-OHDA. Regenerated neurons were produced by clusters of dividing neuroepithelial cells probably derived from rod precursors in the outer nuclear layer. These results demonstrate that dopaminergic neurons will not regenerate after they are selectively ablated but only as part of a developmental process that involves generation of multiple cell types.

scholarly journals A unique combination of plasma membrane Ca2+-ATPase isoforms is expressed in islets of Langerhans and pancreatic β-cell lines

1996 ◽  
Vol 314 (2) ◽  
pp. 663-669 ◽  
Author(s):  
Anikó VÁRADI ◽  
Elek MOLNÁR ◽  
Stephen J. H. ASHCROFT
Keyword(s):  
Plasma Membrane ◽  
Molecular Mass ◽  
Islets Of Langerhans ◽  
Cell Lines ◽  
Cell Types ◽  
Human Islets ◽  
Unique Combination ◽  
Β Cells ◽  
Β Cell ◽  
Calmodulin Binding

Changes in free intracellular Ca2+ concentration regulate insulin secretion from pancreatic β-cells. The existence of steep Ca2+ gradients within the β-cell requires the presence of specialized Ca2+ exclusion systems. In this study we have characterized the plasma membrane Ca2+-ATPases (PMCAs) which extrude Ca2+ from the cytoplasm. PMCA isoform- and subtype-specific mRNA expression was investigated in rodent pancreatic α- and β-cell lines, and in human and rat islets of Langerhans using reverse-transcription PCR with primers flanking the calmodulin-binding region of rat PMCA. The expression pattern of PMCA 1 and 2 was conserved in different species and islet-cell types since both rat and human islets of Langerhans and all cell lines tested contained the 1b and 2b forms. PMCA 4 isoform subtypes, however, were expressed in a cell-type-specific manner since β-cells expressed PMCA 4b only, whereas in islets of Langerhans, which contain α, β, δ and polypeptide-secreting cells, PMCA 4a and 4b were simultaneously present. No evidence was obtained for the expression of PMCA 3. Characterization of the β-cell Ca2+-pump protein showed that it shared several similarities with the erythrocyte PMCA. It is a P-type ATPase; its phosphorylated intermediate was stabilized by La3+; it reacted with a PMCA-specific antibody; and it was not N-glycosylated. However, the β-cell PMCA had a higher molecular mass than that of the erythrocyte; this difference could be explained by either predominant translation of the PMCA 2 form, which has a molecular mass 3–8 kDa higher than the erythrocyte PMCA 1 and 4 proteins, or by a possible sequence insertion. Thus a unique combination of functionally distinct PMCA isoforms (1b, 2b, 4b) participates in Ca2+ homoeostasis in the β-cell.

scholarly journals Distinct Classes of Proteasome-Modulating Agents Cooperatively Augment Recombinant Adeno-Associated Virus Type 2 and Type 5-Mediated Transduction from the Apical Surfaces of Human Airway Epithelia

2004 ◽  
Vol 78 (6) ◽  
pp. 2863-2874 ◽  
Author(s):  
Ziying Yan ◽  
Roman Zak ◽  
Yulong Zhang ◽  
Wei Ding ◽  
Simon Godwin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Virus Type ◽  
Cell Types ◽  
Nuclear Accumulation ◽  
Cell Type Specificity ◽  
Airway Epithelia ◽  
Adeno Associated Virus ◽  
Human Airway ◽  
Human Airway Epithelia

ABSTRACT Tripeptidyl aldehyde proteasome inhibitors have been shown to effectively increase viral capsid ubiquitination and transduction of recombinant adeno-associated virus type 2 (rAAV-2) and rAAV-5 serotypes. In the present study we have characterized a second class of proteasome-modulating agents (anthracycline derivatives) for their ability to induce rAAV transduction. The anthracycline derivatives doxorubicin and aclarubicin were chosen for analysis because they have been shown to interact with the proteasome through a mechanism distinct from that of tripeptidyl aldehydes. Our studies demonstrated that doxorubicin and aclarubicin also significantly augmented rAAV transduction in airway cell lines, polarized human airway epithelia, and mouse lungs. Both tripeptidyl aldehyde and anthracycline proteasome-modulating agents similarly augmented nuclear accumulation of rAAV in A549 and IB3 airway cell lines. However, these two cell types demonstrated cell specificity in the ability of N-acetyl-l-leucyl-l-leucyl-l-norleucine (LLnL) or doxorubicin to augment rAAV transduction. Interestingly, the combined administration of LLnL and doxorubicin resulted in substantially increased transduction (>2,000-fold) following apical infection of human polarized epithelia with either rAAV-2 or rAAV-5. In summary, the cell type specificity of LLnL and doxorubicin to induce rAAV transduction, together with the ability of these compounds to synergistically enhance rAAV transduction in polarized airway epithelial induction, suggests that these two classes of compounds likely modulate different proteasome functions that affect rAAV transduction. Findings from this study provide new insights into how modulation of proteasome function can be effectively used to augment rAAV transduction in airway epithelia for gene therapy of cystic fibrosis.

scholarly journals The Role of β Cell Stress and Neo-Epitopes in the Immunopathology of Type 1 Diabetes

2021 ◽  
Vol 11 ◽  
Author(s):  
Jon D. Piganelli ◽  
Mark J. Mamula ◽  
Eddie A. James
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Cell Types ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack ◽  
Develop Type ◽  
Induced Changes

Due to their secretory function, β cells are predisposed to higher levels of endoplasmic reticulum (ER) stress and greater sensitivity to inflammation than other cell types. These stresses elicit changes in β cells that alter their function and immunogenicity, including defective ribosomal initiation, post-translational modifications (PTMs) of endogenous β cell proteins, and alternative splicing. Multiple published reports confirm the presence of not only CD8+ T cells, but also autoreactive CD4+ T cells within pancreatic islets. Although the specificities of T cells that infiltrate human islets are incompletely characterized, they have been confirmed to include neo-epitopes that are formed through stress-related enzymatic modifications of β cell proteins. This article summarizes emerging knowledge about stress-induced changes in β cells and data supporting a role for neo-antigen formation and cross-talk between immune cells and β cells that provokes autoimmune attack - leading to a breakdown in tissue-specific tolerance in subjects who develop type 1 diabetes.

scholarly journals SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

2020 ◽  
Author(s):  
Carlos Ramirez Alvarez ◽  
Ashwini Kumar Sharma ◽  
Carmon Kee ◽  
Leonie Thomas ◽  
Steeve Boulant ◽  
...  
Keyword(s):  
Serine Protease ◽  
Cell Lines ◽  
Viral Entry ◽  
Liver Tumors ◽  
Diabetes Type 2 ◽  
Cell Types ◽  
Strong Increase ◽  
Secretory Cells ◽  
Different Cell Types

AbstractCOVID-19 outbreak is the biggest threat to human health in recent history. Currently, there are over 1.5 million related deaths and 75 million people infected around the world (as of 22/12/2020). The identification of virulence factors which determine disease susceptibility and severity in different cell types remains an essential challenge. The serine protease TMPRSS2 has been shown to be important for S protein priming and viral entry, however, little is known about its regulation. SPINT2 is a member of the family of Kunitz type serine protease inhibitors and has been shown to inhibit TMPRSS2. Here, we explored the existence of a co-regulation between SPINT2/TMPRSS2 and found a tightly regulated protease/inhibitor expression balance across tissues. We found that SPINT2 negatively correlates with SARS-CoV-2 expression in Calu-3 and Caco-2 cell lines and was down-regulated in secretory cells from COVID-19 patients. We validated our findings using Calu-3 cell lines and observed a strong increase in viral load after SPINT2 knockdown. Additionally, we evaluated the expression of SPINT2 in datasets from comorbid diseases using bulk and scRNA-seq data. We observed its down-regulation in colon, kidney and liver tumors as well as in alpha pancreatic islets cells from diabetes Type 2 patients, which could have implications for the observed comorbidities in COVID-19 patients suffering from chronic diseases.

Asthma in Youth and Early-Onset Type 2 Diabetes: A Nationwide Study of 1.72 Million Israeli Adolescents

2021 ◽  
Author(s):  
Michael Shapiro ◽  
Chen Arbel ◽  
Inbar Zucker ◽  
Gingy Ronen Balmor ◽  
Miri Lutski ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Early Onset ◽  
Military Service ◽  
Population Based ◽  
Diabetes Registry ◽  
Compulsory Military Service ◽  
Obesity Status ◽  
Develop Type ◽  
History Of

Abstract Background The prevalence of both asthma and early onset diabetes is on the rise, however the association between them remains unclear. We examined a possible association of asthma at adolescence with type 2 diabetes in young adulthood. Methods This is a nationwide, population-based study of 1,718,541 Israeli adolescents (59% males; mean age 17.3 years; range 16-19 years), examined before compulsory military service during 1992-2016, with data linked to the Israeli National Diabetes Registry. Asthma diagnosis and severity were determined by a board-certified pulmonologist and based on spirometry tests. Results Type 2 diabetes developed in 58/9,090 (0.64%), 507/97,059 (0.52%), 114/23,332 (0.49%), and 7,095/1,589,060 (0.44%) persons with moderate-to-severe, mild, inactive, and no history of asthma, respectively, during a mean follow-up &gt;13 years. The respective odds ratios (ORs) were 1.33 (95%CI, 1.02-1.74), 1.17 (1.06-1.28), and 1.09 (0.9-1.31), considering those without asthma history as the reference, in a model adjusted for birth year, sex, BMI, and other socio-demographic variables. The association persisted when the analysis accounted for coexisting morbidities, and when persons without asthma, individually matched by age, sex, birth year, and BMI were the reference. Both mild and moderate-to-severe asthma were associated with type 2 diabetes before age 35 years: ORs 1.18 (1.05-1.34) and 1.44 (1.05-2.00), respectively. The strength of the association was accentuated over time. The effect was unchanged when adjusted for oral and inhaled glucocorticoid use. Conclusion Adolescents with active asthma have higher risk to develop type 2 diabetes. This seems related to disease severity, independent of adolescent obesity status, apparent before age 35 years, and more pronounced in recent years

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