Transcription factors Sp1 and Sp4 regulate TRPV1 gene expression in rat sensory neurons

<p>Abstract</p> <p>Background</p> <p>The capsaicin receptor, transient receptor potential vanilloid type -1 (TRPV1) directs complex roles in signal transduction including the detection of noxious stimuli arising from cellular injury and inflammation. Under pathophysiologic conditions, TRPV1 mRNA and receptor protein expression are elevated in dorsal root ganglion (DRG) neurons for weeks to months and is associated with hyperalgesia. Building on our previous isolation of a promoter system for the rat TRPV1 gene, we investigated the proximal TRPV1 P2-promoter by first identifying candidate Sp1-like transcription factors bound <it>in vivo </it>to the P2-promoter using chromatin immunoprecipitation (ChIP) assay. We then performed deletion analysis of GC-box binding sites, and quantified promoter activity under conditions of Sp1 / Sp4 over-expression versus inhibition/knockdown. mRNA encoding Sp1, Sp4 and TRPV1 were quantified by qRT-PCR under conditions of Sp1/Sp4 over-expression or siRNA mediated knockdown in cultured DRG neurons.</p> <p>Results</p> <p>Using ChIP analysis of DRG tissue, we demonstrated that Sp1 and Sp4 are bound to the candidate GC-box site region within the endogenous TRPV1 P2-promoter. Deletion of GC-box "a" or "a + b" within the P2- promoter resulted in a complete loss of transcriptional activity indicating that GC-box "a" was the critical site for promoter activation. Co-transfection of Sp1 increased P2-promoter activity in cultured DRG neurons whereas mithramycin-a, an inhibitor of Sp1-like function, dose dependently blocked NGF and Sp1-dependent promoter activity in PC12 cells. Co-transfection of siRNA directed against Sp1 or Sp4 decreased promoter activity in DRG neurons and NGF treated PC12 cells. Finally, electroporation of Sp1 or Sp4 cDNA into cultures of DRG neurons directed an increase in Sp1/Sp4 mRNA and importantly an increase in TRPV1 mRNA. Conversely, combined si-RNA directed knockdown of Sp1/Sp4 resulted in a decrease in TRPV1 mRNA.</p> <p>Conclusion</p> <p>Based on these studies, we now propose a model of TRPV1 expression that is dependent on Sp1-like transcription factors with Sp4 playing a predominant role in activating TRPV1 RNA transcription in DRG neurons. Given that increases of TRPV1 expression have been implicated in a wide range of pathophysiologic states including persistent painful conditions, blockade of Sp1-like transcription factors represents a novel direction in therapeutic strategies.</p

Do Statins Improve Lung Function in Asthmatic Patients? ARandomized and Double-Blind Trial: Role of statins in asthma

There are evidences that statins have anti-inflammatory effects beyond their cholesterol lowering properties. The study was conducted to assess the effects of atorvastatin on asthma as an inflammatory disease. Patients with moderate to sever easthma were entered this randomized, double blind, crossover clinical trial. The impact of oral atorvastatin (10 mg/day) on the lung function of normolipidemic patients was studied. The study was conducted in the National Research Institute of Tuberculosis and Lung Disease. Patients were randomized to receive either atorvastatin or placebo for 4 weeks separated by a 2-week washout period in a crossover fashion.Patients continued on their usual asthma drug treatment throughout the study.Spirometric parameters were determined at baseline and at completion of drug or placebo administration. Seventeen patients with the age of 37.12±12.41 years completed the trial. Data analysis revealed no significant differences in peak expiratory flow rate (PEF), forced expiratory volume in the first second (FEV1),forced vital capacity (FVC) and FEV1/FVC between placebo and atorvastatin therapy. The results showed no significant improvement in the pulmonary function tests in asthmatic patients receiving atorvastatin. Further studies using higher doses of statins and/or higher period of statin use are recommended

The clinical efficacy of desloratadine, a non-sedating antihistamine, in the management of allergic conditions: A review of the evidence

Desloratadine is a relatively new, second-generation, tricyclic antihistamine which came into medical use in 2001. This study aimed to review the available evidence in the literature around the clinical efficacy of desloratadine on a range of allergic conditions. A database search in Medline, PubMed, Embase, and Google Scholar was conducted for the research articles published until July 2020, using the keyword desloratadine. An additional reference lists search and citation tracking were also performed. Research articles in English pertaining to desloratadine and its efficacy were considered for inclusion. Study designs, including randomized controlled trials (RCT), observational/case-control studies, and case series were considered. The collective evidence from the current literature shows superior efficacy of desloratadine compared to placebo and some of the other treatment options in the management of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), chronic idiopathic urticaria (CIU), and asthmatic symptoms. There is also evidence for potential new roles introduced for desloratadine such as acne treatment, chronic otitis media, and chronic rhinosinusitis, which warrants further investigation. In most studies, desloratadine’s safety and tolerability were comparable with placebo. Current evidence suggest that desloratadine is an ideal option for most of the allergic conditions due to its efficacy as well as favourable safety and tolerability profile. Further large-scale studies are needed to establish the efficacy and safety profile of desloratadine and to compare its effectiveness against other treatments in the management of allergic conditions

The Bioavailability of Salbutamol in Urine via Volumatic and Nonvolumatic Valved Holding Chambers

Purpose Pressurized metered dose inhalers are commonly used in patients with asthma. However, the need to coordinate inhalation with inhaler actuation means that they are not suitable for use per se. Valved holding chamber devices were developed to overcome some of the problems of pressurized metered dose inhalers. Several types of holding chambers of different sizes are available in Iran. This study was designed to compare the effects of 2 commonly used valved holding chambers (Asthm Yar and Dam Yar) in Iran on bioavailability of salbutamol spray and also spirometric parameters in asthmatic patients.Methods This was a comparative experimental crossover study. Patients with mild to moderate asthma were entered in this study. Lung function was assessed using a portable spirometer (Spirolab, Progetti, Italy). Spirometric parameters of forced expiratory flow (FEF)50%, FEF25-75%, peak expiratory flow (PEF), forced expiratory volume in the first second of expiration (FEV1), forced vital capacity (FVC), and FEV1/FVC were measured. Urinary concentration of salbutamol as an index of pulmonary bioavailability was assayed with high-performance liquid chromatography.Results Forty patients (25 women and 15 men) with the mean age of 43.10 ± 12.99 years were studied. Mean ± SD changes of spirometric parameters before and after using Asthm Yar were not significantly different from those of Dam Yar. The relative bioavailability after inhalation with Asthm Yar was significantly higher than after inhalation with Dam Yar (P = 0.002).Conclusions Although the results indicate that relative bioavailability to the lung after inhalation with Asthm Yar was significantly higher than after inhalation with Dam Yar, its clinical importance should be tested. Keywords: asthma, valved holding chamber, urinary concentration, salbutamol, spirometr