The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor β signaling

Aims/hypothesis The conserved hypoxia inducible factor 1 α (HIF1α) injury-response pro-survival pathway has recently been implicated in early beta cell dysfunction but slow beta cell loss in type 2 diabetes. We hypothesised that the unexplained prolonged prediabetes phase in type 1 diabetes may also be, in part, due to activation of the HIF1α signalling pathway. Methods RNA sequencing (RNA-Seq) data from human islets with type 1 diabetes or after cytokine exposure in vitro was evaluated for activation of HIF1α targets. This was corroborated by immunostaining human pancreases from individuals with type 1 diabetes for 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the key effector of HIF1α-mediated metabolic remodelling, and by western blotting of islets and INS-1 832/13 cells exposed to cytokines implicated in type 1 diabetes. Results HIF1α signalling is activated (p = 4.5 × 10 −9) in islets from individuals with type 1 diabetes, and in human islets exposed in vitro to cytokines implicated in type 1 diabetes (p = 1.1 × 10 −14). Expression of PFKFB3 is increased fivefold (p < 0.01) in beta cells in type 1 diabetes and in human and rat islets exposed to cytokines that induced increased lactate production. HIF1α attenuates cytokine-induced cell death in beta cells. Conclusions/interpretation The conserved pro-survival HIF1α-mediated injury-response signalling is activated in beta cells in type 1 diabetes and likely contributes to the relatively slow rate of beta cell loss at the expense of early defective glucose-induced insulin secretion.

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“…5). These findings were corroborated by immunostaining of mitochondria with anti-GRP75 antibody [24][25][26][27] (ESM Fig. 4).…”

Section: Hif1α Signalling Is Activated By Cytokines In Human and Rat supporting

confidence: 56%

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

et al. 2019

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“…It should be noted that treatment with novel derivatives resulted in an increase in metabolic activity and oxidative stress, even when compared to a control that was not preincubated with LPS. The MTT assay is commonly used as an indirect indicator of cell viability, but interpreting its results, one should take into account that many factors can alter the metabolic activity, such as an increase of the number of mitochondria and also their reorganization in developing neurons [47,48].…”

Section: Discussionmentioning

confidence: 99%

Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation

Wakulik

Wiatrak

Szczukowski

et al. 2020

IJMS

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Neuroinflammation is considered to be one of the potential causes for the development of neurodegenerative diseases, including Alzheimer's disease. In this study, we evaluated the effect of four newly synthesized pyrrolo [3,4-d]pyridazinone derivatives on the neuron-like PC12 cells under simulated inflammation conditions by preincubation with lipopolysaccharide (LPS). Our novel derivatives are selective cyclooxygenase-2 (COX-2) inhibitors and have similar effects to nonsteroidal anti-inflammatory drugs (NSAIDs). We assessed viability (LDH assay), metabolic activity (MTT assay), DNA damage (number of double-strand breaks measured by fast halo assay), and the neuronal features of cells (average neurite length and neurite outgrowth measured spectrofluorimetrically). DCF-DA and Griess assays were also performed, which allowed determining the impact of the tested compounds on the level of oxygen free radicals and nitrites. LPS administration significantly negatively affected the results in all tests performed, and treatment with the tested derivatives in most cases significantly reduced this negative impact. Multiple-criteria decision analysis indicated that overall, the best results were observed for compounds 2a and 2b at a concentration of 10 µM. The new derivatives showed intense activity against free oxygen radicals and nitrites. Reduced reactive oxygen species level also correlated with a decrease in the number of DNA damage. The compounds improved neuronal features, such as neurite length and outgrowth, and they also increased cell viability and mitochondrial activity. Our results suggest that derivatives 2a and 2b may also act additionally on mechanisms other than 3a and 3b.

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“…Ascorbic acid and phenolic group have been previously shown to increase cell numbers [ 42 , 43 , 44 , 45 ] and cellular ATP production [ 43 , 46 ]. Additionally, tryptoline derivatives and phenolic derivatives were also able to promote neurite outgrowth [ 47 ], which may be associated with increased mitochondria numbers, accumulated within the neurite [ 48 ]. To understand the potential mechanisms of increased percent cell viability of compounds 2a and 5c (1 nM) under a nontoxic condition, cell proliferation and intracellular ATP levels should be further investigated.…”

Section: Resultsmentioning

confidence: 99%

Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection

et al. 2021

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Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds 2c and 5c exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds 2c and 5c were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2.

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The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor β signaling

Cited by 29 publications

References 58 publications

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation

Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection

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