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      Drug Design, Development and Therapy (submit here)

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      Investigation of the antibacterial activity of pioglitazone

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          Abstract

          Purpose:

          To evaluate the antibacterial potential of pioglitazone, a member of the thiazolidinediones class of drugs, against Gram-positive ( Streptococcus pneumoniae) and Gram-negative ( Escherichia coli and Klebsiella pneumoniae) bacteria.

          Methods:

          Susceptibility testing was done using the antibiotic disk diffusion method and the minimal inhibitory concentration (MIC) of pioglitazone was measured according to the broth micro incubation standard method.

          Results:

          Pioglitazone induced a dose-dependent antibacterial activity in which the optimal concentration was 80 μM. Furthermore, results indicated that while E. coli was sensitive (MIC = 31.25 ± 3.87 mg/L) to pioglitazone-induced cytotoxicity, S. pneumoniae and K. pneumoniae were resistant (MIC = 62.5 ± 3.77 mg/L and MIC = 62.5 ± 4.14 mg/L, respectively). Moreover, pretreatment of bacteria with a suboptimal concentration of pioglitazone (40 μM) before adding amoxicillin, cephalexin, co-trimoxazole, or ciprofloxacin enhanced the antibacterial activity of all agents except co-trimoxazole. This enhancing effect was particularly seen against K. pneumoniae.

          Conclusion:

          These results indicate the possibility of a new and potentially important pioglitazone effect and the authors’ ongoing studies aim to illustrate the mechanism(s) by which this antibacterial effect is induced.

          Most cited references18

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          Pioglitazone: mechanism of action.

          U. Smith (2001)
          Thiazolidinediones, such as pioglitazone, are synthetic ligands for peroxisome proliferator-activated receptors (PPARs). They alter the transcription of genes influencing carbohydrate and lipid metabolism, resulting in changed amounts of protein synthesis and, therefore, metabolic changes. Pioglitazone improves glycaemic control in people with Type 2 diabetes by improving insulin sensitivity through its action at PPAR gamma 1 and PPAR gamma 2, and affects lipid metabolism through action at PPAR alpha. The results of these interactions include increases in glucose transporters 1 and 4, lowered free fatty acids, enhanced insulin signalling, reduced tumour necrosis factor alpha (TNF alpha) and remodelling of adipose tissue. Together, these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver, thereby reducing insulin resistance.
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            Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands: a review.

            Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of a class of nuclear hormone receptors intimately involved in the regulation of expression of myriad genes that regulate energy metabolism, cell differentiation, apoptosis and inflammation. Although originally discovered as a pivotal regulator of adipocyte differentiation, the roles that this transcription factor play in physiology and pathophysiology continue to grow as researchers discover its influence in the function of many cell types. This review highlights the roles that PPARgamma play in the regulation of gene expression associated with normal cell physiology as well as the pathophysiology of multiple diseases including obesity, diabetes and cancer. Additionally, naturally occurring and pharmaceutical ligands for the receptor as well as the potential role of PPARgamma as the receptor responsible for fatty acid-induced effects on gene expression will be described.
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              Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma.

              The glitazones or thiazolidinediones are ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma). The glitazones are used in the treatment of diabetes, regulate adipogenesis, inflammation, cell proliferation, and induce apoptosis in several cancer cell types. High grade astrocytomas are rapidly growing tumors derived from astrocytes, for which new treatments are needed. We determined the effects of two glitazones, ciglitazone and the therapeutic rosiglitazone, on the survival of serum-deprived primary rat astrocytes and glioma cell lines C6 and U251, which were assessed by the methylthiazolyl tetrazolium assay and lactate dehydrogenase release. Rosiglitazone (5-20 microM) decreased survival of glioma cells without affecting primary astrocytes, whereas ciglitazone at 20 microM was toxic for both cell types. Ciglitazone at 10 microM was cytoprotective for primary astrocytes but toxic to glioma cells. Cell death induced by ciglitazone, but not rosiglitazone, presented apoptotic features (Hoechst staining and externalization of phosphatidylserine). Two mechanisms to explain cytotoxicity were investigated: activation of PPARgamma and production of reactive oxygen species (ROS). PPARgamma does not seem to be the main mechanism involved, because the order of efficacy for cytotoxicity, ciglitazone > rosiglitazone, was inverse of their reported affinities for activating PPARgamma. In addition, GW9662, an inhibitor of PPARgamma, only slightly attenuated cytotoxicity. However, the rapid increase in ROS production and the marked reduction of cell death with the antioxidants ebselen and N-acetylcysteine, indicate that ROS have a key role in glitazone cytotoxicity. Ciglitazone caused a dose-dependent and rapid loss (in minutes) of mitochondrial membrane potential in glioma cells. Therefore, mitochondria are a likely source of ROS and early targets of glitazone cytotoxicity. Our results highlight the potential of rosiglitazone and related compounds for the treatment of astrogliomas.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2011
                27 September 2011
                : 5
                : 421-425
                Affiliations
                [1 ]Department of Pharmaceutical Technology;
                [2 ]Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
                Author notes
                Correspondence: Majed M Masadeh, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan, Tel +962 27 201000, Fax +962 27 201075, Email mmmasadeh@ 123456just.edu.jo
                Article
                dddt-5-421
                10.2147/DDDT.S24126
                3210070
                22087061
                fe87dbff-7cab-4ff4-bbae-2da1fdd15201
                © 2011 Masadeh et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                : 26 September 2011
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                pioglitazone,susceptibility testing,antibiotics,diabetes

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