Chelerythrine inhibits the sarco/endoplasmic reticulum Ca2+-ATPase and results in cell Ca2+ imbalance

Vieira, Saulo Martins; Oliveira, Vanessa H.; Valente, Raphael C; Moreira, Otacílio C.; Fontes, Carlos Frederico Leite; Mignaco, Julio A.

doi:10.1016/j.abb.2015.02.019

Cited by 10 publications

(8 citation statements)

References 59 publications

(69 reference statements)

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“…The researchers also stated that metabolism of these compounds by hepatic microsomes can lead to the generation of DNA adducts [ 87 ]. A study conducted by S. M. Vieira et al, also reported that chelerythrine has a significant sarco/endoplasmic reticulum Ca 2 + -ATPase (SERCA1)-inhibitory activity, and this effect could be a possible cause of the chelerythrine cytotoxicity by the resulting loss of the cell calcium homeostasis [ 88 ].…”

Section: Pharmacokinetic and Toxicological Properties Of Chelerythrinementioning

confidence: 99%

“… The in vivo toxicity of chelerythrine is considerably less than it’s in vitro toxicity due to its structural changes. [ 83 , 84 , 88 ] Structural features Chelerythrine exists in two forms: “charged iminium” and “neutral alkanolamine” at neutral to mildly alkaline pH. Chelerythrine exists almost exclusively in the form of “charged iminium” in the pH range 1 to 6, and “alkanolamine” form in the pH range 8.5 to 11.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic potential of chelerythrine as a multi-purpose adjuvant for the treatment of COVID-19

et al. 2021

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Multifunctional nature of phytochemicals and their chemical diversity has attracted attention to develop leads originated from nature to fight COVID-19. Pharmacological activities of chelerythrine and its congeners have been studied and reported in the literature. This compound simultaneously has two key therapeutic effects for the treatment of COVID-19, antiviral and anti-inflammatory activities. Chelerythrine can prevent hyper-inflammatory immune response through regulating critical signaling pathways involved in SARS-CoV-2 infection, such as alteration in Nrf2, NF-κB, and p38 MAPK activities. In addition, chelerythrine has a strong protein kinase C-α/-β inhibitory activity suitable for cerebral vasospasm prevention and eryptosis reduction, as well as beneficial effects in suppressing pulmonary inflammation and fibrosis. In terms of antiviral activity, chelerythrine can fight with SARS-CoV-2 through various mechanisms, such as direct-acting mechanism, viral RNA-intercalation, and regulation of host-based antiviral targets. Although chelerythrine is toxic in vitro, the in vivo toxicity is significantly reduced due to its structural conversion to alkanolamine. Its multifunctional action makes chelerythrine a prominent compound for the treatment of COVID-19. Considering precautions related to the toxicity at higher doses, it is expected that this compound is useful in combination with proper antivirals to reduce the severity of COVID-19 symptoms.

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Section: Pharmacokinetic and Toxicological Properties Of Chelerythrinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of chelerythrine as a multi-purpose adjuvant for the treatment of COVID-19

et al. 2021

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“…In cellular experimental models the IC50 of GF may be ranged from 0.1 to 1 μM (Son, Hong, Kim, Firth, & Park, ). Although the finding that chelerythrine was a potent inhibitor of PKCs with an IC50 of 0.66 μM (Herbert, Augereau, Gleye, & Maffrand, ; Ringvold & Khalil, ) has been challenged by a number of studies in which the enzyme activity of PKCs was found not to be affected by application of this compound (Lee et al, ; Vieira et al, ), it has been demonstrated that CC may inhibit the translocation of PKCs (Chao, Chen, & Cheng, ; Siomboing et al, ). SFK activity can be inhibited by 50% following 4 nM PP2 application in vitro and 0.6–18 μM in cellular experimental models (Hanke et al, ; Karni et al, ).…”

Section: Resultsmentioning

confidence: 99%

Regulation of the firing activity by PKA‐PKC‐Src family kinases in cultured neurons of hypothalamic arcuate nucleus

Sun

Wang

et al. 2019

J of Neuroscience Research

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The cAMP‐dependent protein kinase A family (PKAs), protein kinase C family (PKCs), and Src family kinases (SFKs) are found to play important roles in pain hypersensitivity. However, more detailed investigations are still needed in order to understand the mechanisms underlying the actions of PKAs, PKCs, and SFKs. Neurons in the hypothalamic arcuate nucleus (ARC) are found to be involved in the regulation of pain hypersensitivity. Here we report that the action potential (AP) firing activity of ARC neurons in culture was up‐regulated by application of the adenylate cyclase activator forskolin or the PKC activator PMA, and that the forskolin or PMA application‐induced up‐regulation of AP firing activity could be blocked by pre‐application of the SFK inhibitor PP2. SFK activation also up‐regulated the AP firing activity and this effect could be prevented by pre‐application of the inhibitors of PKCs, but not of PKAs. Furthermore, we identified that forskolin or PMA application caused increases in the phosphorylation not only in PKAs at T197 or PKCs at S660 and PKCα/βII at T638/641, but also in SFKs at Y416. The forskolin or PMA application‐induced increase in the phosphorylation of PKAs or PKCs was not affected by pre‐treatment with PP2. The regulations of the SFK and AP firing activities by PKCs were independent upon the translocation of either PKCα or PKCβII. Thus, it is demonstrated that PKAs may act as an upstream factor(s) to enhance SFKs while PKCs and SFKs interact reciprocally, and thereby up‐regulate the AP firing activity in hypothalamic ARC neurons.

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“…Receptor autoradiography also shows that AT1 receptors are distributed in the circumventricular organs and PVN (Vieira et al . ). AngII administered systemically or locally into the PVN can augment sympathetic output (Li et al .…”

Section: Introductionmentioning

confidence: 97%

“…The Agtr1a mRNA level is high in the circumventricular organs and PVN, whereas Agtr1b mRNA is undetectable in these brain areas (Lenkei et al 1997(Lenkei et al , 1998. Receptor autoradiography also shows that AT1 receptors are distributed in the circumventricular organs and PVN (Vieira et al 2015). AngII administered systemically or locally into the PVN can augment sympathetic output (Li et al 2003;Gabor & Leenen, 2013;Glass et al 2015;Ma et al 2018a).…”

Section: Introductionmentioning

confidence: 98%

Endogenous AT1 receptor–protein kinase C activity in the hypothalamus augments glutamatergic input and sympathetic outflow in hypertension

Chen

Pan

2019

The Journal of Physiology

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Key points The angiotensin AT1 receptor expression and protein kinase C (PKC)‐mediated NMDA receptor phosphorylation levels in the hypothalamus are increased in a rat genetic model of hypertension. Blocking AT1 receptors or PKC activity normalizes the increased pre‐ and postsynaptic NMDA receptor activity of hypothalamic presympathetic neurons in hypertensive animals. Inhibition of AT1 receptor–PKC activity in the hypothalamus reduces arterial blood pressure and sympathetic nerve discharges in hypertensive animals. AT1 receptors in the hypothalamus are endogenously activated to sustain NMDA receptor hyperactivity and elevated sympathetic outflow via PKC in hypertension. Abstract Increased synaptic N‐methyl‐d‐aspartate receptor (NMDAR) activity in the hypothalamic paraventricular nucleus (PVN) plays a major role in elevated sympathetic output in hypertension. Although exogenous angiotensin II (AngII) can increase NMDAR activity in the PVN, whether endogenous AT1 receptor–protein kinase C (PKC) activity mediates the augmented NMDAR activity of PVN presympathetic neurons in hypertension is unclear. Here we show that blocking AT1 receptors with losartan or inhibiting PKC with chelerythrine significantly decreased the frequency of NMDAR‐mediated miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of puff NMDA currents of retrogradely labelled spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs). Also, treatment with chelerythrine abrogated the potentiating effect of AngII on mEPSCs and puff NMDA currents of labelled PVN neurons in SHRs. In contrast, neither losartan nor chelerythrine had any effect on mEPSCs or puff NMDA currents in labelled PVN neurons in Wistar–Kyoto (WKY) rats. Furthermore, levels of AT1 receptor mRNA and PKC‐mediated NMDAR phosphorylation in the PVN were significantly higher in SHRs than in WKY rats. In addition, microinjection of losartan or chelerythrine into the PVN substantially reduced blood pressure and renal sympathetic nerve discharges in SHRs but not in WKY rats. Chelerythrine blocked sympathoexcitatory responses to AngII microinjected into the PVN. Our findings suggest that endogenous AT1 receptor–PKC activity is essential for presynaptic and postsynaptic NMDAR hyperactivity of PVN presympathetic neurons and for the augmented sympathetic outflow in hypertension. This information advances our mechanistic understanding of the interplay between angiotensinergic and glutamatergic excitatory inputs in hypertension.

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Chelerythrine inhibits the sarco/endoplasmic reticulum Ca2+-ATPase and results in cell Ca2+ imbalance

Cited by 10 publications

References 59 publications

Therapeutic potential of chelerythrine as a multi-purpose adjuvant for the treatment of COVID-19

Therapeutic potential of chelerythrine as a multi-purpose adjuvant for the treatment of COVID-19

Regulation of the firing activity by PKA‐PKC‐Src family kinases in cultured neurons of hypothalamic arcuate nucleus

Endogenous AT1 receptor–protein kinase C activity in the hypothalamus augments glutamatergic input and sympathetic outflow in hypertension

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