Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paleopathological study of 31 Italian Renaissance mummies from the Basilica of S. Domenico Maggiore in Naples has allowed us to perform about 20 diagnoses, of which 5 concern infectious (smallpox, hepatitis, condyloma, syphilis and pneumonia), 3 metabolic (obesity, atherosclerosis, gallstones), I articular (DISH) and 2 neoplastic (colon adenocarcinoma and skin carcinoma) diseases. The mummy of an anonymous child, dated back to the 16th century (14C: 1569 +/- 60), presented a diffuse vesiculopustular exanthema. Macroscopic aspects and regional distribution suggested smallpox, while EM revealed many egg-shaped, virus-like particles (250 x 50 nm), with a central dense core. Following incubation with anti-smallpox virus antiserum and protein A-gold complex immunostaining, the particles resulted completely covered with protein A-gold. These results clearly show that this Neapolitan child died of a severe form of smallpox some four centuries ago. The mummy of Maria d'Aragona, Marquise of Vasto (1503-1568), revealed on the left arm an oval, cutaneous ulcer (15 x l0 mm) with linen dressing. Indirect immunofluorescence with anti-treponema pallidum antibody identified a large number of filaments with the morphological characteristics of fluorescent treponemes. Electron microscopy evidenced typical spirochetes, with axial fibril. These findings clearly demonstrate a treponemal, probably venereal, infection. Further examination of the mummy showed a large peduncolate arborescent neoformation (2 x 7 mm) of the right inguinal region, which was rehydrated and submitted to histology by hematoxylineosin, Van Gieson and Masson's trichromic staining. Light microscopy evidenced an exophytic, papillary skin lesion, with typical connective axis and pronounced parakeratosis. These macroscopic and histological aspects seemed peculiar of condyloma acuminatum, a papillomavirus-induced squamous lesion also called "venereal wart". Molecular study revealed the presence of HPV 18, a virus with high oncogenic potential. Automated sequencing of several clones revealed 100% similarity sequences of both HPV 18 and JC9813 DNA, a putative novel HPV with low oncogenic potential. This study represents the first molecular diagnosis of HPV in mummies and could pave the way for further research about the secular evolution of these viruses, very important in human oncology. The buccal surfaces of the teeth of Isabella d'Aragona, duchess of Milan ((1470-1524), covered by a black patina with high mercury levels, have been intensively and intentionally abraded. The black patina can be attributed to chronic mercury intoxication, used therapeutically in the treatment of syphilis. The mummy of Ferrante I d'Aragona, King of Naples (1431-1494), revealed an adenocarcinoma extensively infiltrating the muscles of the small pelvis. A molecular study of the neoplastic tissue evidenced a typical mutation of the K-ras gene codon 12: the normal sequence GGT (glycine) was altered into GAT (aspartic acid). At present this genetic change is the most frequent mutation of the K-ras gene in sporadic colorectal cancer. The alimentary "environment" of the Neapolitan court of the XV century, with its abundance of natural alimentary alkylating agents, well explains this acquired mutation. These and other diseases as, for example, a case of cirrhosis, some cases of anthracosis and other peculiar traumatic conditions, such as a mortal stab-wound, can elucidate the pathocenosis of this wealthy classes of the Italian Renaissance.
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PMID:[The Aragonese mummies of the Basilica of Saint Domenico Maggiore in Naples]. 1817 25

The liver is susceptible to chronic damage through exposure to a variety of toxins (e.g. alcohol) and viruses (e.g. hepatitis C). Obesity, autoimmune diseases (e.g. autoimmune hepatitis) and a variety of genetic diseases (e.g. Wilson's disease) also lead to chronic liver damage. This damage results in scarring fibrogenesis, structural disruption and functional impairment of the organ. Recent work suggests that there is cross-talk between the PXR and NF-kappaB pathways. This cross-talk may explain the observation that PXR activators inhibit liver fibrosis in in vitro and in vivo animal models of the disease. This reveiw will focus on the two transcription factors and their potential interaction.
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PMID:A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: inhibition of NF-kappaB? 1819 34

Childhood obesity is a worldwide health problem associated with an increase in the prevalence and severity of nonalcoholic fatty liver disease (NAFLD). This review covers the progress made between 2005 and 2007 in understanding the epidemiology, histology, and treatment of pediatric NAFLD. The number of children with NAFLD presents a major public health crisis. Noninvasive diagnostic tools offer future promise, but currently are unable to grade and stage disease. Therefore, pediatric NAFLD remains a clinico-pathological diagnosis requiring direct demonstration of liver steatosis and the exclusion of other causes of fatty liver and/or hepatitis. There are currently no proven therapies for NAFLD in children; however, TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children), the first multicenter clinical trial of pediatric NAFLD, is currently in progress. Such studies are imperative to address fundamental questions regarding cause and cure.
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PMID:The obesity epidemic and nonalcoholic fatty liver disease in children. 1841 45

Toll-like receptors (TLRs) form a large family of pattern recognition receptors with at least 11 members in human and 13 in mouse. TLRs recognize a wide variety of microbial components and potential host-derived agonists that have emerged as key mediators of innate immunity. TLR signaling also plays an important role in the activation of the adaptive immune system by inducing proinflammatory cytokines and upregulating costimulatory molecules of antigen presenting cells. The dysregulation of TLR signaling may cause autoimmunity. This review discusses the contribution of TLR signaling to the initiation and progression of autoimmune diseases, such as rheumatoid arthritis, experimental autoimmune encephalitis, myocarditis, hepatitis, kidney disease, systemic lupus erythematosus, diabetes, obesity, and experimental autoimmune uveitis as well as aging. The involvement of TLR signaling in the pathogenesis of autoimmune diseases may provide novel targets for the development of therapeutics.
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PMID:The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. 1935 17

Alcoholic liver disease (ALD) is a lifestyle disease with its pathogenesis and individual predisposition governed by gene-environment interactions. Based on the "second hit" or "multiple hits" hypothesis, patients are predisposed to progressive ALD when a magic combination of gene and environmental interactions exists. Reproduction of second or multiple hits in animal models serves to test a combination and to gain mechanistic insights into synergism achieved by such combination. Numerous environmental factors have been incorporated into animal models, largely classified into nutritional, xenobiotic/pharmacologic, hemodynamic, and viral groups. A loss or gain of function genetic model has become a popular experimental approach to test the role of a gene as a second hit. Future research will need to test more subtle or natural hits combined with excessive alcohol intake to test multiple hits in the genesis of ALD. Additionally, animal models of comorbidities are urgently needed particularly for synergistic liver disease and oncogenesis caused by alcohol, obesity, and hepatitis virus.
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PMID:"Second hit" models of alcoholic liver disease. 1938 17

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, with approximately 70% of cases resulting from hepatitis B and C viral infections, aflatoxin exposure, chronic alcohol use or genetic liver diseases. The remaining approximately 30% of cases are associated with obesity, type 2 diabetes and related metabolic diseases, although a direct link between these pathologies and HCCs has not been established. We tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that C57BL/6J but not A/J males were susceptible to non-alcoholic steatohepatitis (NASH) and HCC on a high-fat but not low-fat diet. This strain-diet interaction represents an important model for genetically controlled, diet-induced HCC. Susceptible mice showed morphological characteristics of NASH (steatosis, hepatitis, fibrosis and cirrhosis), dysplasia and HCC. mRNA profiles of HCCs versus tumor-free liver showed involvement of two signaling networks, one centered on Myc and the other on NFkappaB, similar to signaling described for the two major classes of HCC in humans. miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high-fat to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of HCCs in humans.
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PMID:Diet-induced hepatocellular carcinoma in genetically predisposed mice. 1945 84

The diagnosis of drug-induced liver injury (DILI) is a challenging problem, often confounded by incomplete clinical information and the difficulty of eliciting exposure to herbal products, over-the-counter agents and toxins. The task is further rendered difficult on biopsy, as drugs can mimic all the patterns found in primary liver disease. Acute hepatitis, with or without cholestasis, is the most common histological pattern of DILI, and drugs such as acetaminophen are the leading causes of acute liver failure. Most cases of DILI resolve on discontinuation of the drug, but recovery can take months or rarely the disease can progress despite drug withdrawal. Drugs such as methotrexate can lead to chronic hepatitis and cirrhosis, while others such as minocycline, nitrofurantoin and methyldopa are implicated in autoimmune hepatitis. Prolonged cholestasis and ductopenia resembling primary chronic biliary disease can occur. Drug-induced steatohepatitis is also an uncommon pattern, but is well described with drugs such as amiodarone and irinotecan. In the presence of risk factors such as obesity and diabetes, some drugs such as tamoxifen, oestrogens and nifedipine can precipitate or exacerbate steatohepatitis. Other observed patterns include granulomatous hepatitis, vascular injury (eg, sinusoidal obstruction syndrome), Ito cell lipidosis and neoplasms (eg, adenomas).
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PMID:Histological patterns in drug-induced liver disease. 1947 52

We evaluated the prevalence and the risk factors for gallstone disease in patients with chronic hepatitis C infection. We investigated 453 consecutively admitted patients with chronic infection with hepatitis C virus (HCV) (cirrhosis excluded) and 879 patients without liver disease (October 2006-April 2007). Gallstone disease was diagnosed if gallstones were present at ultrasonography or if there had been a previous cholecystectomy. Variables evaluated were age, gender, gallstone heredity, body mass index, waist circumference, parity, serum lipids, fatty liver, arterial hypertension, diabetes mellitus and metabolic syndrome (International Diabetes Federation criteria). Informed consent was obtained from all patients. We found that 88 of 453 (19%) patients with chronic HCV hepatitis (age 50.1 +/- 11.7 years) and 153 of 879 (17%) controls (age 60.6 +/- 12.6 years) had gallstone disease (GD). Abdominal obesity (OR = 2.108, 95% CI 1.287-3.452) and steatosis (OR = 3.699, 95% CI 2.277-6.008) were risk factors for GD in HCV patients. Gallstone heredity, dyslipidaemia, type 2 diabetes mellitus and metabolic syndrome increased the risk for GD in controls vs HCV patients. Our study shows that even HCV patients with chronic hepatitis but not cirrhosis have an increased prevalence of gallstones. Compared with controls, gallstones are present in HCV patients at a younger age and are associated with central obesity and liver steatosis, but not with gallstone heredity, dyslipidaemia, diabetes mellitus or metabolic syndrome. Although we could not establish a temporal relationship, the association between HCV infection and gall stone disease is real and appears to be causally linked, at least in predisposed individuals (obese and with liver steatosis).
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PMID:Hepatitis C virus infection is a risk factor for gallstone disease: a prospective hospital-based study of patients with chronic viral C hepatitis. 1948 79

Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies.
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PMID:Mitochondrial involvement in drug-induced liver injury. 2002 Feb 67

Probiotic bacteria have well-established beneficial effects in the management of diarrhoeal diseases. Newer evidence suggests that probiotics have the potential to reduce the risk of developing inflammatory bowel diseases and intestinal bacterial overgrowth after gut surgery. In liver health, the main benefits of probiotics might occur through preventing the production and/or uptake of lipopolysaccharides in the gut, and therefore reducing levels of low-grade inflammation. Specific immune stimulation by probiotics through processes involving dendritic cells might also be beneficial to the host immunological status and help prevent pathogen translocation. Hepatic fat metabolism also seems to be influenced by the presence of commensal bacteria, and potentially by probiotics; although the mechanisms by which probiotic might act on the liver are still unclear. However, this might be of major importance in the future because low-grade inflammation, hepatic fat infiltration, and hepatitis might become more prevalent as a result of high fat intake and the increased prevalence of obesity.
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PMID:Probiotics and gut health: a special focus on liver diseases. 2010 63


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