Tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the extrinsic coagulation cascade, and its expression is reported to be relatively stable. Various pathophysiologic agents have been shown to influence TFPI activity by regulating its expression or by modifying the protein. It is not clear how TFPI activity is regulated in normal physiology or in injury. Because thrombin and TFPI are locally elaborated in pleural injury, we sought to determine if thrombin could regulate TFPI in human pleural mesothelial cells (HPMCs). Thrombin significantly decreased TFPI mRNA and protein levels by . 70%. Thrombin-mediated down-regulation of TFPI promoted factor X activation by HPMCs. The ability of thrombin to significantly decrease TFPI mRNA and protein levels was maintained at nanomolar concentrations. Protease-activated receptor (PAR)-1, a mediator of thrombin signaling, is detectable in the mesothelium in human and murine pleural injury. PAR-1 silencing blocked thrombin-mediated decrements of TFPI in HPMCs. Thrombin activates PI3K/Akt and nuclear factor kB (NF-kB) signaling in HPMCs. Inhibition of PI3K (by PX-866) and NF-kB (by SN50) prevented thrombin-mediated TFPI mRNA and protein downregulation. These are the first studies to demonstrate that thrombin decreases TFPI expression in HPMCs. Our findings demonstrate a novel mechanism by which thrombin regulates TFPI expression in HPMCs and promotes an unrestricted procoagulant response, and suggest that interactions between PI3K and NF-kB signaling pathways are linked in HPMCs and control TFPI expression. These findings raise the possibility that targeting this pathway could limit the ability of the mesothelium to support extravascular fibrin deposition and organization associated with pleural injury.
Background: Impetigo is a contagious bacterial skin infection that affects both adults and children. Topical antibacterials such as mupirocin and fusidic acid are the most commonly used in both primary and secondary impetigo. Clinical trials have shown high efficacy of retapamulin in the treatment of secondary impetigo. However, its use in primary impetigo is limited. To this purpose, we compared the safety, efficacy and adherence to treatment of fusidic acid with retapamulin in primary impetigo.Methods: A total of 50 patients with a clinical diagnosis of primary impetigo, between 2-12 years of age, having <10 lesions, 3/5 signs and symptoms, skin infection rating score ≥4 and pus score ≥ one were involved. Patients who were having secondary impetigo leions were excluded. Twenty-five patients received 2% fusidic acid cream three times a day, and the remaining 25 patients received 1% retapamulin ointment two times a day for seven days. Skin Infection Rating Scale (SIRS) was used to assess the severity of disease at baseline and end of treatment. Clinical success was considered when SIRS score of zero each for pus, crust and pain and 0/1 each for erythema and itching. Clinical failure is a SIRS score of ≥1 for pus.Results: Baseline disease characteristics such as a number of lesions, the severity of disease (SIRS) and pus scores were statistically similar between the two groups. The clinical improvement observed with both fusidic acid and Retapamulin (20/25, 80%) and (21/25, 84%) treatments was not statistically different (p>0.05). Both drugs were well tolerated.Conclusions: Both fusidic and retapamulin showed similar clinical success in patients with primary impetigo. Since fusidic acid has anti-inflammatory property and its treatment is cost-effective, it can be considered as first-line treatment and retapamulin in fusidic acid-resistant impetigo.
Psoriasis is one of the skin disorder, mainly characterized by scaly papules and plaques. The etiology of psoriasis is multifactorial and still not properly understood. In our study, we tried to elucidate the relation between psoriasis and trace elemens namely Zinc, Copper and Selenium. Materials and Methods: This study enrolled 50 psoriasis patients with 37 males and 13 females, with 10-80 years age. The patients were randomly selected from the outpatient clinic of Dermatology, Venereology and Leprosy Department, Narayana medical college and hospital. The age, sex matched 50 healthy volunteers included as controls in this study. Levels of serum Copper (Cu), Zinc(Zn), and Selenium(Se) analysed using Atomic absorption Spectrophotometery. Results: In our study, the mean Serum Zinc, Selenium and Copper levels were 61.9680±15.96824, 64.2060±17.44780 and 56.4120±8.51976 respectively, lower than the controls which was stastically significant (P<0.05). Conclusion:In psoriasis, serum Cu, Zn and Se levels were observed to be low, needs to manage therapeutically by oral supplementation. More studies are required to carryout to standardize the diagnostic levels of Cu, Zn and Se and their role in psoriasis pathogenseis.
Background: Oxidative stress and generation of lipid peroxidation (LPO) products are detrimental in the pathogenesis of atherosclerosis and associated acute thrombotic events. However, recent studies suggest that moderate oxidative stress and low levels of LPO products can induce adaptive immune responses and exert beneficial effects. Tissue factor (TF) is a critical initiator of coagulation and aberrant TF expression on vascular cells under inflammation triggers intravascular thrombosis. HNE, a highly reactive LPO product and TF have been shown to be associated with atherosclerosis. Recently, we demonstrated that HNE decrypts procoagulant activity of pre-existing TF on activated monocytes and endothelial cells and generates TF+ microparticles. Here, we investigated the effect of HNE on induction of TF and cell adhesion molecules in monocytes and endothelial cells that were not perturbed earlier. Methods and results: THP-1 monocytic cells and endothelial cells (HUVEC) were stimulated with LPS and TNF-α/IL1-β, respectively, in the presence of a control vehicle or varying concentrations of HNE that are pathophysiologically relevant. TF induction was measured at mRNA (by qRT-PCR), protein (by immunoblotting) and activity levels (in factor X activation assay). Pre-treating cells with HNE inhibited TNF-α/IL1-β- or LPS-stimulated TF procoagulant activity in a dose-dependent manner. THP-1 and HUVEC varied in their sensitivities to HNE (THP-1> HUVEC). HNE-mediated inhibition of TF activity correlated with lower TF mRNA and protein levels. Our results demonstrate that HNE prevents TNF-α/IL1-β- and LPS-induced IKKβ degradation and thereby inhibits NFκβ activation. In addition to inhibiting TF expression, HNE significantly reduced monocyte adhesion to endothelial cells through downregulating TNF-α/IL1-β-induced expression of endothelial adhesion molecules VCAM-1 and ICAM-1. Conclusion: HNE may play a dual role in regulating TF activity in atherosclerosis. HNE could act as a prothrombotic mediator by increasing coagulant activity of pre-existing TF through decryption process. HNE can also elicit anti-thrombotic and anti-inflammatory effect by inhibiting TF and adhesion molecules in response to stimulus by impairing the NF-ĸB pathway.
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