Molecular mechanisms of corticosteroid resistance

Most patients with asthma are successfully treated with conventional therapy. Nevertheless, there is a small proportion of asthmatic patients, including present cigarette smokers and former cigarette smokers, who fail to respond well to therapy with high-dose glucocorticoids (GCs) or with supplementary therapy. In addition, high doses of steroids have a minimal effect on the inexorable decline in lung function in COPD patients and only a small effect on reducing exacerbations. GC insensitivity, therefore, presents a profound management problem in these patients. GCs act by binding to a cytosolic GC receptor (GR), which is subsequently activated and is able to translocate to the nucleus. Once in the nucleus, the GR either binds to DNA and switches on the expression of antiinflammatory genes or acts indirectly to repress the activity of a number of distinct signaling pathways such as nuclear factor (NF)-kappaB and activator protein (AP)-1. This latter step requires the recruitment of corepressor molecules. Importantly, this latter interaction is mutually repressive in that high levels of NF-kappaB and AP-1 attenuate GR function. A failure to respond may therefore result from reduced GC binding to GR, reduced GR expression, enhanced activation of inflammatory pathways, or lack of corepressor activity. These events can be modulated by oxidative stress, T-helper type 2 cytokines, or high levels of inflammatory mediators, all of which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new antiinflammatory drugs or may reverse the relative steroid insensitivity that is characteristic of patients with these diseases.     

Molecular mechanisms of cobalt-catalyzed hydrogen evolution

Several cobalt complexes catalyze the evolution of hydrogen from acidic solutions, both homogeneously and at electrodes. The detailed molecular mechanisms of these transformations remain unresolved, largely owing to the fact that key reactive intermediates have eluded detection. One method of stabilizing reactive intermediates involves minimizing the overall reaction free-energy change. Here, we report a new cobalt(I) complex that reacts with tosylic acid to evolve hydrogen with a driving force of just 30 meV/Co. Protonation of Co^I produces a transient Co^III-H complex that was characterized by nuclear magnetic resonance spectroscopy. The Co^III-H intermediate decays by second-order kinetics with an inverse dependence on acid concentration. Analysis of the kinetics suggests that Co^III-H produces hydrogen by two competing pathways: a slower homolytic route involving two Co^III-H species and a dominant heterolytic channel in which a highly reactive Co^II-H transient is generated by Co^I reduction of Co^III-H.     

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC)represents 90%of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV),hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.     

Molecular clock of viral evolution, and the neutral theory.

Evolution of viral genes is characterized by enormously high speed compared with that of nuclear genes of eukaryotic organisms. In this paper, the evolutionary rates and patterns of base substitutions are examined for retroviral oncogenes, human immunodeficiency viruses (HIV), hepatitis B viruses (HBV), and influenza A viruses. Our results show that the evolutionary process of these viral genes can readily be explained by the neutral theory of molecular evolution. In particular, the neutral theory is supported by our observation that synonymous substitutions always much predominate over nonsynonymous substitutions, even though the substitution rate varies considerably among the viruses. Furthermore, the exact correspondence between the high rates of evolutionary base substitutions and the high rates of production of mutants in RNA viruses fits very nicely to the prediction of the theory. The linear relationship between substitution numbers and time was examined to evaluate the clock-like property of viral evolution. The clock appears to be quite accurate in the influenza A viruses in man.     

Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir

Raltegravir is a recently, Food and Drug Administration-approved, small-molecule drug that inhibits retroviral integrase, thereby preventing HIV DNA from inserting itself into the human genome. We report here that the activity profile of raltegravir on the replication of murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role. While NZW and BALB/c mice, which do not succumb to autoimmune disease, are not affected by raltegravir, lupus-prone (NZBxNZW) F₁ mice die of glomerulonephritis more than a month earlier than untreated mice. Raltegravir-treated NZB mice, which share the H-2 haplotype with BALB/c mice, but which are predisposed to autoimmune hemolytic anemia, develop auto-antibodies to their red blood cells >3 months earlier than untreated mice of the same strain. Because nonautoimmune mice are not affected by raltegravir, we consider off-target effects unlikely and attribute the exacerbation of autoimmunity to the inhibition of retroviral integrase.     

Molecular mechanisms of insulin resistance and the role of the adipocyte

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFalpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFalpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.     

A covalent complex between retroviral integrase and nicked substrate DNA.

Purified retroviral integrase (IN) from avian sarcoma-leukosis viruses can appropriately process the termini of linear viral DNA, cleave host DNA in a sequence-independent manner, and catalyze integrative recombination; an exogenous source of energy is not required for these reactions. Using DNA substrates containing radioactive phosphate groups, we demonstrate that IN becomes covalently joined to the new 5' phosphate ends of DNA produced at sites of cleavage. Most of the phosphodiester linkages between IN and DNA involve serine, but some involve threonine. Computer-assisted alignment of 80 retroviral and retrotransposon IN sequences identified one serine that is conserved in all of these proteins and three less-conserved threonine residues. These results identify candidate active-site residues and provide support for the participation of a covalent IN-DNA intermediate in retroviral integration.     

结核杆菌异烟肼耐药的分子机制

在抗结核治疗策略中,异烟肼是最重要的一线药物.在过去50年的抗结核治疗中,异烟肼发挥了非常重要的作用,而耐异烟肼结核菌的出现使这种效果减弱.本文从异烟肼的抗结核机制人手,对异烟肼耐药的分子机制作一综述.     

Molecular mechanisms of DNA repair inhibition by caffeine.

Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.     

Molecular mechanisms involved in hepatic steatosis and insulin resistance

Increased hepatic lipid content is associated with hepatic as well as whole‐body insulin resistance and is typical for individuals with type 2 diabetes mellitus. However, whether insulin resistance causes hepatic steatosis or whether hepatic steatosis per se reduces insulin sensitivity remains unclear. Multiple metabolic pathways lead to the development of hepatic steatosis, including enhanced free fatty acid release from adipose tissues (lipolysis), increased de novo fatty acid synthesis (lipogenesis), decreased mitochondrial β‐oxidation and decreased very low‐density lipoprotein secretion. Although the molecular mechanisms leading to the development of hepatic steatosis in the pathogenesis of type 2 diabetes mellitus are complex, several recent animal models have shown that modulating important enzymes involved in hepatic fatty acid and glycerolipid synthesis might be a key for treating hepatic insulin resistance. We highlight recent advances in the understanding of the molecular mechanisms leading to the development of hepatic steatosis and insulin resistance. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00111.x, 2011)     

Molecular and signaling mechanisms of atherosclerosis in insulin resistance.

Although the prevalence of cardiovascular complications is increased in insulin-resistant individuals, the underlying causes of this link have been elusive. Recent work suggests that several intracellular signal transduction pathways are inappropriately activated by hyperinsulinemia, hyperglycemia, increased free fatty acids, dyslipidemia, various inflammatory cytokines and adipokines--factors that are increased in insulin resistance. Once activated, substantial cross talk occurs between these pathways, especially a self-reinforcing cascade of vascular inflammation and cell dysfunction, greatly increasing the risk and severity of atherosclerosis in the insulin-resistant individual. We review several key cell-signalling pathways, describe how they are activated in they insulin-resistant state and the damage they induce, and discusses possible therapeutic approaches to limit vascular damage.     

Molecular mechanisms of insulin resistance in chronic hepatitis C

It is now widely recognized that chronic hepatitis C （CHC） is associated with insulin resistance （IR） and type 2 diabetes, so can be considered a metabolic disease. IR is most strongly associated with hepatitis C virus （HCV） genotype 1, in contrast to hepatic steatosis, which is associated with genotype 3 infection. Apart from the well-described complications of diabetes, IR in CHC predicts faster progression to fibrosis and cirrhosis that may culminate in liver failure and hepatocellular carcinoma. More recently, it has been recognized that IR in CHC predicts a poor response to antiviral therapy. The molecular mechanisms for the association between IR and HC＇V infection are not well defined. This review will elaborate on the clinical associations between CHC and IR and summarize current knowledge regarding the molecular mechanisms that potentially mediate HCV-associated IR.     

Molecular mechanisms of increased intrahepatic resistance in portal hypertension

Portal hypertension is associated with changes in the intrahepatic, systemic, and portosystemic collateral circulation. Alterations in vasoreactivity (vasodilation and vasoconstriction) play a central role in the pathogenesis of portal hypertension by contributing to increased intrahepatic resistance, hyperdynamic circulation, and expansion of the collateral circulation. Portal hypertension is also importantly characterized by changes in vascular structure; termed vascular remodeling, which is an adaptive response of the vessel wall that occurs in response to chronic changes in the environment such as shear stress. These complementary processes of vasoreactivity and vascular remodeling contribute importantly to increased intrahepatic resistance and represent important targets in the treatment of portal hypertension. This review will focus on these processes within the intrahepatic circulation, a circulatory bed whose study, that Dr Roberto Groszmann has pioneered.