Search PubMed⌕ Search

Biomedical subjects

Craig McClain

Publications and source records attributed to Craig McClain.

13 recordsLinked to original sources
PubMed2006

Chronic ethanol-mediated decrease in cAMP primes macrophages to enhanced LPS-inducible NF-kappaB activity and TNF expression: relevance to alcoholic liver disease.

Increased plasma and hepatic TNF-alpha activity has been implicated in the pathogenesis of alcoholic liver disease (ALD). We previously reported that monocytes from alcoholic patients show enhanced constitutive as well as LPS-inducible NF-kappaB activation and TNF-alpha production. Studies in monocytes have shown that cAMP plays an important role in regulating TNF-alpha expression, and elevation of cellular cAMP suppresses TNF-alpha production. The effects of chronic ethanol exposure on the cellular levels of cAMP as well as TNF expression in monocytes were examined in vitro and in rat primary hepatic Kupffer cells obtained from a clinically relevant enteral alcohol feeding model of ALD. Chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes. Consistent with the decrease in cAMP levels, ethanol led to an increase in LPS-inducible TNF-alpha production by affecting NF-kappaB activation and induction of TNF mRNA expression, without any change in TNF mRNA stability. Enhancement of cellular cAMP with dibutyryl cAMP abrogated LPS-mediated TNF-alpha expression in ethanol-treated cells. Importantly, cAMP did not affect LPS-inducible NF-kappaB activation but significantly decreased its transcriptional activity. Together, these data strongly suggest that ethanol can synergize with LPS to upregulate the induction of TNF gene expression and consequent TNF overproduction by decreasing the cellular cAMP levels in monocytes/macrophages. Furthermore, these data also support the notion that cAMP-elevating agents could constitute an effective therapeutic approach in attenuating or preventing the progression of liver disease in alcoholic patients.

Animals↗
PubMed2006

Polyphenols and gastrointestinal diseases.

PURPOSE OF REVIEW: This article will review the role of polyphenols in gastrointestinal diseases. Ingested polyphenols are concentrated in the gastrointestinal tract and are not well absorbed into the rest of the body. Thus, the high luminal concentrations achieved support a potential for therapeutic uses in the gastrointestinal tract. Additionally, there is great interest from the general public in complementary and alternative medicine. RECENT FINDINGS: Dietary polyphenols are a major source of antioxidants consumed by humans. Polyphenols possess not only antioxidant properties but also antiviral, antibacterial, antiinflammatory and anticarcinogenic effects, as well as the ability to modulate certain signaling pathways such as nuclear factor-kappaB activation. Green tea polyphenols have been shown to have efficacy in various models of inflammatory bowel disease. Silymarin, or milk thistle, is hepatoprotective against many forms of experimental liver injury and is widely used in human liver diseases, such as hepatitis C and alcoholic cirrhosis, with an excellent safety profile (but with unclear efficacy). SUMMARY: Substantial in-vitro and animal studies support the beneficial effects of polyphenols in many gastrointestinal diseases. Well designed multicenter trials in humans, such as those called for in the 2005 National Institutes of Health Requests for Applications for Silymarin Centers, will be critical for defining the safety, appropriate dosing and therapeutic efficacy of such agents.

Animals↗
PubMed2006

Interactions of cytokines, S-Adenosylmethionine, and S-Adenosylhomocysteine in alcohol-induced liver disease and immune suppression.

Alcoholic liver disease (ALD) remains a leading cause of death in the USA. Defining mechanisms for liver cell death in ALD in order to develop potential new agents for therapeutic intervention is a major focus of the authors' work. Abnormal cytokine metabolism is a major feature of ALD, and a thorough understanding of both mechanisms and interactions of cytokine overproduction and sensitization are critical to developing a possible treatment for ALD. S-Adenosylmethionine has been used in a variety of animal studies and clinical trials and has been reported to improve biochemical parameters of liver function. Last, immunosuppression associated with chronic alcohol abuse is an important predisposing factor to opportunistic infections and cancer. It is the authors' working hypothesis that alcohol consumption leads to chronic activation of the immune system.

Animals↗
PubMed2006

Silymarin protects against acute ethanol-induced hepatotoxicity in mice.

BACKGROUND: Accumulated evidence has demonstrated that both oxidative stress and abnormal cytokine production, especially tumor necrosis factor-alpha (TNF), play important etiological roles in the pathogenesis of alcoholic liver disease (ALD). Agents that have both antioxidant and anti-inflammation properties, particularly anti-TNF production, represent promising therapeutic interventions for ALD. We investigated the effects and the possible mechanism(s) of silymarin on liver injury induced by acute ethanol (EtOH) administration. METHODS: Nine-week-old mice were divided into 4 groups, control, silymarin treatment, EtOH treatment, and silymarin/EtOH treatment, with 6 mice in each group. Because control and silymarin values were virtually identical, only control treatment is shown for ease of viewing. Ethanol-treated mice received EtOH [5 g/kg body weight (BW)] by gavage every 12 hours for a total of 3 doses. Control mice received an isocalorical maltose solution. In the silymarin/EtOH group, silymarin was dissolved in the EtOH and gavaged simultaneously with EtOH at a dose of 200 mg/kg BW. At 4 hours after the last dosing, the mice were anesthetized and subsequent serum alanine aminotransferase (ALT) level, hepatic lipid peroxidation, enzymatic activity of hepatic cytochrome P450 2E1, hepatic TNF-alpha, and glutathione (GSH) levels were measured. Histopathological change was assessed by hematoxylin and eosin staining. RESULTS: Acute EtOH administration caused prominent hepatic microvesicular steatosis with mild necrosis and an elevation of serum ALT activity, induced a significant decrease in hepatic GSH in conjunction with enhanced lipid peroxidation, and increased hepatic TNF production. Supplementation with a standardized silymarin attenuated these adverse changes induced by acute EtOH administration. CONCLUSIONS: Silymarin protects against the liver injury caused by acute EtOH administration. In view of its nontoxic nature, it may be developed as an effective therapeutic agent for alcohol-induced liver disease by its antioxidative stress and anti-inflammatory features.

Alanine Transaminase↗
PubMed2006

The use of selected nutrition supplements and complementary and alternative medicine in liver disease.

Almost all patients with liver disease, especially advanced liver disease, have some evidence of malnutrition, including mineral/vitamin deficiency. A major health trend in the United States has been the significant growth in the use of complementary and alternative medicine (CAM), including nutrition supplements and herbal agents. In the 1990s, the United States government created the National Center for Complementary and Alternative Medicine (NCCAM), as well as the Office on Dietary Supplements, to extend our knowledge in these areas. CAM users are often highly educated and frequently use CAM therapy for chronic diseases, including chronic liver disease. Indeed, most studies suggest that patients with chronic liver disease frequently use nutrition supplements and CAM agents in addition to their traditional medicines. The purpose of this review is to provide an update on the role of nutrition supplements and herbals in liver disease. This article will focus mainly on 7 selected agents (vitamin E, zinc, magnesium, S-adenosylmethionine, betaine, silymarin, and glycyrrhizin), for which there have been not only in vitro and animal studies but also human clinical trials, and we will review both potential efficacy and safety issues.

Complementary Therapies↗
PubMed2005

S-adenosylmethionine (SAMe) modulates interleukin-10 and interleukin-6, but not TNF, production via the adenosine (A2) receptor.

S-adenosylmethionine (SAMe) is the first product in methionine metabolism and serves as a precursor for glutathione (GSH) as well as a methyl donor in most transmethylation reactions. The administration of exogenous SAMe has beneficial effects in many types of liver diseases. One mechanism for the hepatoprotective action is its ability to regulate the immune system by modulating cytokine production from LPS stimulated monocytes. In the present study, we investigated possible mechanism(s) by which exogenous SAMe supplementation modulated production of TNF, IL-10 and IL-6 in LPS stimulated RAW 264.7 cells, a murine monocyte cell line. Our results demonstrated that exogenous SAMe supplementation inhibited TNF production but enhanced both IL-10 and IL-6 production. SAMe increased intracellular GSH level, however, N-acetylcysteine (NAC), the GSH pro-drug, decreased the production of all three cytokines. Importantly, SAMe increased intracellular adenosine levels, and exogenous adenosine supplementation had effects similar to SAMe on TNF, IL-10 and IL-6 production. 3-Deaza-adenosine (DZA), a specific inhibitor of S-adenosylhomocysteine (SAH) hydrolase, blocked the elevation of IL-10 and IL-6 production induced by SAMe, which was rescued by the addition of exogenous adenosine. Furthermore, the enhancement of LPS-stimulated IL-10 and IL-6 production by both SAMe and adenosine was inhibited by ZM241385, a specific antagonist of the adenosine (A(2)) receptor. Our results suggest that increased adenosine levels with subsequent binding to the A(2) receptor account, at least in part, for SAMe modulation of IL-10 and IL-6, but not TNF production, from LPS stimulated monocytes.

Adenosine A2 Receptor Antagonists↗
PubMed2005

Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival.

BACKGROUND & AIMS: Colchicine improved survival and reversed cirrhosis in several small clinical trials. We compared the efficacy and safety of long-term colchicine, as compared with placebo, in patients with advanced alcoholic cirrhosis. METHODS: Five hundred forty-nine patients with advanced (Pugh B or C) alcoholic cirrhosis were randomized to receive either colchicine 0.6 mg twice per day (n = 274) or placebo (n = 275). Treatment lasted from 2 to 6 years. The primary outcome was all-cause mortality. Secondary outcomes were liver-related morbidity and mortality. Liver biopsy was requested prior to entry and after 24 months of treatment. RESULTS: Attendance at scheduled clinic visits and adherence with study medication were similar in colchicine and placebo groups. Alcohol intake was less than 1 drink per day in 69% of patients. In an intention-to-treat analysis, all-cause mortality was similar in colchicine (49%) and placebo (45%) patients (P = .371). Mortality attributed to liver disease was 32% in colchicine and 28% in placebo patients (P = .337). Fewer patients receiving colchicine developed hepatorenal syndrome. In 54 patients with repeat liver biopsies after 24 or more months of treatment, cirrhosis improved to septal fibrosis in 7 patients (3 colchicine, 4 placebo) and to portal fibrosis in 1 patient (colchicine). CONCLUSIONS: In patients with advanced alcoholic cirrhosis, colchicine does not reduce overall or liver-specific mortality. Liver histology improves to septal fibrosis in a minority of patients after 24 months of treatment, with similar rates of improvement in patients receiving placebo and colchicine. Colchicine is not recommended for patients with advanced alcoholic cirrhosis.

Colchicine↗
PubMed2005

Dysregulated cytokine metabolism, altered hepatic methionine metabolism and proteasome dysfunction in alcoholic liver disease.

Alcoholic liver disease (ALD) remains an important complication and cause of morbidity and mortality from alcohol abuse. Major developments in our understanding of the mechanisms of ALD over the past decade are now being translated into new forms of therapy for this disease process which currently has no FDA approved treatment. Cytokines are low molecular weight mediators of cellular communication, and the pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to play a pivotal role in the development of experimental ALD. Similarly, TNF levels are elevated in the serum of alcoholic hepatitis patients. Abnormal methionine metabolism is well documented in patients with ALD, with patients having elevated serum methionine levels, but low S-adenosylmethionine levels in the liver. On the other hand, S-adenosylhomocysteine and homocysteine levels are elevated in ALD. Recent studies have documented potential interactions between homocysteine and S-adenosylhomocysteine with TNF in the development of ALD. Altered proteasome function also is now well documented in ALD, and decreased proteasome function can cause hepatocyte apoptosis. Recently it has been shown that decreased proteasome function can also act synergistically to enhance TNF hepatotoxicity. Hepatocytes dying of proteasome dysfunction release pro-inflammatory cytokines such as Interleukin-8 to cause sustained inflammation. This article reviews the interactions of cytokines, altered methionine metabolism, and proteasome dysfunction in the development of ALD.

Cytokines↗
PubMed2003

S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice.

Although S-Adenosylmethionine (SAMe) has beneficial effects in many hepatic disorders, the effects of SAMe on acute alcohol-induced liver injury are unknown. In the present study, we investigated effects of SAMe on liver injury in mice induced by acute alcohol administration. Male C57BL/6 mice received ethanol (5 g/kg BW) by gavage every 12 hrs for a total of 3 doses. SAMe (5 mg/kg BW) was administrated i.p. once a day for three days before ethanol administration. Subsequent serum ALT level, hepatic lipid peroxidation, enzymatic activity of CYP2E1 and hepatic mitochondrial glutathione levels were measured colorimetrically. Intracellular SAMe concentration was measured by high-performance liquid chromatography (HPLC). Histopathological changes were assessed by H&E staining. Our results showed that acute ethanol administration caused prominent microvesicular steatosis with mild necrosis and an elevation of serum ALT activity. SAMe treatment significantly attenuated the liver injury. In association with the hepatocyte injury, acute alcohol administration induced significant decreases in both hepatic SAMe and mitochondrial GSH levels along with enhanced lipid peroxidation. SAMe treatment attenuated hepatic SAMe and mitochondrial GSH depletion and lipid peroxidation following acute alcohol exposure. These results demonstrate that SAMe protects against the liver injury and attenuates the mitochondrial GSH depletion caused by acute alcohol administration. SAMe may prove to be an effective therapeutic agent in many toxin-induced liver injuries including those induced by alcohol.

Animals↗
PubMed2003

S-adenosylmethionine (AdoMet) modulates endotoxin stimulated interleukin-10 production in monocytes.

IL-10 is produced by a large variety of cells including monocytes, macrophages, B and T lymphocytes, as well as natural killer cells and is an important suppressor for both immunoproliferative and inflammatory responses. IL-10 exerts antifibrotic effects in the liver, and decreased monocyte synthesis of IL-10 is well documented in alcoholic cirrhosis. Intracellular deficiency of S-adenosylmethionine (AdoMet) is a hallmark of toxin-induced liver injury. Although the administration of exogenous AdoMet attenuates this injury, the mechanisms of its actions are not fully established. This study was performed to investigate the effect of exogenous AdoMet on IL-10 production in LPS-stimulated RAW 264.7 cells, a murine macrophage cell line. Our results demonstrated that exogenous AdoMet administration enhanced both protein production and gene expression of IL-10 in RAW 264.7 cells. Ethionine, an inhibitor for methionine adenosyltransferases, inhibited LPS-stimulated IL-10 both at the protein and mRNA levels. Exogenous AdoMet increased the intracellular cAMP concentration as early as 3 h and continued for 24 h after AdoMet treatment; however, the inhibitors for both adenylyl cyclase and PKA did not significantly affect IL-10 production. On the basis of these results, we conclude that AdoMet administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-10 production.

Animals↗
PubMed2002

The regulation of Fas (CD95/Apo-1)-mediated liver apoptosis in Kupffer cell-depleted mice.

The purpose of this study was to further characterize Fas-mediated liver apoptosis. We investigated whether Fas-mediated apoptosis in the liver requires induction of apoptosis-related regulators and whether Kupffer cells play a role in this process. Mice were injected with GdCl(3) to deplete/suppress Kupffer cells, followed by treatment with an anti-Fas agonistic antibody, Jo2. Hepatic mRNA levels of several pro- and anti-apoptotic regulators were determined 0.5, 1.5 and 4.0 h after Jo2 injection. Liver histology, TUNEL response, the activity of caspases-3, -8, and -9, and reduced and oxidized glutathione, were also evaluated. Jo2 dramatically increased the number of apoptotic nuclei in the liver, up-regulated mRNA for Bcl-w, Bfl-1, and Bcl-X(L,) but did not affect pro-apoptotic regulator mRNA expression. Caspase-3, -8 and -9 activity increased at 1.5 h after Jo2-injection. GdCl(3) treatment was associated with an increase in the apoptotic effect of Jo2. No effect of Jo2 was recorded on redox state of the free cellular thiol system. These data suggest that: (1) the prompt apoptotic response to Fas-mediated signaling in the liver does not require induction of pro-apoptotic factors; (2) Kupffer cells may play a major role in the liver apoptotic response to Fas ligation by clearing apoptotic cells by phagocytosis; (3) oxidative stress does not seem to play an important role in Fas-mediated liver apoptosis.

Journal Article↗
PubMed2002

Molecular pathology and clinical aspects of alcohol-induced tissue injury.

Proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada; organized and co-chaired by Patricia E. Molina and Manuela Neuman. The presentations were (1) Mechanisms of alcohol-induced cell injury by Craig McClain; (2) Cytokines in alcoholic steatohepatitis and non-alcoholic steatohepatitis by Manuela Neuman; (3) Combination of alcohol and hepatitis C virus and liver injury by Dominique Valla; (4) Chronic ethanol exposure potentiates lipopolysaccharide liver injury, despite inhibiting Jun N-Terminal kinase and caspase 3 activation by Anna Mae Diehl; (5) Glutathione homeostasis in alcoholism: Role in alveolar epithelial barrier and lung injury by David M. Guidot; (6) Metabolic and inflammatory contribution of alcohol to trauma-induced tissue injury by Patricia E. Molina; (7) Growth factor and protein synthesis dysregulation: Role in alcoholic myopathy by Charles H. Lang.

Alcohol-Induced Disorders↗