scholarly journals Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

2021 ◽  
Vol 22 (21) ◽  
pp. 11913
Author(s):  
Laura Rullo ◽  
Silvia Franchi ◽  
Giada Amodeo ◽  
Francesca Felicia Caputi ◽  
Benedetta Verduci ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nuclear Receptors ◽  
Cellular Differentiation ◽  
Histone Demethylase ◽  
Epigenetic Mechanisms ◽  
Mice Model ◽  
Painful Neuropathy ◽  
Chemokine Family ◽  
Pro Inflammatory Cytokines

Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

scholarly journals Infiltration of Blood-Derived Macrophages Contributes to the Development of Diabetic Neuropathy

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jing-Jing Sun ◽  
Lin Tang ◽  
Xiao-Pei Zhao ◽  
Jun-Mei Xu ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Flow Cytometry ◽  
Gradient Flow ◽  
Percoll Gradient ◽  
Mice Model ◽  
Diabetic Neuropathic Pain ◽  
Painful Neuropathy ◽  
Clodronate Liposomes ◽  
And Function

Background and Objective. Diabetic neuropathic pain (DNP) is a common complication associated with diabetes. Currently, its underlying pathomechanism remains unknown. Studies have revealed that the recruitment of blood monocyte-derived macrophages (MDMs) to the spinal cord plays a pivotal role in different models of central nervous system injury. Therefore, the present study aimed at exploring the infiltration and function of MDMs in DNP using a mice model. Methods. Diabetes was induced using streptozotocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Quantitative analysis of CD11b was performed and visualized by immunofluorescence. Spinal cord cells were isolated from myelin and debris by Percoll gradient. Flow cytometry was used to label CD11b and CD45 antibodies to differentiate MDMs (CD45highCD11b+) from resident microglia (CD45lowCD11b+). Mice were injected with clodronate liposomes to investigate the role of MDMs in DNP. The successful depletion of monocytes was determined by flow cytometry. Results. The DNP mice model was successfully established. Compared with nondiabetic mice, diabetic mice displayed a markedly higher level of CD11b immunofluorescence in the spinal cord. The number of CD11b-positive microglia/macrophages gradually increased over the 28 days of testing after STZ injection, and a significant increase was observed on Day 14 (P<0.01) and 28 (P<0.01). Further analysis by flow cytometry showed that the infiltration of peripheral macrophages began to increase in 2 weeks (P<0.001) and reached a maximum at 4 weeks (P<0.001) post-STZ injection compared to the control. The depletion of MDMs by clodronate liposomes alleviated diabetes-induced tactile allodynia (P<0.05) and reduced the infiltration of MDMs (P<0.001) as well as the expression of IL-1β and TNF-α in the spinal cord (P<0.05). Conclusions. The infiltration of blood MDMs in the spinal cord may promote the development of painful neuropathy in diabetes.

scholarly journals LSD1, a double-edged sword, confers dynamic chromatin regulation but commonly promotes aberrant cell growth

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2016 ◽  
Author(s):  
Meghan M Kozub ◽  
Ryan M Carr ◽  
Gwen L Lomberk ◽  
Martin E Fernandez-Zapico
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Cellular Differentiation ◽  
Critical Role ◽  
Histone Demethylase ◽  
Epigenetic Changes ◽  
Lysine Specific Demethylase ◽  
Wide Range ◽  
Histone Modifying Enzymes

Histone-modifying enzymes play a critical role in chromatin remodeling and are essential for influencing several genome processes such as gene expression and DNA repair, replication, and recombination. The discovery of lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, dramatically revolutionized research in the field of epigenetics. LSD1 plays a pivotal role in a wide range of biological operations, including development, cellular differentiation, embryonic pluripotency, and disease (for example, cancer). This mini-review focuses on the role of LSD1 in chromatin regulatory complexes, its involvement in epigenetic changes throughout development, and its importance in physiological and pathological processes.

scholarly journals Decrease of IL-1β and TNF in the Spinal Cord Mediates Analgesia Produced by Ankle Joint Mobilization in Complete Freund Adjuvant-Induced Inflammation Mice Model

2022 ◽  
Vol 12 ◽  
Author(s):  
Carlos Minoru Omura ◽  
Daniela Dero Lüdtke ◽  
Verônica Vargas Horewicz ◽  
Paula Franson Fernandes ◽  
Taynah de Oliveira Galassi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Ankle Joint ◽  
Inflammatory Cytokines ◽  
Mechanical Hyperalgesia ◽  
M2 Macrophages ◽  
Macrophage Phenotype ◽  
Mice Model ◽  
Joint Mobilization ◽  
Arginase 1 ◽  
Pro Inflammatory Cytokines

ObjectiveThis study aims to investigate the effects of ankle joint mobilization (AJM) on mechanical hyperalgesia and peripheral and central inflammatory biomarkers after intraplantar (i.pl.) Complete Freund’s Adjuvant (CFA)-induced inflammation.MethodsMale Swiss mice were randomly assigned to 3 groups (n = 7): Saline/Sham, CFA/Sham, and CFA/AJM. Five AJM sessions were carried out at 6, 24, 48, 72, and 96 h after CFA injection. von Frey test was used to assess mechanical hyperalgesia. Tissues from paw skin, paw muscle and spinal cord were collected to measure pro-inflammatory (TNF, IL-1β) and anti-inflammatory cytokines (IL-4, IL-10, and TGF-β1) by ELISA. The macrophage phenotype at the inflammation site was evaluated by Western blotting assay using the Nitric Oxide Synthase 2 (NOS 2) and Arginase-1 immunocontent to identify M1 and M2 macrophages, respectively.ResultsOur results confirm a consistent analgesic effect of AJM following the second treatment session. AJM did not change cytokines levels at the inflammatory site, although it promoted a reduction in M2 macrophages. Also, there was a reduction in the levels of pro-inflammatory cytokines IL-1β and TNF in the spinal cord.ConclusionTaken together, the results confirm the anti-hyperalgesic effect of AJM and suggest a central neuroimmunomodulatory effect in a model of persistent inflammation targeting the pro-inflammatory cytokines IL-1β and TNF.

Antioxidants improve oxaliplatin-induced peripheral neuropathy in tumor-bearing mice model: role of spinal cord oxidative stress and inflammation

2021 ◽  
Author(s):  
Jonathan Paulo Agnes ◽  
Vitória Wibbelt Dos Santos ◽  
Raquel Nascimento das Neves ◽  
Rosângela Mayer Gonçalves ◽  
Marina Delgobo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Peripheral Neuropathy ◽  
Mice Model ◽  
Tumor Bearing

scholarly journals Iron Overload Is Associated With Accelerated Progression of Osteoarthritis: The Role of DMT1 Mediated Iron Homeostasis

2021 ◽  
Vol 8 ◽  
Author(s):  
Xingzhi Jing ◽  
Jiamin Lin ◽  
Ting Du ◽  
Zhensong Jiang ◽  
Tao Li ◽  
...  
Keyword(s):  
Iron Overload ◽  
Inflammatory Cytokines ◽  
Iron Homeostasis ◽  
Cartilage Destruction ◽  
Mice Model ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis ◽  
Pro Inflammatory Cytokines

Objective: Iron overload is common in elderly people which is associated with an increased prevalence of osteoarthritis (OA), but the exact role of iron in the development of OA has not been established. The aim of the present study is to elucidate the connection between iron overload and OA using an iron overloaded mice model, as well as to explore the role of iron homeostasis, iron transporters dependent iron influx in OA pathogenesis.Methods: The iron overloaded mice model was established and OA was surgically induced. OA progression was assessed at 8 weeks after surgery. Next, primary chondrocytes were treated with pro-inflammatory cytokines and iron regulators mediated iron homeostasis were evaluated. Involvement of iron transporters was analyzed using chondrocytes mimicking an osteoarthritis-related phenotype in vitro.Results: Iron overloaded mice exhibited greater cartilage destruction and elevated ADAMTS5 as well as MMP13 expression along with increased iron accumulation and dysregulated iron regulators. Pro-inflammatory cytokines could disturb cellular iron homeostasis via upregulating iron import proteins, TFR1 and DMT1, downregulating iron efflux protein FPN, thus result in cellular iron overload. Among iron transporters, DMT1 was found to play pivotal roles in iron overload induced OA progress. Inhibition of DMT1 suppressed IL-1β induced inflammatory response and ECM degradation via blockade of MAPK and PI3K/AKT/NF-κB pathways.Conclusions: Our results suggest that iron takes parts in the development of OA and cutting iron influx via inhibiting DMT1 activity could be an attractive new target for OA treatment.

The role of inflammatory cytokines in the pathogenesis of premature labor in multiple pregnancy as a result of ART

2016 ◽  
pp. 73-76
Author(s):  
B.M. Ventskivskiy ◽  
◽  
I.V. Poladych ◽  
S.O. Avramenko ◽  
◽  
...  
Keyword(s):  
Assisted Reproductive Technology ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Local Level ◽  
Multiple Pregnancy ◽  
Reproductive Technology ◽  
System Level ◽  
Premature Labor ◽  
Pro Inflammatory Cytokines

In recent years there has been an increase in the frequency of multiple pregnancies and the associated perinatal losses. It is a result of multiple pregnancy in ART refers to a high-risk gestation, at which premature births occur in 2 times more often than in singleton pregnancies. The objective: to determine the role of pro-inflammatory cytokines in the pathogenesis of premature labor in multiple pregnancy, as a result of assisted reproductive technology. Patients and methods. to determine the pro-inflammatory cytokines that all pregnant with bagtopliddyam held immunosorbent assay, defined concentrations of interleukin (IL) in serum and cervical mucus. Results. The analysis of the levels of pro-inflammatory cytokines (IL-1, IL-8) in the test environment, found high concentrations in the surveyed women with multiple pregnancy, due to the use of ART, compared with spontaneous multiple and singleton pregnancy. Increased concentration of proinflammatory cytokines in patients with multiple pregnancy by ART is associated with their synthesis at the system level, it stimulated foci of inflammation in the female genitals and extragenital localization. This correlates with the clinical data and statistical analysis, patients with multiple pregnancy as a result of ART had weighed infectious-inflammatory history. Conclusion. The study showed that elevated levels of proinflammatory cytokines in the systemic and local level in patients with multiple pregnancy due to ART, typical for women with miscarriage, because of the physiological course of pregnancy characterized by the predominance of anti-inflammatory cytokines that prevent rejection of the fetus as a foreign factor. Based on the data obtained proved the role of systemic inflammatory factors in the genesis of preterm labor in women with a multiple pregnancy, as a result of assisted reproductive technology. Key words: multiple pregnancy, assisted reproductive technology, premature birth, interleukine-1, interleukine-8.

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