1.
Latest developments in the treatment of hepatitis B.
Dandri, M, Petersen, J
Minerva gastroenterologica e dietologica. 2016;(1):88-102
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide. Currently available antiviral treatment options for chronic hepatitis B include pegylated interferon alpha (PEG-IFN) or nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. The advantages of PEG-IFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Although several studies have confirmed certain virological advantages of combination therapies, pivotal prospective studies demonstrating long-term clinical benefit to patients are still missing and monotherapy with PEG_IFN or NAs remains the therapy of choice. Furthermore, with the current treatment approaches, only a limited number of patients reach the aim HBsAg loss, which is closest to clinical cure. The limited efficacy of current approved therapeutic regimens demands the development of more efficient therapeutic approaches enabling not only suppression of viral replication, but resolution of HBV infection. The unique replication strategy employed by HBV enables its persistence within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment. Both the persistence of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, as well as the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. The recent development and availability of innovative in vitro and in vivo systems and sensitive molecular techniques have opened new possibilities to study the complex network of interactions that HBV establishes with the host in the course of infection and to define new targets for antiviral strategies. Several new antiviral or immunomodulatory compounds have reached preclinical or clinical testing with the aim of a clinical cure of chronic HBV with the loss of HBsAg. This review summarizes the most recent therapeutic strategies designed to directly target the virus or to improve immune responses during chronic HBV infection.
2.
Secretory phospholipase A2 enzymes as pharmacological targets for treatment of disease.
Quach, ND, Arnold, RD, Cummings, BS
Biochemical pharmacology. 2014;(4):338-48
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Abstract
Phospholipase A2 (PLA2) cleave phospholipids preferentially at the sn-2 position, liberating free fatty acids and lysophospholipids. They are classified into six main groups based on size, location, function, substrate specificity and calcium requirement. These classes include secretory PLA2 (sPLA2), cytosolic (cPLA2), Ca(2+)-independent (iPLA2), platelet activating factor acetylhydrolases (PAF-AH), lysosomal PLA2 (LyPLA2) and adipose specific PLA2 (AdPLA2). It is hypothesized that PLA2 can serve as pharmacological targets for the therapeutic treatment of several diseases, including cardiovascular diseases, atherosclerosis, immune disorders and cancer. Special emphasis has been placed on inhibitors of sPLA2 isoforms as pharmacological moieties, mostly due to the fact that these enzymes are activated during inflammatory events and because their expression is increased in several diseases. This review focuses on understanding how sPLA2 isoform expression is altered during disease progression and the possible therapeutic interventions to specifically target sPLA2 isoforms, including new approaches using nano-particulate-based strategies.
3.
[Pharmacological and other options in preventing dementia: a literature review].
Csukly, G, Sirály, E, Hidasi, Z, Salacz, P, Szabó, Á, Csibri, É
Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology. 2014;(3):121-6
Abstract
BACKGROUND At present 34 million people live with Alzheimer's disease around the world. This figure is expected to triple in the next 40 years. The major cause of this increase is the well-known aging of the society in Europe and in the US as well. AIMS AND METHODS In this paper we review the results of the last 10 years, and discuss those pharmaceutical and other methods, which can be effective in the prevention of dementias. RESULTS The most important pharmaceutical agents are beta secretase inhibitors, and active and passive immunizations. Several drugs in these groups are in phase III at the moment. The results from studies with intranasal insulin are also encouraging. As a non-drug option Mediterranean diet can be effective. However at present cognitive trainings seem to be the most effective in the prevention of dementias. These remediation therapies are based on the lifelong plasticity of the human brain. CONCLUSIONS In summary we can conclude that there are promising drug developments in progess for the prevention of dementias, but the breakthrough has not been achieved yet. At present the best option is decreasing risk factors, that is treatment of hypertension, prevention of obesity and diabetes, and cognitive trainings are recommended for prevention.
4.
A novel endogenous inhibitor of the secreted streptococcal NAD-glycohydrolase.
Meehl, MA, Pinkner, JS, Anderson, PJ, Hultgren, SJ, Caparon, MG
PLoS pathogens. 2005;(4):e35
Abstract
The Streptococcus pyogenes NAD-glycohydrolase (SPN) is a toxic enzyme that is introduced into infected host cells by the cytolysin-mediated translocation pathway. However, how S. pyogenes protects itself from the self-toxicity of SPN had been unknown. In this report, we describe immunity factor for SPN (IFS), a novel endogenous inhibitor that is essential for SPN expression. A small protein of 161 amino acids, IFS is localized in the bacterial cytoplasmic compartment. IFS forms a stable complex with SPN at a 1:1 molar ratio and inhibits SPN's NAD-glycohydrolase activity by acting as a competitive inhibitor of its beta-NAD+ substrate. Mutational studies revealed that the gene for IFS is essential for viability in those S. pyogenes strains that express an NAD-glycohydrolase activity. However, numerous strains contain a truncated allele of ifs that is linked to an NAD-glycohydrolase-deficient variant allele of spn. Of practical concern, IFS allowed the normally toxic SPN to be produced in the heterologous host Escherichia coli to facilitate its purification. To our knowledge, IFS is the first molecularly characterized endogenous inhibitor of a bacterial beta-NAD(+)-consuming toxin and may contribute protective functions in the streptococci to afford SPN-mediated pathogenesis.