Chemoprevention of hepatocarcinogenesis: S-adenosylmethionine.
Accumulation of genetic changes characterizes the progression of cells, initiated by carcinogens, to full malignancy. Various epigenetic mechanisms, such as high polyamine synthesis, aberrant DNA methylation, and production of reactive oxygen species, may favor this process by stimulating growth and inducing DNA damage. We observed a decrease in S-adenosylmethionine (SAMe) content in the liver, associated with DNA hypomethylation in rat liver, during the development of preneoplastic foci, and in neoplastic nodules and hepatocellular carcinomas, induced in diethylnitrosamine-initiated rats by "resistant hepatocyte" (RH) protocol. Reconstitution of the methyl donor level in the liver by SAMe administration inhibits growth and induces phenotypic reversion and apoptosis of preneoplastic cells. A six-month SAMe treatment results in a sharp and persistent decrease in development of neoplastic nodules, suggesting a long duration of SAMe chemopreventive effect. Various observations support the suggestion of a role of DNA methylation in chemoprevention by SAMe: (1) Exogenous SAMe reconstitutes the SAMe pool in preneoplastic and neoplastic liver lesions. (2) DNA methylation is positively correlated with SAMe:S-adenosylhomocysteine (SAH) ratio in these lesions. (3) 5-Azacytidine, a DNA methyltransferase inhibitor, inhibits chemoprevention by SAMe. (4) c-Ha-ras, c-Ki-ras, and c-myc are hypomethylated and overexpressed in preneoplastic liver. Their expression is inversely correlated with SAM:SAH ratio in SAMe-treated rats. (5) S-Adenosyl-L-methionine treatment results in overall DNA methylation and partial methylation of these genes. Other possible mechanisms of SAMe treatment include inhibition of polyamine synthesis, linked to partial transformation of SAMe into 5'-methylthioadenosine (MTA), and antioxidant and antifibrogenic activities of both SAMe and MTA.
Alcohol 2002 Jul;27(3):193-8
The pathogenesis of alcohol-induced liver disease is not well understood, and many factors have been described to contribute to the progressive loss of liver functions, including the overgeneration of reactive oxygen species. Mitochondria are specific targets of the toxic effects of ethanol, reflected in the loss of phosphorylative oxidation and defective ATP generation, which underlie one of the hallmarks of the hepatic alterations induced by chronic alcohol intake. Mitochondrial reduced glutathione (GSH), whose primary function is to maintain a competitive functional organelle, becomes depleted by alcohol intake. Furthermore, GSH depletion in hepatocyte mitochondria has been revealed as an important mechanism in the sensitization of liver to alcohol-induced injury. This depletion of the mitochondrial GSH level is determined by an impaired transport of GSH from the cytosol into the mitochondrial matrix owing to a partial inactivation of mitochondrial GSH carrier. The loss of function of this specific mitochondrial transporter is due to the alterations in the physicochemical properties of the inner mitochondrial membrane caused by alcohol. Because of the primary defect in the transport of cytosolic GSH into mitochondria, GSH precursors are inefficient in replenishing the levels of mitochondrial GSH despite significant increase in cytosolic GSH. Supplementation of S-adenosylmethionine (SAMe) to rats fed alcohol chronically has been shown to replete the mitochondrial GSH levels because of normalization of the microviscosity of the mitochondrial inner membrane. Because of the instrumental role of GSH in mitochondria in hepatocyte survival against inflammatory cytokines, its repletion by SAMe feeding may underlie the potential therapeutic use of this hepatoprotective agent in the treatment of alcohol-induced liver injury.
Alcohol 2002 Jul;27(3):179-83
Liver in sepsis and systemic inflammatory response syndrome.
In patients with sepsis and SIRS, the liver has two opposing roles: a source of inflammatory mediators and a target organ for the effects of the inflammatory mediators. The liver is pivotal in modulating the systemic response to severe infection, because it contains the largest mass of macrophages (Kupffer cells) in the body; these macrophages can clear the endotoxin and bacteria that initiate the systemic inflammatory response. This article summarizes the functional changes that take place in the liver during sepsis and systemic inflammatory response syndrome and discusses the cellular and molecular mechanisms that underlie clinical outcomes.
Clin Liver Dis 2002 Nov;6(4):1045-66, x
Rhinovirus and coronavirus infection-associated hospitalizations among older adults.
Rhinoviruses and coronaviruses are recognized as the major causes of the common cold syndrome. The role of these viruses in more serious respiratory illnesses resulting in hospitalization is less well defined. During a winter when influenza A infection was prevalent, 100 elderly adults hospitalized because of cardiopulmonary illnesses were evaluated for rhinovirus and coronavirus infection. Patients who tested negative for influenza or respiratory syncytial virus had nasal swab samples tested for rhinovirus, coronavirus OC43, and coronavirus 229E by reverse-transcription polymerase chain reaction and for coronaviruses by serologic testing. Twelve percent of patients had rhinovirus or coronavirus identified (rhinovirus, four patients; coronavirus 229E, four patients; coronavirus OC43, three patients; and mixed rhinovirus/coronavirus 229E infection, one patient). All patients had significant underlying diseases. Although all patients recovered, the mean length of stay was eight days; four persons had pneumonia, and one required ventilator support. These data suggest that rhinoviruses and coronaviruses may be associated with serious respiratory illnesses in frail older adults.
J Infect Dis 2002 May 1;185(9):1338-41
Coronavirus infections of man associated with diseases other than the common cold.
About 14,000 paired sera, from patients with various types of acute infectious diseases with suspected viral origin, were screened by complement fixation against a wide set of viral antigens, including coronavirus OC43. A significant change in OC43 antibodies was recorded in 33 cases and a constant high titre, defined as a titre occurring in the respective age group in less than 1% of all sera examined, was found in 45 cases. On the basis of careful retrospective analysis of hospital case records it was concluded that in 28 cases with an increase of OC43 antibody titres, and in two with titre decrease, a disease could be associated with an acute coronavirus infection. In 16 cases the disease was dominated by respiratory symptoms. Eight of these patients, four children and four adults, had pneumonia. Three of the eight pneumonia patients had, however, another concomitant infection, too. Four patients had neurological symptoms, one had severe perimyocarditis, and in five cases fever was the only symptom recorded. Among the patients with a statistically significant high titre of OC43 antibodies, there were 14 cases where a suggestive association with a disease could be envisaged on the basis of hospital records. Five of these patients had pneumonia. These results suggest that human coronaviruses, so far considered only as one group of causative agents of the common cold, may also be associated with other and more severe diseases in all age groups.
J Med Virol 1980;6(3):259-65
BACKGROUND: Severe Acute Respiratory syndrome (SARS) is a condition of unknown cause that has recently been recognized in patients in Asia, North America and Europe. This report summarizes the initial epidemiologic findings, clinical description, and diagnostic findings that followed the identification of SARS in Canada. METHODS: SARS was first identified in Canada in early March 2003. We collected epidemiologic, clinical and diagnostic data from each of the first 10 cases prospectively as they were identified. Specimens from all cases were sent to local, provincial, national, and international laboratories for studies to identify an etiologic agent. RESULTS: The patients ranged from 24 to 78 years old; 60 percent were men. Transmission occurred only after close contact. The most common presenting symptoms were fever (in 100% of cases) and malaise (in 70%), followed by nonproductive cough (in 100%) and dyspnea (in 80%) associated with infiltrates on chest radiography (in 100 percent). Lymphopenia (in 89% of those for whom data were available), elevated lactate dehydrogenase levels (in 80%), elevated aspartate aminotransferase levels (in 78%), and elevated creatinine kinase levels (in 56%) were common. Empirical therapy most commonly included antibiotics, oseltamivir, and intravenous ribavirin. Mechanical ventilation was required in five patients. Three patients died, and five have had clinical improvement. The results of laboratory investigations were negative or not clinically significant except for the amplification of human metapneumovirus from respiratory specimens from five of nine patients and the isolation and amplification of a novel coronavirus from five of nine patients. In four cases both pathogens were isolated. CONCLUSIONS: SARS is a condition associated with substantial morbidity and mortality. It appears to be of viral origin, with patterns suggesting droplet or contact transmission. The role of human metapneumovirus, a novel coronavirus, or both requires further investigation. [Notice: Because of possible public health implications, this article has been published at www.nejm.org on March 31, 2003.]
N Engl J Med 2003 Apr 4; [epub ahead of print]
Spectrum of clinical illness in hospitalized patients with "common cold" virus infections.
The viruses associated most frequently with the "common cold" are rhinoviruses and coronaviruses. The first prospective cohort study to determine the prevalence of rhinovirus and coronavirus infections in patients of all ages hospitalized for acute respiratory illnesses is described. Hospital admissions for acute respiratory illnesses were identified, and cell culture for rhinovirus and serologic assays on paired sera for coronaviruses 229E and OC43 were performed. A total of 61 infections with rhinoviruses and coronaviruses were identified from 1198 respiratory illnesses (5.1%); in addition, nine additional infections associated with >/=1 other respiratory viruses were identified. Of those infected with only rhinovirus or coronavirus, underlying cardiopulmonary diseases were present in 35% of the patients aged < five years, in 93% aged between five and 35 years, and in 73% aged >35 years. The predominant clinical syndromes varied by age: pneumonia and bronchiolitis in children aged < five years; exacerbations of asthma in older children and young adults; and pneumonia and exacerbations of chronic obstructive pulmonary disease and congestive heart failure in older adults. Therefore, rhinovirus and coronavirus infections in hospitalized patients were associated with lower respiratory tract illnesses in all age groups.
Clin Infect Dis 2000 Jul;31(1):96-100