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Preeclampsia is the most common and serious complication of pregnancy. Variants of Sirtuin-1 (SIRT1) as a key player in the regulation of oxidant/antioxidant signaling pathways might be involved in the pathogenesis of preeclampsia. In the present case–control study 300 women with and without preeclampsia were studied for SIRT1 variants (rs7895833, rs7069102, and rs2273773) and haplotypes. Also, the relationship of glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities and Zn, Cu, and Se levels to the polymorphisms were investigated. The SIRT1 rs7895833 A > G, rs7069102 C > G, and the rs2273773 C > T polymorphisms were associated with the risk of preeclampsia. We found the haplotypes G (rs7895833) C (rs7069102) C (rs2273773), GCC, and ACC compared to the AGT decreased the risk of preeclampsia. The risk haplotype of AGT was associated with higher GPx activity compared to the GCC haplotype. A significantly higher level of Cu and lower levels of Zn and Se in patients with preeclampsia compared to controls were detected. Also, a significantly lower SOD and higher GPx activity in preeclamptic patients compared to controls were found. The three risk genotypes of AA (rs7895833), GG (rs7069102), and TT (rs2273773) significantly decreased the Zn level and SOD activity, and the TT genotype (rs2273773) increased the Cu level in all studied women. The presence of rs7069102 polymorphism was associated with enhanced systolic blood pressure. For the first time, we indicated three SIRT1 polymorphisms and the AGT haplotype are risk factors for preeclampsia development. Also, SIRT1 variants and haplotypes affect the levels of antioxidant enzymes and their cofactors, complicating the pregnancy outcome. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia is a multifactorial hypertensive disorder of pregnancy with multisystem involvement. Recent studies have demonstrated that preeclampsia is associated with increased placental oxidative stress at the cellular level. The nuclear factor erythroid-2-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling is an antioxidant pathway that plays an important role in protecting cells against oxidative stress. Here, we aimed to determine the possible association between the Keap1 variants and genetic susceptibility to preeclampsia. Methods: In a case-control study, 150 preeclampsia patients and 150 women with normal pregnancy from Northern Iran were selected to evaluate the genotypes of Keap1 (rs11085735) using the polymerase chain reaction (PCR)-restriction length polymorphism (RFLP) method. Results: A significant association between genotypes of Keap1 rs11085735 polymorphism with the renal function biomarkers and the risk of preeclampsia was not found. However, the aspartate aminotransferase (AST) level was higher in the presence of the Keap1 AA genotype compared to AC and CC genotypes. We found a significantly higher prevalence of gestational diabetes mellitus (GDM) in mild- and severe- preeclampsia and also hypothyroidism in severe preeclampsia compared to controls. Conclusions: We found an association between preeclampsia with GDM and hypothyroidism. Our findings suggest that the Keap1rs11085735 polymorphism may not be a risk factor for susceptibility to preeclampsia in our studied population; however, this polymorphism could affect the activity of AST. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a serious global health problem affecting many people worldwide. While patients with leishmaniasis can be treated with several agents, drug toxicicty and the emergence of resistant strains render available treatments ineffective in the long run. Inhibitors of the mammalian target of rapamycin (mTOR) have been demonstrated to exert anti-pathogen properties. In this study, we tested the therapeutic efficacy of several mTOR inhibitors in controlling infection with Leishmania major. Rapamycin, GSK-2126458 and KU-0063794 were administered to BALB/c mice, which had received an intrafootpad injection of the parasite. Footpad swelling and parasite burden were assessed, and cytokine production by mouse splenocytes and phenotypic changes in draining lymph node cells were evaluated. Treatment with a clinically relevant dose of rapamycin or with GSK-2126458, but not with KU-0063794, dramatically lowered both the footpad swelling and the parasite load in the draining lymph node. Importantly, the employed dose of rapamycin did not kill the promastigotes in vitro as judged by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and electron microscopy. Moreover, the IL-4 production capacity of splenocytes harvested from infected mice that were treated with rapamycin was significantly reduced. Consequently, the IFN-γ:IL-4 production ratio was elevated, suggesting a T helper-type 1 (Th1)-skewed cytokine profile. Finally, the expression level of CD69, an early activation marker, on splenic and lymph node CD4+ and CD8+ T cells was enhanced in rapamycin-treated mice. Taken together, our findings suggest that select mTOR inhibitors may be used in therapeutic settings for the management of leishmaniasis. We propose that the beneficial effects of such inhibitors stem from their immunomodulatory properties. Therefore, the adjuvanticity of mTOR inhibitors may also be considered in vaccination strategies against Leishmania species. [ABSTRACT FROM AUTHOR]

Introduction: The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy. Background: Aerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction. Methods: Wild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9. Results: We demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise. Conclusions: Our findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy. [ABSTRACT FROM AUTHOR]

Corrigendum to "Antileishmanial effect of rapamycin as an alternative approach to control Leishmania tropica infection" [Vet. Parasitol. [Extracted from the article]

• Rapamycin can inhibit the propagation of Leishmania tropica. • SEM and TEM showed negative effect of rapamycin on the shape of the parasites. • Clinically relevant dose of rapamycin is a promising treatment against Leishmania tropica. • Combination therapies of rapamycin with AmB or glucantime were not successful. Cutaneous leishmaniosis (CL) is a parasitic disease in animals and human with no satisfactory treatments and vaccination. Rapamycin is a potent inhibitor of mammalian target of rapamycin (mTOR) with various applications. Here, the effect of rapamycin alone or in combination with two other drugs, namely amphotericin B (AmB) and glucantime, was investigated against Leishmania tropica infection. In vitro viability and electron microscopy evaluation of the parasites showed detrimental changes in their appearance and viability. Treatment with clinically relevant dose of rapamycin (10.2 μg/dose) is able to control the parasite load in BALB/c mice infected with L. tropica. Furthermore, the cytokine profiles showed significant polarization towards Th1 immune response. Surprisingly, combination therapy with either AmB or glucantime was not efficient. Rapamycin is showed an effective alternative therapy against leishmaniosis caused by L. tropica. [ABSTRACT FROM AUTHOR]

Background: The vector-borne disease leishmaniasis is transmitted to humans by infected female sand flies, which transmits Leishmania parasites together with saliva during blood feeding. In Iran, cutaneous leishmaniasis (CL) is caused by Leishmania (L.) major and L. tropica, and their main vectors are Phlebotomus (Ph.) papatasi and Ph. sergenti, respectively. Previous studies have demonstrated that mice immunized with the salivary gland homogenate (SGH) of Ph. papatasi or subjected to bites from uninfected sand flies are protected against L. major infection. Methods and results: In this work we tested the immune response in BALB/c mice to 14 different plasmids coding for the most abundant salivary proteins of Ph. sergenti. The plasmid coding for the salivary protein PsSP9 induced a DTH response in the presence of a significant increase of IFN-γ expression in draining lymph nodes (dLN) as compared to control plasmid and no detectable PsSP9 antibody response. Animals immunized with whole Ph. sergenti SGH developed only a saliva-specific antibody response and no DTH response. Mice immunized with whole Ph. sergenti saliva and challenged intradermally with L. tropica plus Ph. sergenti SGH in their ears, exhibited no protective effect. In contrast, PsSP9-immunized mice showed protection against L. tropica infection resulting in a reduction in nodule size, disease burden and parasite burden compared to controls. Two months post infection, protection was associated with a significant increase in the ratio of IFN-γ to IL-5 expression in the dLN compared to controls. Conclusion: This study demonstrates that while immunity to the whole Ph. sergenti saliva does not induce a protective response against cutaneous leishmaniasis in BALB/c mice, PsSP9, a member of the PpSP15 family of Ph. sergenti salivary proteins, provides protection against L. tropica infection. These results suggest that this family of proteins in Ph. sergenti, Ph. duboscqi and Ph. papatasi may have similar immunogenic and protective properties against different Leishmania species. Indeed, this anti-saliva immunity may act as an adjuvant to accelerate the cell-mediated immune response to co-administered Leishmania antigens, or even cause the activation of infected macrophages to remove parasites more efficiently. These findings highlight the idea of applying arthropod saliva components in vaccination approaches for diseases caused by vector-borne pathogens. [ABSTRACT FROM AUTHOR]

This correction notice addresses errors in the funding statement of a research article titled "DNA plasmid coding for Phlebotomus sergenti salivary protein PsSP9, a member of the SP15 family of proteins, protects against Leishmania tropica." The correct funding statement includes support from the Pasteur Institute of Iran, the Iran National Science Foundation, the International Center for Genetic Engineering and Biotechnology, and the Intramural Research Program of the NIH. The funders did not have a role in the study design, data collection and analysis, decision to publish, or manuscript preparation. The article is authored by multiple individuals and covers the topic of protection against Leishmania tropica. [Extracted from the article]