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Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low ...selectivity. Targeted drug delivery is a promising approach to decrease side effects of therapy. Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer cells while low level of expression is observed in normal cells. In this study we describe the development of Glu-urea-Lys based PSMA-targeting conjugates with paclitaxel. A series of new PSMA targeting conjugates with paclitaxel was designed and synthesized. The cytotoxicity of conjugates was evaluated against prostate (LNCaP, 22Rv1 and PC-3) and non-prostate (Hek293T, VA13, A549 and MCF-7) cell lines. The most promising conjugate 21 was examined in vivo using 22Rv1 xenograft mice model. It demonstrated good efficiency comparable with paclitaxel, while reduced toxicity. 3D molecular docking study was also performed to understand underlying mechanism of binding and further optimization of the linker substructure and conjugates structure for improving the target affinity. These conjugates may be useful for further design of novel PSMA targeting delivery systems for PC.
Prostate cancer (PC) is the prevalent malignancy widespread among men in the Western World. Prostate specific membrane antigen (PSMA) is an established PC marker and has been considered as a ...promising biological target for anti-PC drug delivery and diagnostics. The protein was found to be overexpressed in PC cells, including metastatic, and the neovasculature of solid tumors. These properties make PSMA-based approach quite appropriate for effective PC imaging and specific drug therapy. Through the past decade, a variety of PSMA-targeted agents has been systematically evaluated. Small-molecule compounds have several advantages over other classes, such as improved pharmacokinetics and rapid blood clearance. These low-weight ligands have similar structure and can be divided into three basic categories in accordance with the type of their zinc-binding core-head. Several PSMA binders are currently undergoing clinical trials generally for PC imaging. The main goal of the present review is to describe the recent progress achieved within the title field and structure activity relationships (SAR) disclosed for different PSMA ligands. Recent in vitro and in vivo studies for each type of the compounds described have also been briefly summarized.
Transforming growth factor β (TGF-β) is a well characterized cytokine that appears to play a major role in directing the cellular response to injury, driving fibrogenesis, and, thus, potentially ...underlying the progression of chronic injury to fibrosis. In this study, we report the use of a novel TGF-β receptor antagonist to block fibrogenesis induced by ligation of the common bile duct in rats. The antagonist consisted of a chimeric IgG containing the extracellular portion of the TGF-β type II receptor. This "soluble receptor" was infused at the time of injury; in some experiments it was given at 4 days after injury, as a test of its ability to reverse fibrogenesis. The latter was assessed by expression of collagen, both as the mRNA in stellate cells isolated from control or injured liver and also by quantitative histochemistry of tissue sections. When the soluble receptor was administered at the time of injury, collagen I mRNA in stellate cells from the injured liver was 26% of that from animals receiving control IgG (P < 0.0002); when soluble receptor was given after injury induction, collagen I expression was 35% of that in control stellate cells (P < 0.0001). By quantitative histochemistry, hepatic fibrosis in treated animals was 55% of that in controls. We conclude that soluble TGF-β receptor is an effective inhibitor of experimental fibrogenesis in vivo and merits clinical evaluation as a novel agent for controlling hepatic fibrosis in chronic liver injury.
The liver is the only organ in mammals that fully regenerates even after major injury. To identify orchestrators of this regenerative response, we performed quantitative large-scale proteomics ...analysis of cytoplasmic and nuclear fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly upregulated after two-third hepatectomy, with the ubiquitin ligase Nedd4-1 being a top hit. In vivo knockdown of Nedd4-1 in hepatocytes through nanoparticle-mediated delivery of small interfering RNA caused severe liver damage and inhibition of cell proliferation after hepatectomy, resulting in liver failure. Mechanistically, we demonstrate that Nedd4-1 is required for efficient internalization of major growth factor receptors involved in liver regeneration and their downstream mitogenic signaling. These results highlight the power of large-scale proteomics to identify key players in liver regeneration and the importance of posttranslational regulation of growth factor signaling in this process. Finally, they identify an essential function of Nedd4-1 in tissue repair.
•Proteomics identified regulated proteins and pathways in the regenerating liver•The ubiquitin ligase Nedd4-1 is an essential regulator of liver regeneration•Nedd4-1 promotes growth factor receptor internalization and efficient signaling•Posttranslational regulation of growth factor signaling controls liver regeneration
Using large-scale quantitative proteomics, Bachofner, Speicher et al. identified the ubiquitin ligase Nedd4-1 as an essential regulator of liver regeneration. Nedd4-1 deficiency attenuated growth factor receptor internalization and signaling, demonstrating a crucial role of posttranslational modification of growth factor signaling in liver regeneration.
Interleukin (IL)-13 is a key mediator of tissue fibrosis caused by T helper cell type 2 inflammation. We hypothesized that the fibrogenic effects of IL-13 are mediated by transforming growth factor ...(TGF)-β. To test this hypothesis we compared the regulation of TGF-β in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-β1 production in transgenic animals and macrophages were the major site of TGF-β1 production and deposition in these tissues. IL-13 also activated TGF-β1 in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-β–binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-β1 activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in progeny of crosses of CC10-IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13–induced fibrosis was also significantly ameliorated by treatment with the TGF-β antagonist soluble TGFβR-Fc (sTGFβR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-β1 in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9–dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-β pathway.
Angiogenesis is a complex process, involving functional cooperativity between cytokines and endothelial cell (EC) surface integrins. In this study, we investigated the mechanisms through which the α
...1
β
1
and α
2
β
1
integrins support angiogenesis driven by vascular endothelial growth factor (VEGF). Dermal microvascular EC attachment through either α
1
β
1
or α
2
β
1
supported robust VEGF activation of the Erk1/Erk2 (p44/42) mitogen-activated protein kinase signal transduction pathway that drives EC proliferation. Haptotactic EC migration toward collagen I was dependent on α
1
β
1
and α
2
β
1
as was VEGF-stimulated chemotaxis of ECs in a uniform collagen matrix. Consistent with the functions of α
1
β
1
and α
2
β
1
in supporting signal transduction and EC migration, antibody antagonism of either integrin resulted in potent inhibition of VEGF-driven angiogenesis in mouse skin. Moreover, combined antagonism of α
1
β
1
and α
2
β
1
substantially reduced tumor growth and angiogenesis of human squamous cell carcinoma xenografts. Collectively, these studies identify critical collaborative functions for the α
1
β
1
and α
2
β
1
integrins in supporting VEGF signal transduction, EC migration, and tumor angiogenesis.
Non-structural 5A (NS5A) protein plays a crucial role in the replication of hepatitis C virus (HCV) and during the past decade has attracted increasing attention as a promising biological target for ...the treatment of viral infections and related disorders. Small-molecule NS5A inhibitors have shown significant antiviral activity in vitro and in vivo. Several lead molecules are reasonably regarded as novel highly potent drug candidates with favorable ADME features and tolerable side effects. The first-in-class daclatasvir has recently been launched into the market and 14 novel molecules are currently under evaluation in clinical trials. From this perspective, we provide an overview of the available chemical space of small-molecule NS5A inhibitors and their PK properties, mainly focusing on the diversity in structure and scaffold representation.
In the present study, we investigated the role of the CD40L-CD40 pathway in a model of progressive atherosclerosis. ApoE-/- mice were treated with an anti-CD40L antibody or a control antibody for 12 ...wk. Antibody treatment started early (age 5 wk) or was delayed until after the establishment of atherosclerosis (age 17 wk). In both the early and delayed treatment groups, anti-CD40L antibody did not decrease plaque area or inhibit lesion initiation or age-related increase in lesion area. The morphology of initial lesions was not affected, except for a decrease in T-lymphocyte content. Effects of anti-CD40L antibody treatment on the morphology of advanced lesions were pronounced. In both the early and delayed treatment groups, T-lymphocyte content was significantly decreased. Furthermore, a pronounced increase in collagen content, vascular smooth muscle cell/myofibroblast content, and fibrous cap thickness was observed. In the delayed treatment group, a decrease in lipid core and macrophage content occured. Interestingly, advanced lesions of anti-CD40L antibody-treated mice exhibited an increased transforming growth factor β 1 immunoreactivity, especially in macrophages. In conclusion, both early and delayed treatment with an anti-CD40L antibody do not affect atherosclerotic lesion initiation but do result in the development of a lipid-poor collagen-rich stable plaque phenotype. Furthermore, delayed treatment with anti-CD40L antibody can transform the lesion profile from a lipid-rich to a lipid-poor collagen-rich phenotype. Postulated mechanisms of this effect on plaque phenotype are the down-regulation of proinflammatory pathways and up-regulation of collagen-promoting factors like transforming growth factor β .
N6-methyladenosine (m6A) is ubiquitously present in the RNA of living organisms from Escherichia coli to humans. Methyltransferases that catalyze adenosine methylation are drastically different in ...specificity from modification of single residues in bacterial ribosomal or transfer RNA to modification of thousands of residues spread among eukaryotic mRNA. Interactions that are formed by m6A residues range from RNA–RNA tertiary contacts to RNA–protein recognition. Consequences of the modification loss might vary from nearly negligible to complete reprogramming of regulatory pathways and lethality. In this review, we summarized current knowledge on enzymes that introduce m6A modification, ways to detect m6A presence in RNA and the functional role of this modification everywhere it is present, from bacteria to humans.
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•RNA contains m6A residues.•In bacteria, each residue is modified by separate enzyme.•m6A fulfills a structural role in bacteria.•In eukarya, one enzymatic complex modifies thousands of residues.•Modifications destabilize RNA.
In recent years, nonstructural protein 5A (NS5A) has rapidly emerged as a promising therapeutic target for Hepatitis C (HCV) virus therapy. It is involved in both viral RNA replication and virus ...assembly and NS5A plays a critical role in the regulation of HCV life cycle. NS5A replication complex inhibitors (NS5A RCIs) have demonstrated strong antiviral activity in vitro and in vivo. However, wild-type resistance mutations and a wide range of genotypes significantly reduce their clinical efficacy. The exact mechanism of NS5A action still remains elusive, therefore several in silico models have been constructed to gain insight into the drug binding and subsequent structural optimization to overcome resistance. This paper provides a comprehensive overview of the computational studies towards NS5A mechanism of action and the design of novel small-molecule inhibitors.
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