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Fulltext Phorbol esters isolated from Jatropha meal induced apoptosis-mediated inhibition in proliferation of chang and Vero cell lines

Oskoueian E, Abdullah N, Ahmad S

Int J Mol Sci, 2012;13(11):13816-29.
PMID: 23203036 DOI: 10.3390/ijms131113816

The direct feeding of Jatropha meal containing phorbol esters (PEs) indicated mild to severe toxicity symptoms in various organs of different animals. However, limited information is available on cellular and molecular mechanism of toxicity caused by PEs present in Jatropha meal. Thus, the present study was conducted to determine the cytotoxic and mode of action of PEs isolated from Jatropha meal using human hepatocyte (Chang) and African green monkey kidney (Vero) cell lines. The results showed that isolated PEs inhibited cell proliferation in a dose-dependent manner in both cell lines with the CC(50) of 125.9 and 110.3 μg/mL, respectively. These values were compatible to that of phorbol 12-myristate 13-acetate (PMA) values as positive control i.e., 124.5 and 106.3 μg/mL respectively. Microscopic examination, flow cytometry and DNA fragmentation results confirmed cell death due to apoptosis upon treatment with PEs and PMA at CC(50) concentration for 24 h in both cell lines. The Western blot analysis revealed the overexpression of PKC-δ and activation of caspase-3 proteins which could be involved in the mechanism of action of PEs and PMA. Consequently, the PEs isolated form Jatropha meal caused toxicity and induced apoptosis-mediated proliferation inhibition toward Chang and Vero cell lines involving over-expression of PKC-δ and caspase-3 as their mode of actions.

Matched MeSH terms: Protein Kinase C/metabolism
Fulltext Possible Participation of Ionotropic Glutamate Receptors and l-Arginine-Nitric Oxide-Cyclic Guanosine Monophosphate-ATP-Sensitive K+ Channel Pathway in the Antinociceptive Activity of Cardamonin in Acute Pain Animal Models

Pui Ping C, Akhtar MN, Israf DA, Perimal EK, Sulaiman MR

Molecules, 2020 Nov 18;25(22).
PMID: 33217904 DOI: 10.3390/molecules25225385

The perception of pain caused by inflammation serves as a warning sign to avoid further injury. The generation and transmission of pain impulses involves various pathways and receptors. Cardamonin isolated from Boesenbergia rotunda (L.) Mansf. has been reported to exert antinociceptive effects in thermal and mechanical pain models; however, the precise mechanism has yet to be examined. The present study investigated the possible mechanisms involved in the antinociceptive activity of cardamonin on protein kinase C, N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors, l-arginine/cyclic guanosine monophosphate (cGMP) mechanism, as well as the ATP-sensitive potassium (K+) channel. Cardamonin was administered to the animals intra-peritoneally. Present findings showed that cardamonin significantly inhibited pain elicited by intraplantar injection of phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator) with calculated mean ED50 of 2.0 mg/kg (0.9-4.5 mg/kg). The study presented that pre-treatment with MK-801 (NMDA receptor antagonist) and NBQX (non-NMDA receptor antagonist) significantly modulates the antinociceptive activity of cardamonin at 3 mg/kg when tested with glutamate-induced paw licking test. Pre-treatment with l-arginine (a nitric oxide precursor), ODQ (selective inhibitor of soluble guanylyl cyclase) and glibenclamide (ATP-sensitive K+ channel inhibitor) significantly enhanced the antinociception produced by cardamonin. In conclusion, the present findings showed that the antinociceptive activity of cardamonin might involve the modulation of PKC activity, NMDA and non-NMDA glutamate receptors, l-arginine/nitric oxide/cGMP pathway and ATP-sensitive K+ channel.

Matched MeSH terms: Protein Kinase C
Fulltext Possible participation of nitric oxide/cyclic guanosine monophosphate/protein kinase C/ATP-sensitive K(+) channels pathway in the systemic antinociception of flavokawin B

Mohamad AS, Akhtar MN, Khalivulla SI, Perimal EK, Khalid MH, Ong HM, et al.

Basic Clin Pharmacol Toxicol, 2011 Jun;108(6):400-5.
PMID: 21214864 DOI: 10.1111/j.1742-7843.2010.00670.x

The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg/kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K(+) channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO/cyclic guanosine monophosphate/PKC/ATP-sensitive K(+) channel pathway possibly participated in the antinociceptive action induced by FKB.

Matched MeSH terms: Protein Kinase C/physiology*
Role of protein kinase C in hydroxyapatite- induced phagocytosis by a murine macrophage cell line (RAW264.7)

Gopinath VK, Musa M, Samsudin AR, Sosroseno W

Immunopharmacol Immunotoxicol, 2006;28(3):485-9.
PMID: 16997796

The role of protein kinase C (PKC) in hydroxyapatite (HA)-induced phagocytosis by RAW 264.7 cells was investigated. The cells were incubated with HA particles at various incubation time and the levels of PKC activity were determined from the cell lysate. To determine the role of PKC, particles were incubated with the cells pretreated with the various concentrations of bisindolylmaleimide, a PKC inhibitor, and phagocytosis was then assessed at 60 min. Latex beads were used as a control. Our results showed that following incubation with HA particles, the levels of PKC activity in RAW264.7 cells was highest at 7 min and then decreased to reach the baseline levels of the controls at 30 min. Pretreatment of the cells with bisindolylmaleimide significantly reduced phagocytosis of HA particles in a dose-dependent pattern. The results of our present study suggest therefore that ingestion of HA by RAW264.7 cells may depend on PKC activity that may act in the early stages of phagocytosis.

Matched MeSH terms: Protein Kinase C/antagonists & inhibitors; Protein Kinase C/metabolism*; Protein Kinase C/physiology
Suppressive effect of maslinic acid on PMA-induced protein kinase C in human B-lymphoblastoid cells

Mooi LY, Yew WT, Hsum YW, Soo KK, Hoon LS, Chieng YC

Asian Pac J Cancer Prev, 2012;13(4):1177-82.
PMID: 22799301

Protein kinase C (PKC) has been implicated in carcinogenesis and displays variable expression profiles during cancer progression. Studies of dietary phytochemicals on cancer signalling pathway regulation have been conducted to search for potent signalling regulatory agents. The present study was designed to evaluate any suppressive effect of maslinic acid on PKC expression in human B-lymphoblastoid cells (Raji cells), and to identify the PKC isoforms expressed. Effects of maslinic acid on PKC activity were determined using a PepTag assay for non-radioactive detection of PKC. The highest expression in Raji cells was obtained at 20 nM PMA induced for 6 hours. Suppressive effects of maslinic acid were compared with those of four PKC inhibitors (H- 7, rottlerin, sphingosine, staurosporine) and two triterpenes (oleanolic acid and ursolic acid). The IC₅₀ values achieved for maslinic acid, staurosporine, H-7, sphingosine, rottlerin, ursolic acid and oleanolic acid were 11.52, 0.011, 0.767, 2.45, 5.46, 27.93 and 39.29 μM, respectively. Four PKC isoforms, PKC βI, βII, δ, and ζ, were identified in Raji cells via western blotting. Maslinic acid suppressed the expression of PKC βI, δ, and ζ in a concentration-dependent manner. These preliminary results suggest promising suppressive effects of maslinic acid on PKC activity in Raji cells. Maslinic acid could be a potent cancer chemopreventive agent that may be involved in regulating many downstream signalling pathways that are activated through PKC receptors.

Matched MeSH terms: Protein Kinase C/drug effects; Protein Kinase C/metabolism*
The effect of palm oil-derived tocotrienol-rich fraction in preserving normal retinal vascular diameter in streptozotocin-induced diabetic rats

Abdul Ghani NA, Abdul Nasir NA, Lambuk L, Sadikan MZ, Agarwal R, Ramli N

Graefes Arch Clin Exp Ophthalmol, 2023 Jun;261(6):1587-1596.
PMID: 36622408 DOI: 10.1007/s00417-022-05965-3

PURPOSE: Angiogenesis in diabetic retinopathy (DR) is associated with increased retinal expression of angiopoietin-2 (Ang-2) and protein kinase C (PKC). Tocotrienol-rich fraction (TRF) has been shown to reduce the expression vascular endothelial growth factor (VEGF) in several experimental models. However, its effect against other angiogenic markers such as Ang-2 and PKC in rat model of diabetes remains unknown. Therefore, we investigated the effect of TRF on the retinal vascular changes and Ang-2 and PKC expressions in rats with streptozotocin (STZ)-induced DR.
METHODS: Sprague-Dawley rats were divided into normal control rats (N) which received vehicle, and diabetic rats which either received vehicle (DV) or 100 mg/kg of TRF (DT). Diabetes was induced with intraperitoneal injection of STZ (60 mg/kg body weight). Treatments were given orally, once daily, for 12 weeks after confirmation of hyperglycaemia. Fundus photographs were captured at baseline, 6- and 12-week post-STZ injection and average diameter of retinal veins and arteries were measured. At 12-week post-STZ injection, rats were euthanised, and retinae were collected for measurement of Ang-2 and PKC gene and protein expressions.
RESULTS: Retinal venous and arterial diameters were significantly greater in DV compared to DT at week 12 post-STZ injection (p protein expressions compared to DV.
CONCLUSION: Oral TRF reduces the expression of retinal angiogenic markers and preserves the retinal vascular diameter of rats with STZ-induced DR.

Matched MeSH terms: Protein Kinase C/metabolism
The effects of acute ethanol administration on ethanol withdrawal-induced anxiety-like syndrome in rats: A biochemical study

Kumar J, Hapidin H, Get Bee YT, Ismail Z

Alcohol, 2016 Feb;50:9-17.
PMID: 26626323 DOI: 10.1016/j.alcohol.2015.10.001

Withdrawal from long-term ethanol consumption results in overexcitation of glutamatergic neurotransmission in the amygdala, which induces an anxiety-like syndrome. Most alcoholics that suffer from such symptoms frequently depend on habitual drinking as self-medication to alleviate their symptoms. Metabotropic glutamate receptor subtype 5 (mGlu5) and protein kinase C (PKC) epsilon have been reported to mediate acute and chronic effects of ethanol. This study explores the changes in mGlu5 and PKC epsilon in the amygdala following acute administration of ethanol during ethanol withdrawal (EW) induced anxiety. Male Wistar rats were fed a modified liquid diet containing low-fat cow milk, sucrose, and maltodextrin, with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into EW, the rats were intraperitoneally injected with normal saline and ethanol (2.5 g/kg, 20% v/v), and exposed to open-field and elevated plus maze tests. Then, amygdala tissue was dissected from the rat brain for Western blot and gene expression studies. EW-induced anxiety was accompanied by a significant increase in mGlu5, total PKC epsilon, and phosphorylated PKC epsilon protein levels, and also of mRNA of mGlu5 (GRM5) in the amygdala. Acute administration of ethanol significantly attenuated EW-induced anxiety as well as an EW-induced increase in GRM5. The acute challenge of ethanol to EW rats had little effect on the phosphorylated and total protein levels of PKC epsilon in the amygdala. Our results demonstrate that amygdala PKC epsilon may not be directly involved in the development of anxiety following EW.

Matched MeSH terms: Protein Kinase C-epsilon
Fulltext Zerumbone-induced antinociception: involvement of the L-arginine-nitric oxide-cGMP -PKC-K+ ATP channel pathways

Perimal EK, Akhtar MN, Mohamad AS, Khalid MH, Ming OH, Khalid S, et al.

Basic Clin Pharmacol Toxicol, 2011 Mar;108(3):155-62.
PMID: 20955360 DOI: 10.1111/j.1742-7843.2010.00635.x

This study investigated the antinociceptive effects of zerumbone in chemical behavioural models of nociception in mice. Zerumbone given through intraperitoneal route (i.p.) produced dose-related antinociception when assessed on acetic acid-induced abdominal writhing test in mice. In addition, the i.p. administration of zerumbone exhibited significant inhibition of the neurogenic pain induced by intraplantar (i.pl.) injection of capsaicin and bradykinin. Likewise, zerumbone given by i.p. route reduced the nociception produced by i.pl. injection of glutamate and phorbol myristate acetate (PMA). The antinociception caused by zerumbone in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with l-arginine (nitric oxide precursor) and glibenclamide (ATP-sensitive K(+) channel inhibitor). However, the antinociception of zerumbone was enhanced by methylene blue (non-specific gyanylyl cyclase inhibitor). Together, these results indicate that zerumbone produces pronounced antinociception against chemical models of nociception in mice. It also strongly suggests that the l-arginine-nitric oxide-cGMP-PKC-K(+) ATP channel pathways, the TRPV1 and kinin B2 receptors play an important role in the zerumbone-induced antinociception.

Matched MeSH terms: Protein Kinase C/metabolism*
mTORC and PKCε in Regulation of Alcohol Use Disorder

Hanim A, Mohamed IN, Mohamed RMP, Das S, Nor NSM, Harun RA, et al.

Mini Rev Med Chem, 2020;20(17):1696-1708.
PMID: 32579497 DOI: 10.2174/1389557520666200624122325

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

Matched MeSH terms: Protein Kinase C-epsilon/genetics; Protein Kinase C-epsilon/metabolism*