GYY4137 protected the integrity of the blood‐brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis

Cui, Wei; Chen, Jing; Yu, Feng; Liu, Wenhong; He, Miao

doi:10.1096/fj.202100074r

Cited by 17 publications

(14 citation statements)

References 57 publications

(110 reference statements)

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“…More recently, two studies have shown that the pretreatment of GYY4137 (25 mg/kg and 50 mg/kg intraperitoneal injection), a novel slow-releasing H 2 S donor, protected against acute lung injury caused by CLP-induced sepsis in mice [ 154 , 155 ]. A similar salutary effect of H 2 S was also reported in urinary-derived sepsis, pseudomonas aeruginosa sepsis and pneumococcal pneumosepsis, together with LPS-induced endotoxemia [ 21 , 156 , 157 , 158 , 159 ].…”

Section: Gaseous Mediators In Sepsis/septic Shocksupporting

confidence: 68%

Gases in Sepsis: Novel Mediators and Therapeutic Targets

Zhu

Chambers

Zeng

et al. 2022

IJMS

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Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very complicated and is not yet fully understood. Worse still, the development of effective therapeutic agents is still an unmet need and a great challenge. Gases, including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), are small-molecule biological mediators that are endogenously produced, mainly by enzyme-catalyzed reactions. Accumulating evidence suggests that these gaseous mediators are widely involved in the pathophysiology of sepsis. Many sepsis-associated alterations, such as the elimination of invasive pathogens, the resolution of disorganized inflammation and the preservation of the function of multiple organs and systems, are shaped by them. Increasing attention has been paid to developing therapeutic approaches targeting these molecules for sepsis/septic shock, taking advantage of the multiple actions played by NO, CO and H2S. Several preliminary studies have identified promising therapeutic strategies for gaseous-mediator-based treatments for sepsis. In this review article, we summarize the state-of-the-art knowledge on the pathophysiology of sepsis; the metabolism and physiological function of NO, CO and H2S; the crosstalk among these gaseous mediators; and their crucial effects on the development and progression of sepsis. In addition, we also briefly discuss the prospect of developing therapeutic interventions targeting these gaseous mediators for sepsis.

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Section: Gaseous Mediators In Sepsis/septic Shocksupporting

confidence: 68%

Gases in Sepsis: Novel Mediators and Therapeutic Targets

Zhu

Chambers

Zeng

et al. 2022

IJMS

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“…ML385, an inhibitor of Nrf2 [ 30 ], was used to further confirm whether the Keap1-Nrf2 pathway and its mediated antioxidative stress were involved in the protective effect of ICS on METH neurotoxicity. First, we focused on the effect of ML385, ICS, and METH on the Keap1-Nrf2 pathway and oxidative stress response.…”

Section: Resultsmentioning

confidence: 99%

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway

Huang

Ding

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.

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“…Kelch-like ECH-associated protein 1 (KEAP1) is a regulatory protein that retains NRF2 in the cytoplasm and leads it to ubiquitination and proteasomal degradation. It is known that H 2 S donors can induce KEAP1 sulfhydration, a modification that leads to the NRF2 release, translocation to the nucleus, and promotion of gene transcription [ 26 , 37 , 38 , 39 , 40 ]. To determine whether GYY4137 affected the KEAP1 levels in basal conditions and in the context of RSV infection, the total cell lysates isolated from SAECs infected with RSV and treated with GYY4137 were analyzed by Western blot with anti-KEAP1 antibody.…”

Section: Resultsmentioning

confidence: 99%

Hydrogen Sulfide Donor GYY4137 Rescues NRF2 Activation in Respiratory Syncytial Virus Infection

et al. 2022

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Respiratory syncytial virus (RSV) can cause severe respiratory illness in infants, immunocompromised, and older adults. Despite its burden, no vaccine or specific treatment is available. RSV infection is associated with increased reactive oxygen species (ROS) production, degradation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), and decreased antioxidant enzymes (AOEs), leading to oxidative damage and lung injury. Hydrogen sulfide (H2S) is an endogenous gaseous molecule that plays a physiological role in numerous cellular processes and a protective role in multiple pathological conditions, displaying vasoactive, cytoprotective, anti-inflammatory, and antioxidant activities. H2S can promote NRF2 activation through the sulfhydration of Kelch-like ECH-associated protein 1, the cytoplasmic repressor of NRF2. Here we investigated whether increasing cellular H2S levels could rescue NRF2 and NRF2-dependent gene expression in RSV-infected primary airway epithelial cells. We found that treatment with the H2S donor GYY4137 significantly increased NRF2 levels and AOEs gene expression by decreasing KEAP1 levels, and by modulating pathways involved in RSV-induced NRF2 degradation, such as NRF2 ubiquitination, and promyelocytic leukemia (PML) protein levels. These results suggest that the administration of exogenous H2S can positively impact the altered redox balance associated with RSV infection, which represents an important determinant of RSV-induced lung disease.

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GYY4137 protected the integrity of the blood‐brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis

Cited by 17 publications

References 57 publications

Gases in Sepsis: Novel Mediators and Therapeutic Targets

Gases in Sepsis: Novel Mediators and Therapeutic Targets

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway

Hydrogen Sulfide Donor GYY4137 Rescues NRF2 Activation in Respiratory Syncytial Virus Infection

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