Increased gut permeability (leaky gut) and endotoxin-mediated Kupffer cell activation are proposed as the mechanisms of alcoholic liver injury. Although ethanol feeding is shown to sensitize the liver for injury induced by parental administration of lipopolysaccharide (LPS), how enteral LPS loading affects alcoholic liver injury is yet to be tested. The present study provides direct evidence for enhanced entrance to portal circulation of LPS enterally administered to the intragastric ethanol infusion model. Portal and systemic blood endotoxin levels increased to 43.0 ؎ 4.1 and 6.2 ؎ 4.3 pg/mL at 2 hours following enteral LPS administration (5 mg/kg) in alcohol-fed animals, while no such increases were observed in pair-fed controls. However, endotoxin levels in systemic blood of alcohol-fed rats were reduced to 0 to 1.5 pg/mL 16 hours after LPS administration. Development of effective therapies for alcoholic liver disease (ALD) depends on the understanding of the mechanisms that contribute to the disease process. Experimental and clinical findings to date suggest that endotoxin and proinflammatory cytokines constitute the main effector molecules in alcohol-induced liver injury. 1-5 Endotoxin (lipopolysaccharide [LPS]), a prominent agonist of Kupffer cells, interacts with its specific carrier, LPS-binding protein (LBP) to stimulate hepatic macrophages via binding of the LPS-LBP complex to the CD14 receptor. [6][7][8] This stimulation results in the release of proinflammatory mediators by the macrophages and consequent immunological and cytotoxic events leading to development of liver injury.In rats given continuous infusion of ethanol and a high-fat diet, focal hepatic inflammation and necrosis may be evident after 4 weeks 9 and are accompanied by the pretranslational induction of proinflammatory cytokine expression in Kupffer cells. 10 Hepatic expression of tumor necrosis factor ␣ (TNF-␣) mRNA is induced when pathological changes in the liver become evident. 11 Simultaneous increases in the plasma endotoxin level and mRNA expression of proinflammatory cytokines are noted in ethanol-fed rats. 12,13 Taken together, these results suggest that induction of progressive alcoholic liver injury may require increased plasma endotoxin levels as a mechanism of proinflammatory cytokine induction. In support of this notion, alcoholic patients with chronic liver disease exhibit increased intestinal permeability. 14,15 Patients with alcoholic cirrhosis have higher endotoxin levels than heavy drinkers without cirrhosis and healthy controls. 16 Peripheral blood mononuclear cells isolated from patients with alcoholic cirrhosis secrete more interleukin-6, interleukin-8, and TNF-␣ than those from healthy controls. 17,18 In the intragastric infusion model, plasma endotoxin levels and enhanced LBP and CD14 expression are correlated with the presence of liver necrosis, [19][20][21][22] and the treatment of the animals with lactobacillus 23 or antibiotics 24 ameliorates alcoholic liver injury. Furthermore, intestinal permeability is als...
We previously reported a link between ethanol-induced elevation of homocysteine, endoplasmic reticulum (ER) stress, and alcoholic liver injury in the murine model of intragastric ethanol feeding. We studied the role of TNF␣ in this setting by using TNFR1 knockout mice (C57 BL/6). There was a 7.4-fold increase of homocysteine in wild-type and a 6-fold increase in TNFR1 knockout mice with intragastric alcohol exposure for 4 weeks. Plasma TNF␣ increased in the wild-type (18.4 ؎ 3.3 pg/mL vs. 8.4 ؎ 1.3 pg/mL (control)) and in the knockouts (12.9 ؎ 1.4 pg/mL vs. 7.2 ؎ 1.6 pg/mL (control)). Similar extent of fatty liver was observed in both types. Increased ALT was observed in both groups. Necroinflammatory foci were increased significantly in ethanol-fed knockouts but not to the same extent as in the ethanol-fed wild type. Increase of hepatic apoptosis and reduction of S-adenosyl-L-methionine was detected in both types of animals fed ethanol. ER stress demonstrated by RT-PCR of mRNA of selective ER stress markers GRP78, CHOP, and SREBP1 was increased equivalently in both types of mice. Betaine administration decreased ER stress in conjunction with attenuation of the elevated plasma homocysteine in both types of animals. Betaine increased hepatic S-adenosyl-L-methionine by 28 fold in the knockouts and by 24-fold in wild type. In conclusion, TNF␣ makes a moderate contribution to the ALT elevation, necroinflammation, apoptosis, a small contribution to the fatty liver and no contribution to hyperhomocysteinemia and ER stress in intragastric alcohol fed mice. (HEPATOLOGY 2004;40:442-451.)
Prostate cancer (PC) is the most prevalent strain of cancer in men, but it is often slow-acting or undetected. Common diagnostic tools for PC include prostate biopsy and consequent analysis by the Gleason scoring of the tissue samples, as well as tests for the presence and levels of prostate-specific antigens. Common treatments for androgen-dependent PC include prostatectomy or irradiation, which can be invasive and significantly lower the patient's quality of life. Alternative treatments exist, such as androgen ablation therapy, which, though effective, causes relapse into androgen-independent PC, which is far more invasive and likely to metastasize to other parts of the body. MicroRNAs (miRNA) are short nucleotide sequences (between 19 and 25 nucleotides long) that bind to various targeted messenger RNA (mRNA) sequences post-transcriptionally through complementary binding and control gene expression, often through silencing or leading to the degradation of targeted mRNA. Studies have shown that miRNAs are expressed abnormally in various cancers, suggesting that they play a pivotal role in cancer development and progression. Some miRNAs are oncogenes that incite cancerous growth, while others are involved in tumor suppression and cell cycle controls. MiRNA expression also differs in various types of cancers. Studies of PC-specific miRNAs show potential for their utilization in the prevention, diagnosis, and treatment of PC to more effectively target tumor growth and provide patients with better therapeutic options.
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