Dexmedetomidine protects against lidocaine-induced neurotoxicity through SIRT1 downregulation-mediated activation of FOXO3a

2020 ◽  
Vol 39 (9) ◽  
pp. 1213-1223 ◽  
Author(s):  
L-N Zheng ◽  
F-Q Guo ◽  
Z-S Li ◽  
Z Wang ◽  
J-H Ma ◽  
...  
Keyword(s):  
Protein Level ◽  
Sirtuin 1 ◽  
Apoptotic Pathway ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Theoretical Support ◽  
Novel Target ◽  
Induced Changes

Lidocaine, a typical local anesthetic, has been shown to directly induce neurotoxicity in clinical settings. Dexmedetomidine (DEX) is an alpha-2-adrenoreceptor agonist that has been used as anxiolytic, sedative, and analgesic agent which has recently found to protect against lidocaine-induced neurotoxicity. Nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1)/forkhead box O3 (FOXO3a) signaling is critical for maintaining neuronal function and regulation of the apoptotic pathway. In the present study, we designed in vitro and in vivo models to investigate the potential effects of lidocaine and DEX on SIRT1 and FOXO3a and to verify whether SIRT1/FOXO3a-mediated regulation of apoptosis is involved in DEX-induced neuroprotective effects against lidocaine. We found that in both PC12 cells and brains of mice, lidocaine decreased SIRT1 level through promoting the degradation of SIRT1 protein. Lidocaine also increased FOXO3a protein level and increased the acetylation of SIRT1 through inhibiting SIRT1. Upregulation of SIRT1 or downregulation of FOXO3a significantly inhibited lidocaine-induced changes in both cell viability and apoptosis. DEX significantly inhibited the lidocaine-induced decrease of SIRT1 protein level and increase of FOXO3a protein level and acetylation of FOXO3a. Downregulation of SIRT1 or upregulation of FOXO3a suppressed DEX-induced neuroprotective effects against lidocaine. The data suggest that SIRT1/FOXO3a is a potential novel target for alleviating lidocaine-induced neurotoxicity and provide more theoretical support for the use of DEX as an effective adjunct to alleviate chronic neurotoxicity induced by lidocaine.

scholarly journals Adipokines expression and epithelial cell polarity in normal and cancerous breast tissue

2020 ◽  
Vol 41 (10) ◽  
pp. 1402-1408
Author(s):  
Danila Coradini ◽  
Simone Gambazza ◽  
Saro Oriana ◽  
Federico Ambrogi
Keyword(s):  
Cell Polarity ◽  
Protein Level ◽  
Normal Tissue ◽  
Functional Organization ◽  
Epithelial Tissue ◽  
Cancer Etiology ◽  
In Vivo Models ◽  
Glutamyl Transferase

Abstract Cell polarity is crucial for the correct structural and functional organization of epithelial tissue. Its disruption can lead to loss of the apicobasal polarity, alteration in the intracellular components, misregulation of the pathways involved in cell proliferation and cancer promotion. Very recent in vitro/in vivo findings demonstrated that obesity-associated alterations in tissue adipokines protein level negatively affect epithelial polarity. We performed an in silico study to investigate whether such alterations also occur in surgical samples. We aimed to explore the relationship among the expression of the genes coding for leptin (LEP), adiponectin (ADIPOQ), adipokine receptors (LEPR, ADIPOR1 and ADIPOR2), and a panel of polarity-associated genes in normal tissue from breast reduction mammoplasty, and a series of paired samples of histologically normal (HN) tissue and invasive cancer. Results indicated that, in normal tissue, the expression of adipokines and their receptors negatively correlated with that of the polarity-associated genes and GGT1, which codes for γ-glutamyl transferase (GGT) enzyme, a marker of cell distress and membrane disruption. This negative correlation progressively decreased in HN and cancerous tissue, and loss of correlation between ADIPOR2 and polarity-associated genes appeared the most noticeable alteration. Given the growing role of obesity in breast cancer etiology and the opposite action of leptin and adiponectin in epithelial tissue remodeling, ADIPOR2 loss could be addressed as a key mechanism leading to an unbalanced leptin stimulatory activity, subsequent cell polarity disruption and eventually tumor initiation, a finding that requires to be confirmed also at the protein level and with in vivo models.

scholarly journals Neutrophil extracellular traps activate IL-8 and IL-1 expression in human bronchial epithelia

2020 ◽  
Vol 319 (1) ◽  
pp. L137-L147 ◽  
Author(s):  
Kristin M. Hudock ◽  
Margaret S. Collins ◽  
Michelle Imbrogno ◽  
John Snowball ◽  
Elizabeth L. Kramer ◽  
...  
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Gm Csf ◽  
Extracellular Traps ◽  
Tnf Α ◽  
Multiple Donors ◽  
Novel Target ◽  
Induced Changes ◽  
Air Liquid Interface

Neutrophil extracellular traps (NETs) provide host defense but can contribute to the pathobiology of diverse human diseases. We sought to determine the extent and mechanism by which NETs contribute to human airway cell inflammation. Primary normal human bronchial epithelial cells (HBEs) grown at air-liquid interface and wild-type (wt)CFBE41o- cells (expressing wtCFTR) were exposed to cell-free NETs from unrelated healthy volunteers for 18 h in vitro. Cytokines were measured in the apical supernatant by Luminex, and the effect on the HBE transcriptome was assessed by RNA sequencing. NETs consistently stimulated IL-8, TNF-α, and IL-1α secretion by HBEs from multiple donors, with variable effects on other cytokines (IL-6, G-CSF, and GM-CSF). Expression of HBE RNAs encoding IL-1 family cytokines, particularly IL-36 subfamily members, was increased in response to NETs. NET exposure in the presence of anakinra [recombinant human IL-1 receptor antagonist (rhIL-1RA)] dampened NET-induced changes in IL-8 and TNF-α proteins as well as IL-36α RNA. rhIL-36RA limited the increase in expression of proinflammatory cytokine RNAs in HBEs exposed to NETs. NETs selectively upregulate an IL-1 family cytokine response in HBEs, which enhances IL-8 production and is limited by rhIL-1RA. The present findings describe a unique mechanism by which NETs may contribute to inflammation in human lung disease in vivo. NET-driven IL-1 signaling may represent a novel target for modulating inflammation in diseases characterized by a substantial NET burden.

scholarly journals ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

2015 ◽  
Vol 36 (4) ◽  
pp. 1539-1551 ◽  
Author(s):  
Qian Yu ◽  
Zhihong Lu ◽  
Lei Tao ◽  
Lu Yang ◽  
Yu Guo ◽  
...  
Keyword(s):  
Brain Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
In Vivo Models ◽  
The Brain

Background/Aims: Stroke is among the top causes of death worldwide. Neuroprotective agents are thus considered as potentially powerful treatment of stroke. Methods: Using both HT22 cells and male Sprague-Dawley rats as in vitro and in vivo models, we investigated the effect of NaHS, an exogenous donor of H2S, on the focal cerebral ischemia-reperfusion (I/R) induced brain injury. Results: Administration of NaHS significantly decreased the brain infarcted area as compared to the I/R group in a dose-dependent manner. Mechanistic studies demonstrated that NaHS-treated rats displayed significant reduction of malondialdehyde content, and strikingly increased activity of superoxide dismutases and glutathione peroxidase in the brain tissues compared with I/R group. The enhanced antioxidant capacity as well as restored mitochondrial function are NaHS-treatment correlated with decreased cellular reactive oxygen species level and compromised apoptosis in vitro or in vivo in the presence of NaHS compared with control. Further analysis revealed that the inhibition of PARP-1 cleavage and AIF translocation are involved in the neuroprotective effects of NaHS. Conclusion: Collectively, our results suggest that NaHS has potent protective effects against the brain injury induced by I/R. NaHS is possibly effective through inhibition of oxidative stress and apoptosis.

Neuroprotective effects of a new synthetic peptide, CMX-9236, in in vitro and in vivo models of cerebral ischemia

2003 ◽  
Vol 963 (1-2) ◽  
pp. 214-223 ◽  
Author(s):  
Victor E Shashoua ◽  
David S Adams ◽  
Anne Boyer-Boiteau ◽  
Ann Cornell-Bell ◽  
Fuhai Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Synthetic Peptide ◽  
Neuroprotective Effects ◽  
In Vivo Models

Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease

2015 ◽  
Vol 84 ◽  
pp. 331-343 ◽  
Author(s):  
Zaijun Zhang ◽  
Guohui Li ◽  
Samuel S.W. Szeto ◽  
Cheong Meng Chong ◽  
Quan Quan ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Protocatechuic Acid ◽  
Neuroprotective Effects ◽  
In Vivo Models

Hypothermia and Isoflurane Similarly Inhibit Glutamate Release Evoked by Chemical Anoxia in Rat Cortical Brain Slices

1996 ◽  
Vol 85 (3) ◽  
pp. 600-607. ◽  
Author(s):  
Helge Eilers ◽  
Philip E. Bickler
Keyword(s):  
Minimum Alveolar Concentration ◽  
Glutamate Release ◽  
Brain Slices ◽  
Neuronal Cell ◽  
Release Rates ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Chemical Anoxia

Background Accumulation of the excitatory neurotransmitter glutamate in ischemic brain tissue contributes to neuronal cell death. Volatile anesthetics at clinically relevant concentrations are neuroprotective in in vivo models of brain ischemia and reduce glutamate release in vivo and in vitro, but they appear to have weaker neuroprotective effects than hypothermia. The purpose of this study was to determine whether isoflurane reduces glutamate release in hypoxic brain slices, how large this effect is compared to that of hypothermia, and if it is diminished by hyperthermia. Methods Glutamate released from rat cortical brain slices during chemical anoxia (100 microM NaCN) was measured continuously with a fluorescence assay. The release rate was compared at three temperatures (28 degrees C, 37 degrees C, and 39 degrees C) with and without isoflurane at concentrations equipotent to 1 minimum alveolar concentration. At the same three temperatures, glutamate release rates before and after exposure to isoflurane were compared. Results Isoflurane reduced glutamate release from brain slices during chemical anoxia at 37 degrees C (19.6%, P < 0.01) and at 39 degrees C (25.4%, P < 0.01), but not at 28 degrees C. The reduction in glutamate release with hypothermia was similar to that with isoflurane. Hyperthermia (39 degrees C) caused greater glutamate release under basal and anoxic conditions than normo- and hypothermia. Isoflurane caused a slight increase in basal glutamate release rates, although this effect was smaller than the increase caused by hyperthermia. Conclusions In a brain slice model of cerebral anoxia, 1 minimum alveolar concentration isoflurane decreases glutamate release to a similar extent that hypothermia (28 degrees C) does. The increased glutamate release with hyperthermia (39 degrees C) is not prevented by isoflurane.

scholarly journals The Good, the Bad, the Question–H19 in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1261 ◽  
Author(s):  
Lysann Tietze ◽  
Sonja M. Kessler
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Therapy ◽  
Liver Cancer ◽  
Primary Liver Cancer ◽  
Human Patient ◽  
In Vivo Models ◽  
Study Results ◽  
Novel Target

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is challenging to treat due to its typical late diagnosis, mostly at an advanced stage. Therefore, there is a particular need for research in diagnostic and prognostic biomarkers and therapeutic targets for HCC. The use of long noncoding (lnc) RNAs can widen the list of novel molecular targets improving cancer therapy. In hepatocarcinogenesis, the role of the lncRNA H19, which has been known for more than 30 years now, is still controversially discussed. H19 was described to work either as a tumor suppressor in vitro and in vivo, or to have oncogenic features. This review attempts to survey the conflicting study results and tries to elucidate the potential reasons for the contrary findings, i.e., different methods, models, or readout parameters. This review encompasses in vitro and in vivo models as well as studies on human patient samples. Although the function of H19 in HCC remains elusive, a short outlook summarizes some ideas of using the H19 locus as a novel target for liver cancer therapy.

scholarly journals Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson’s Disease and Amyotrophic Lateral Sclerosis

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7643
Author(s):  
Sonia Burgaz ◽  
Concepción García ◽  
Claudia Gonzalo-Consuegra ◽  
Marta Gómez-Almería ◽  
Francisco Ruiz-Pino ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Bv2 Cells ◽  
Lateral Sclerosis ◽  
Glial Reactivity

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson’s disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.

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