Penehyclidine hydrochloride regulates mitochondrial dynamics and apoptosis through p38MAPK and JNK signal pathways and provides cardioprotection in rats with myocardial ischemia–reperfusion injury

Feng, Mei; Wang, Lirui; Chang, Siyuan; Yuan, Pu

doi:10.1016/j.ejps.2018.05.023

Cited by 22 publications

(13 citation statements)

References 31 publications

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“…DRP1 phosphorylations are modulated by the ERK1/2, PKA and JNK signal pathways [26,27,28,29,30]. Furthermore, CDDO-Me influences ERK1/2 [20,31] and JNK phosphorylations [32,33].…”

Section: Resultsmentioning

confidence: 99%

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CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

Kim

Park

Choi

et al. 2019

Cells

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2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that exhibits promising anti-cancer, anti-inflammatory, antioxidant and neuroprotective activities. In addition, CDDO-Me affects cellular differentiation and cell cycle arrest, and irreversibly inhibits Lon protease-1 (LONP1). In the present study, we evaluate the effects of CDDO-Me on mitochondrial dynamics and its downstream effectors in order to understand the underlying mechanism of the neuronal death following status epilepticus (SE, a prolonged seizure activity). CDDO-Me increased dynamin-related proteins 1 (DRP1)-serine 616 phosphorylation via activating extracellular-signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but not protein kinase A (PKA) or protein phosphatases (PPs). In addition, CDDO-Me facilitated DRP1-mediated mitochondrial fissions, which selectively attenuated SE-induced CA1 neuronal death. Unlike CDDO-Me, LONP1 knockdown led to SE-induced massive degeneration of dentate granule cells, CA1 neurons and hilus interneurons without altering the expression and phosphorylation of DRP1, ERK1/2, JNK and PP2B. LONP1 knockdown could not inhibit SE-induced mitochondrial elongation in CA1 neurons. Co-treatment of CDDO-Me with LONP1 siRNA ameliorated only CA1 neuronal death, concomitant with abrogation of mitochondrial elongation induced by SE. Thus, our findings suggest that CDDO-Me may selectively attenuate SE-induced CA1 neuronal death by rescuing the abnormal mitochondrial machinery, independent of LONP1 activity.

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“…DRP1 phosphorylations are modulated by the ERK1/2, PKA and JNK signal pathways [26,27,28,29,30]. Furthermore, CDDO-Me influences ERK1/2 [20,31] and JNK phosphorylations [32,33].…”

Section: Resultsmentioning

confidence: 99%

“…DRP1-S616 phosphorylation is regulated by the ERK1/2 and JNK signal pathways, which facilitate mitochondrial fission [27,29,30]. However, DRP1-S637 phosphorylation by PKA leads to detached DRP1 from mitochondria, thus inhibiting mitochondrial fission [26,28].…”

Section: Discussionmentioning

confidence: 99%

CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

Kim

Park

Choi

et al. 2019

Cells

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show abstract

“…Although the pathogenesis of myocardial I/R injury is complex, apoptosis is one of the major pathogenic mechanisms of I/R injury, because calcium overload, oxygen free radicals, and inflammatory reaction all can lead to cardiomyocyte apoptosis . Qin et al showed that miR‐497 inhibited cardiomyocyte apoptosis via down‐regulating the expression of Mfn2 in mouse heart following myocardial I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Hydromorphine postconditioning protects isolated rat heart against ischemia‐reperfusion injury via activating P13K/Akt/eNOS signaling

Liu

et al. 2018

Cardiovascular Therapeutics

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Summary Introduction Myocardial ischemia/reperfusion injury (myocardial I/R injury) has a high disability rate and mortality. Novel treatments for myocardial I/R injury are necessary. Aim In order to explore the protective effect of hydromorphine on myocardial I/R injury, we illuminate the underlying mechanism of the protective effect. Results Hydromorphine significantly reduced myocardial infarct size (IFN/AAR), CKMB (Creatine Kinase MB) and TN‐T (Troponin T) release, and improved cardiac function compared with I/R group. However, these advantageous effects were partly suppressed in the presence of hydromorphine. Myocardial I/R injury significantly decreased the phosphorylation of Akt and eNOS, and down‐regulated total nitric oxide and nitrotyrosine content, while these inhibitory effects were partly abolished by hydromorphine. Conversely, the activated effects of hydromorphine on the phosphorylation of Akt and eNOS, and NO release were totally reversed by LY294002, which, used individually, show the same influence on reperfusion injury. Conclusions These findings suggest that hydromorphine postconditioning may protect isolated rat heart against reperfusion injury via activating P13K/Akt/eNOS signaling.

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“…PHC interaction with the M receptor diminishes endothelial injury in LPS-stimulated human pulmonary microvascular endothelial cells (45). The protective effect of PHC in rats with myocardial ischemia or reperfusion injury has also been studied (46,47). The present study established an LPS-induced ARDS model.…”

Section: Discussionmentioning

confidence: 88%

Penehyclidine hydrochloride alleviates lipopolysaccharide‑induced acute respiratory distress syndrome in cells via regulating autophagy‑related pathway

Wang

Liu

et al. 2020

Mol Med Rep

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Acute progressive hypoxic respiratory failure caused by various predisposing factors is known as acute respiratory distress syndrome (ARDS). Although penehyclidine hydrochloride (PHC), an anticholinergic drug, is widely applied in clinical practice, the specific mechanisms underlying PHC in the treatment of ARDS are not completely understood. In the present study, BEAS-2B cells were treated with 10 ng/ml lipopolysaccharide (LPS) to establish an ARDS cell model and a rat model of acute lung injury (ALI). The influences of PHC and/or autophagy inhibitor (3-methyladenine (3-MA)) on the morphology, autophagy, proliferation and apoptosis of cells and tissues were evaluated using hematoxylin and eosin staining, Cell Counting Kit-8 assays, Hoechst staining, TUNEL staining, flow cytometry, immunofluorescence assays, ELISAs and scanning electron microscopy. The expression levels of apoptosis-and autophagy-related proteins were measured via western blotting. The results indicated that PHC enhanced proliferation and autophagy, and decreased apoptosis and the inflammatory response in LPS-induced BEAS-2B cells and ALI model rats. In addition, 3-MA reversed the effects of PHC on proliferation, inflammation, apoptosis and autophagy in LPS-induced BEAS-2B cells. Therefore, the present study suggested that PHC demonstrated a protective effect in LPS-induced ARDS by regulating an autophagy-related pathway.

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Penehyclidine hydrochloride regulates mitochondrial dynamics and apoptosis through p38MAPK and JNK signal pathways and provides cardioprotection in rats with myocardial ischemia–reperfusion injury

Cited by 22 publications

References 31 publications

CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

Hydromorphine postconditioning protects isolated rat heart against ischemia‐reperfusion injury via activating P13K/Akt/eNOS signaling

Penehyclidine hydrochloride alleviates lipopolysaccharide‑induced acute respiratory distress syndrome in cells via regulating autophagy‑related pathway

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