Nitric oxide synthase inhibitors modulate lipopolysaccharide-induced hepatocyte injury: dissociation between in vivo and in vitro effects

Farghali, Hassan; Canová, Nikolina Kutinová; Kučera, Tomáš; Martínek, J; Mašek, K.

doi:10.1016/s1567-5769(03)00185-1

Cited by 19 publications

(10 citation statements)

References 30 publications

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“…This high level of spontaneous NO production can be explained by the greater number of hepatocytes available at the end of the 0-24 h period, as demonstrated by measurement of total protein content of cell mass (data not shown), and by induction of iNOS expression since Figure 2B clearly demonstrates that iNOS protein was present in at least 20% of control hepatocytes. The early spontaneous NO production has been described as being caused by nuclear factor-kappa B (NF-κB)-mediated postisolation mRNA and de novo protein iNOS expression due to collagenase used during hepatocyte isolation (Wang et al, 1998;Dilworth et al, 2001;Farghali et al, 2002Farghali et al, , 2003. The postisolation elevated nitrite levels were shown to exert no effect on ATP, reduced glutathione, or the basal level of apoptosis in freshly cultured hepatocytes (Dilworth et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…The induction of NO production in certain situations is envisioned as an early adaptive response, which may become a mediator of tissue damage when there is overproduction (Farghali et al, 2003;Liu and Waalkes, 2005). NO can have both pro-apoptotic and anti-apoptotic properties depending on the rate of NO production, the physiological cellular state, cell type, and the interaction with biological molecules such as iron, thiols, proteins, and reactive oxygen species (ROS) (Li and Billiar, 1999;Chung et al, 2001;Kim PK et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Thapsigargin, a selective inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases, modulates nitric oxide production and cell death of primary rat hepatocytes in culture

et al. 2007

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Increased cytosolic calcium ([Ca2+]i) and nitric oxide (NO) are suggested to be associated with apoptosis that is a main feature of many liver diseases and is characterized by biochemical and morphological features. We sought to investigate the events of increase in [Ca2+]i and endoplasmic reticulum (ER) calcium depletion by thapsigargin (TG), a selective inhibitor of sarco-ER-Ca2+ -ATPases, in relation to NO production and apoptotic and necrotic markers of cell death in primary rat hepatocyte culture. Cultured hepatocytes were treated with TG (1 and 5 micromol/L) for 0-24 or 24-48 h. NO production and inducible NO synthase (iNOS) expression were determined as nitrite levels and by iNOS-specific antibody, respectively. Hepatocyte apoptosis was estimated by caspase-3 activity, cytosolic cytochrome c content and DNA fragmentation, and morphologically using Annexin-V/propidium iodide staining. Hepatocyte viability and mitochondrial activity were evaluated by ALT leakage and MTT test. Increasing basal [Ca2+]i by TG, NO production and apoptotic/necrotic parameters were altered in different ways, depending on TG concentration and incubation time. During 0-24 h, TG dose-dependently decreased iNOS-mediated spontaneous NO production and simultaneously enhanced hepatocyte apoptosis. In addition, TG 5 micromol/L produced secondary necrosis. During 24-48 h, TG dose-dependently enhanced basal NO production and rate of necrosis. TG 5 micromol/L further promoted mitochondrial damage as demonstrated by cytochrome c release. A selective iNOS inhibitor, aminoguanidine, suppressed TG-stimulated NO production and ALT leakage from hepatocytes after 24-48 h. Our data suggest that the extent of the [Ca2+]i increase and the modulation of NO production due to TG treatment contribute to hepatocyte apoptotic and/or necrotic events.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thapsigargin, a selective inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases, modulates nitric oxide production and cell death of primary rat hepatocytes in culture

et al. 2007

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“…Secondary necrosis of hepatocytes resulting in severe hepatitis has been described in rodents with extensive hepatocyte apoptosis induced by LPS [164], Fas antibody [138,165], galactosamine [166] or carbon tetrachloride [137]. Apoptotic secondary necrosis was also reported in brains subjected to focal ischemia [167], in hepatic [112] and renal [168] ischemia-reperfusion, in acute myocardial infarction [169,170], and in other heart pathologies [171].…”

Section: Introductionmentioning

confidence: 99%

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

2008

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In metazoans apoptosis is a major physiological process of cell elimination during development and in tissue homeostasis and can be involved in pathological situations. In vitro, apoptosis proceeds through an execution phase during which cell dismantling is initiated, with or without fragmentation into apoptotic bodies, but with maintenance of a near-to-intact cytoplasmic membrane, followed by a transition to a necrotic cell elimination traditionally called "secondary necrosis". Secondary necrosis involves activation of self-hydrolytic enzymes, and swelling of the cell or of the apoptotic bodies, generalized and irreparable damage to the cytoplasmic membrane, and culminates with cell disruption. In vivo, under normal conditions, the elimination of apoptosing cells or apoptotic bodies is by removal through engulfment by scavengers prompted by the exposure of engulfment signals during the execution phase of apoptosis; if this removal fails progression to secondary necrosis ensues as in the in vitro situation. In vivo secondary necrosis occurs when massive apoptosis overwhelms the available scavenging capacity, or when the scavenger mechanism is directly impaired, and may result in leakage of the cell contents with induction of tissue injury and inflammatory and autoimmune responses. Several disorders where secondary necrosis has been implicated as a pathogenic mechanism will be reviewed.

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“…In those articles, we looked for possible underlying common mechanisms of cytoprotection from molecular levels to whole animal studies of various structurally unrelated molecules. We found that several compounds experimentally showed some hepato-ameliorative properties and enumerated possible explanations (Canova et al, 2007;Cerny et al, 2009;Farghali & Masek, 1998;Farghali et al, 1991aFarghali et al, ,b, 1994Farghali et al, , 1996aFarghali et al, ,b, 1997Farghali et al, , 2000bFarghali et al, , 2002Farghali et al, , 2003Gasbarrini et al, 1992aGasbarrini et al, ,b, 1993Kmonickova et al, 2001;Lekic et al, 2011;Sakr et al, 1991a,b).…”

Section: Scientific Rationale For the Traditional Use Of Some Plants mentioning

confidence: 83%

Hepatoprotective properties of extensively studied medicinal plant active constituents: Possible common mechanisms

Farghali

Canová

Zakhari³

2014

Pharmaceutical Biology

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Context: We focused on certain plant active constituents considered to be the most promising/ studied for liver disease and that were critically investigated from the basic science point of view and, to some extent, the clinical one. Due to insufficient pharmacological data, most of the herbal formulations containing these molecules cannot be recommended for the treatment of liver disease. Objective: To present the most promising compounds tested experimentally and/or clinically and describe in brief popular models in experimental testing of potential hepatoprotective compounds. Methods: A literature search using Web of Science (WOS), PubMed, and Google search was performed.Results: Focusing on a few herbal hepatoprotective active constituents is useful to health professionals working in the field of therapeutics to develop evidence-based hepatoprotective agents by conducting research on pure chemical structures or on molecular modifications using computational chemistry. This review demonstrates that multi-pathways in the liver pathobiology can be interrupted at one or more levels by natural hepatoprotective studied, such as interference with the oxidative stress at multiple levels to reduce reactive oxygen/ nitrogen species, resulting in ameliorating hepatotoxicity. Conclusion: Hepatoprotective constituents of herbal medications are poorly absorbed after oral administration; methods that can improve their bioavailability are being developed. It is recommended that controlled prospective double-blind multicenter studies on isolated active plant constituents, or on related newly designed molecules after structural modifications, should be performed. This effort will lead to expanding the existing, limited drugs for the vast majority of liver diseases.

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Nitric oxide synthase inhibitors modulate lipopolysaccharide-induced hepatocyte injury: dissociation between in vivo and in vitro effects

Cited by 19 publications

References 30 publications

Thapsigargin, a selective inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases, modulates nitric oxide production and cell death of primary rat hepatocytes in culture

Thapsigargin, a selective inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases, modulates nitric oxide production and cell death of primary rat hepatocytes in culture

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

Hepatoprotective properties of extensively studied medicinal plant active constituents: Possible common mechanisms

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