Corticosteroids: the mainstay in asthma therapy

Inflammation is now marked as a central feature of asthma pathophysiology and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a number of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are associated with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a number of aerosol preparations have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favours using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve additional control in severe asthma cases, other drugs such as beta-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.     

Combinatorial identification of a novel consensus sequence for the covalent DNA-binding polyamide tallimustine

Many agents successfully used in cancer chemotherapy either directly or indirectly covalently modify DNA. Examples include cisplatin, which forms a covalent adduct with guanines, and doxorubicin, which traps a cleavage intermediate between topoisomerase II and torsionally strained DNA. In most cases, the efficacy of these drugs depends on the efficiency and specificity of their DNA binding, as well as the discrimination between normal and neoplastic cells in their handling of the drug-DNA adducts. While much is known about the chemistry of drug-DNA adducts, little is known regarding the overall specificity of their formation, especially in the context of a whole human genome, where potentially billions of binding sites are possible. We used the combinatorial selection method restriction endonuclease protection, selection, and amplification (REPSA) to determine the DNA-binding specificity of the semisynthetic covalent DNA-binding polyamide tallimustine, which contains a benzoic acid nitrogen mustard appended to the minor groove DNA-binding natural product distamycin A. After investigating over 134 million possible sequences, we found that the highest affinity tallimustine binding sites contained one of two consensus sequences, either the expected distamycin hexamer binding sites followed by a CG base pair (e.g., 5'-TTTTTTC-3' and 5'-AAATTTC-3') or the unexpected sequence 5'-TAGAAC-3'. Curiously, we found that tallimustine preferentially alkylated the N7 position of guanines located on the periphery of these consensus sequences. These findings suggested a cooperative binding model for tallimustine in which one molecule noncovalently resides in the DNA minor groove and locally perturbs the DNA structure, thereby facilitating alkylation by a second tallimustine of an exposed guanine on another side of the DNA.     

Design, synthesis, and evaluation of novelly substituted benzimidazole compounds as angiotensin II receptor antagonists

5-Nitrobenzimidazole derivatives with varying substituents at 2-position have been designed, synthesized, and evaluated for angiotensin II antagonistic activity. A drug-receptor interaction model has been proposed.     

Compartment-specific Synthesis of Phosphatidylethanolamine Is Required for Normal Heavy Metal Resistance

Control of lipid composition of membranes is crucial to ensure normal cellular functions. Saccharomyces cerevisiae has two different phosphatidylserine decarboxylase enzymes (Psd1 and Psd2) that catalyze formation of phosphatidylethanolamine. The mitochondrial Psd1 provides roughly 70% of the phosphatidylethanolamine (PE) biosynthesis in the cell with Psd2 carrying out the remainder. Here, we demonstrate that loss of Psd2 causes cells to acquire sensitivity to cadmium even though Psd1 remains intact. This cadmium sensitivity results from loss of normal activity of a vacuolar ATP-binding cassette transporter protein called Ycf1. Measurement of phospholipid levels indicates that loss of Psd2 causes a specific reduction in vacuolar membrane PE levels, whereas total PE levels are not significantly affected. The presence of a phosphatidylinositol transfer protein called Pdr17 is required for Psd2 function and normal cadmium tolerance. We demonstrate that Pdr17 and Psd2 form a complex in vivo that seems essential for maintenance of vacuolar PE levels. Finally, we refine the localization of Psd2 to the endosome arguing that this enzyme controls vacuolar membrane phospholipid content by regulating phospholipids in compartments that will eventually give rise to the vacuole. Disturbance of this regulation of intracellular phospholipid balance leads to selective loss of membrane protein function in the vacuole.     

Oxygen Therapy Use in Older Adults with Chronic Obstructive Pulmonary Disease

Rationale

Oxygen therapy improves survival and function in severely hypoxemic chronic obstructive pulmonary disease (COPD) patients based on two landmark studies conducted over 40 years ago. We hypothesize that oxygen users in the current era may be very different. We examined trends and subject characteristics associated with oxygen therapy use from 2001–2010 in the United States.

Methods

We examined Medicare beneficiaries with COPD who received oxygen from 2001 to 2010. COPD subjects were identified by: 1) ≥2 outpatient visits >30 days apart within one year with an encounter diagnosis of COPD; or 2) an acute care hospitalization with COPD as the primary or secondary discharge diagnosis. Oxygen therapy and sustained oxygen therapy were defined as ≥1 and ≥11 claims for oxygen, respectively, in the durable medical equipment file in a calendar year. Primary outcome measures were factors associated with oxygen therapy and sustained oxygen therapy over the study period.

Results

Oxygen therapy increased from 33.7% in 2001 to 40.5% in 2010 (p-value of trend <0.001). Sustained oxygen therapy use increased from 19.5% in 2001, peaked in 2008 to 26.9% and declined to 18.5% in 2010. The majority of subjects receiving oxygen therapy and sustained oxygen therapy were female. Besides gender, factors associated with any oxygen use or sustained oxygen therapy were non-Hispanic white race, low socioeconomic status and ≥2 comorbidities.

Conclusions

Any oxygen use among fee-for service Medicare beneficiaries with COPD is high. Current users of oxygen are older females with multiple comorbidities. Decline in sustained oxygen therapy use after 2008 may be related to reimbursement policy change.     

Interaction pattern for the complex of B-DNA Fullerene compounds with a set of known replication proteins using docking study

Fullerenes have attracted considerable attention due to their unique chemical structure and potential applications which has opened wide venues for possible human exposure to various fullerene types. Therefore, in depth knowledge of how fullerene may interfere with various cellular processes becomes quite imperative. The present study was designed to investigate how the presence of fullerene affect the binding of DNA with different enzymes involved in replication process. Different fullerenes were first docked with DNA and then binding scores of different enzymes was analyzed with fullerene docked DNA. C30, C40 & C50 once docked with DNA, reduced the binding score of primase, whereas no significant change in the binding score was observed with the helicase, ssb protein, dna pol δ, dna pol ε, ligase, DNA clamp, and topoisomerases. On the contrast, the binding score of RPA14 decreases in fluctuating manner while interacting with increasing molecular weight of fullerene bound single-stranded DNA complex. The study revealed the affect of fullerene family interacting with DNA on the binding pattern of enzymes involved in replication process. Study suggests that the presence of most of fullerenes may not affect the activity of these enzymes necessary for replication process whereas C30, C40 & C50 may disrupt the activity of primase, (strating point for DNA polymerase) its docking score decreases from 13820 to 10702.