The CBS/CSE system: a potential therapeutic target in NAFLD?

Lk, Sarna; Siow, Yaw L.

doi:10.1139/cjpp-2014-0394

Cited by 39 publications

(28 citation statements)

References 144 publications

(254 reference statements)

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“…Moreover, our results showed an increase in total protein and albumin after administration of olive oil and N. sativa oil to rats received CCl 4 . This result is also consistent with Al-Malki and El Rabey [25], Salem et al [61] and Jin et al [63]. …”

Section: Discussionsupporting

confidence: 92%

The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats

Al‐Seeni

Rabey

Zamzami

et al. 2016

BMC Complement Altern Med

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BackgroundLiver disease is the major cause of serious health problem leading to morbidity and mortality worldwide and the problem has increased in search for hepatotherapeutic agents from plants. The present study was designed to compare the probable hepatoprotective activity of olive oil and N. sativa oil on CCl4 induced liver damage in male rats.MethodsForty males of a new model of albino rats (Wistar strain) (175–205 g) were divided into four groups. The 1st Group (G1) was the negative control group, the remaining rats were injected with CCl4 (1 ml/kg body weight) with equal amount of olive oil on the 1st and 4th day of every week for 4 weeks. The 2nd group (G2) was the positive control, the 3rd group (G3) and the fourth group (G4) were treated orally with N. sativa oil and olive oils using stomach tube.ResultsThe positive control group showed an increase in hepatic enzymes, total bilirubin, creatinine, uric acid, lipid peroxide total cholesterol, triglyceride, low density lipoprotein, very low density lipoproteins, interleukin-6, and a decrease in antioxidant enzymes, high density lipoprotein cholesterol, a decrease in total protein and albumin an when compared with negative control group. Histology of the CCl4 treated group revealed inflammation and damage of liver cells. Treating the hepatotoxic rats with olive oil and N. sativa oil showed a significant improvement in all biochemical tests compared with the positive CCl4 control group. In addition, the liver tissues of olive oil treated group showed mild improvement in inflammatory infiltration and in N. sativa oil treated group showed normal hepatocytes with no evidence of inflammation.ConclusionThis study revealed that olive oil and N. sativa oil have a protective effect against CCl4-induced hepatotoxicity in male rats. Nigella sativa oil was more effective than olive oil.

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Section: Discussionsupporting

confidence: 92%

The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats

Al‐Seeni

Rabey

Zamzami

et al. 2016

BMC Complement Altern Med

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“…Ascorbate has the benefit of being safe and free of common toxic side effects that often accompany chemotherapies. Good tolerability to IVC has now been observed in over 10 clinical trials (15). Because of its low-toxicity, IVC is worth considering for the treatment of neuroblastomas.…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis

Chen

Wilkins

et al. 2017

Free Radical Biology and Medicine

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An ascorbate-mediated production of oxidative stress has been shown to retard tumor growth. Subsequent glycolysis inhibition has been suggested. Here, we further define the mechanisms relevant to this observation. Ascorbate was cytotoxic to human neuroblastoma cells through the production of H2O2, which led to ATP depletion, inhibited GAPDH, and non-apoptotic and non-autophagic cell death. The mechanism of cytotoxicity is different when PARP-dependent DNA repair machinery is active or inhibited. Ascorbate-generated H2O2 damaged DNA, activated PARP, depleted NAD+, and reduced glycolysis flux. NAD+ supplementation prevented ATP depletion and cell death, while treatment with a PARP inhibitor, olaparib, preserved NAD+ and ATP levels but led to increased DNA double-strand breakage and did not prevent ascorbate-induced cell death. These data indicate that in cells with an intact PARP-associated DNA repair system, ascorbate-induced cell death is caused by NAD+ and ATP depletion, while in the absence of PARP activation ascorbate-induced cell death still occurs but is a consequence of ROS-induced DNA damage. In a mouse xenograft model, intraperitoneal ascorbate inhibited neuroblastoma tumor growth and prolonged survival. Collectively, these data suggest that ascorbate could be effective in the treatment of glycolysis-dependent tumors. Also, in cancers that use alternative energy metabolism pathways, combining a PARP inhibitor with ascorbate treatment could be useful.

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“…Pharmacological inhibition or knockdown of CBS inhibits the proliferation of cancer cell lines and reduces the growth of tumor xenografts in vivo, identifying CBS as a preclinically-validated anticancer drug target [11][12][13][14][15][16]. CBS has also been proposed as a therapeutic target for non-alcoholic fatty liver disease [17] and stroke [18,19].…”

Section: Introductionmentioning

confidence: 99%

Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer

Druzhyna

Szczesny

Oláh

et al. 2016

Pharmacological Research

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Cystathionine-β-synthase (CBS) has been recently identified as a drug target for several forms of cancer. Currently no potent and selective CBS inhibitors are available. Using a composite collection of 8871 clinically used drugs and well-annotated pharmacological compounds (including the LOPAC library, the FDA Approved Drug Library, the NIH Clinical Collection, the New Prestwick Chemical Library, the US Drug Collection, the International Drug Collection, the `Killer Plates' collection and a small custom collection of PLP-dependent enzyme inhibitors), we conducted an in vitro screen in order to identify inhibitors for CBS using a primary 7-azido-4-methylcoumarin (AzMc) screen to detect CBS-derived hydrogen sulfide (H2S) production. Initial hits were subjected to counterscreens using the methylene blue assay (a secondary assay to measure H2S production) and were assessed for their ability to quench the H2S signal produced by the H2S donor compound GYY4137. Four compounds, hexachlorophene, tannic acid, aurintricarboxylic acid and benserazide showed concentration-dependent CBS inhibitory actions without scavenging H2S released from GYY4137, identifying them as direct CBS inhibitors. Hexachlorophene (IC50: ~60 μM), tannic acid (IC50: ~40 μM) and benserazide (IC50: ~30 μM) were less potent CBS inhibitors than the two reference compounds AOAA (IC50: ~3 μM) and NSC67078 (IC50: ~1 μM), while aurintricarboxylic acid (IC50: ~3 μM) was equipotent with AOAA. The second reference compound NSC67078 not only inhibited the CBS-induced AzMC fluorescence signal (IC50: ~1 μM), but also inhibited with the GYY4137-induced AzMC fluorescence signal with (IC50 of ~6 μM) indicative of scavenging/non-specific effects. Hexachlorophene (IC50: ~6 μM), tannic acid (IC50: ~20 μM), benserazide (IC50: ~20 μM), and NSC67078 (IC50: ~0.3 μM) inhibited HCT116 colon cancer cells proliferation with greater potency than AOAA (IC50: ~300 μM). In contrast, although a CBS inhibitor in the cell-free assay, aurintricarboxylic acid failed to inhibit HCT116 proliferation at lower concentrations, and stimulated cell proliferation at 300 μM. Copper-containing compounds present in the libraries, were also found to be potent inhibitors of recombinant CBS; however this activity was due to the CBS inhibitory effect of copper ions themselves. However, copper ions, up to 300 μM, did not inhibit HCT116 cell proliferation. Benserazide was only a weak inhibitor of the activity of the other H2S-generating enzymes CSE and 3-MST activity (16% and 35% inhibition at 100 μM, respectively) in vitro. Benserazide suppressed HCT116 mitochondrial function and inhibited proliferation of the high CBS-expressing colon cancer cell line HT29, but not the low CBS-expressing line, LoVo. The major benserazide metabolite 2,3,4-trihydroxybenzylhydrazine also inhibited CBS activity and suppressed HCT116 cell proliferation in vitro. In an in vivo study of nude mice bearing human colon cancer cell xenografts, benserazide (50 mg/kg/day s.q.) prevented tumor growth. In silico docking simulations...

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The CBS/CSE system: a potential therapeutic target in NAFLD?

Cited by 39 publications

References 144 publications

The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats

The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats

Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis

Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer

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