Abstracts


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Microrna-21: From Cancer to Cardiovascular Disease
Virginija Jazbutyte and Thomas Thum

MicroRNA-21 (miR-21) expression is activated in multiple types of cancers, such as breast, liver, brain, prostate, myometrial cancers but also in cardiovascular disease. MiR-21 regulates a plethora of target proteins which are involved in cellular survival, apoptosis and cell invasiveness. MiR-21 regulation is complex due to an own promoter that is target for various transcription factors and hormones. The consistent miR-21 overexpression under pathophysiological conditions points to miR-21 as a valuable tool for new therapeutic strategies. In this review, we present and analyze current data about miR-21 expression in various pathologies ranging from cancer to cardiovascular disease. Further, miR21 regulatory mechanisms and miR-21 downstream targets are discussed. Finally, we highlight the particular role of miR21 as a therapeutic target in various diseases.


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Future Prospect of RNA Interference for Cancer Therapies
Eishi Ashihara, Eri Kawata and Taira Maekawa

RNA interference (RNAi) is a phenomenon of sequence-specific gene silencing in mammalian cells and its discovery has lead to its wide application as a powerful tool in post-genomic research. Recently, short interfering RNA (siRNA), which induces RNAi, has been experimentally introduced as a cancer therapy and is expected to be developed as a nucleic acid-based medicine. Selection of appropriate gene targets is an important parameter in the potential success of siRNA cancer therapies. Candidate targets include genes associated with cell proliferation, metastasis, angiogenesis, and drug resistance. Importantly, silencing of such genes must not affect the functions of normal cells. Development of suitable drug delivery systems (DDSs) is also an important issue. Numerous methods to transfect siRNAs into cells have been developed, and the use of non-viral DDSs is preferred because it offers greater safety for clinical application than does the use of viral DDSs. Currently, atelocollagen and cationic liposomes represent the most advantageous non-viral DDSs available. In this article, we briefly review the mechanism of RNAi and non-viral DDSs. Next we discuss in detail some of the most recent findings concerning the administration of potential nucleic acid-based drugs against polo-like kinase-1 (PLK-1), which regulates the mitotic process in mammalian cells. These promising results demonstrate that PLK-1 is a suitable target for cancer therapy. Finally, several current clinical trials of RNAi therapies against cancers are discussed. Results of current studies and clinical trials demonstrate that manipulation of RNAi mechanism by use of targeted siRNA offers promising strategies for cancer therapies.


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Gabapentin and Pregabalin for the Acute Post-Operative Pain Management. A Systematic-Narrative Review of the Recent Clinical Evidences
M. Dauri, S. Faria, A. Gatti, L. Celidonio, R. Carpenedo and A.F. Sabato

Background: Gabapentin and pregabalin inhibit Ca2+ currents via high-voltage-activated channels containing the α2δ-1 subunit, reducing neurotransmitter release and attenuating the postsynaptic excitability. They are antiepileptic drugs successfully used also for the chronic pain treatment. A large number of clinical trials indicate that gabapentin and pregabalin could be effective as postoperative analgesics. This systematic-narrative review aims to analyse the most recent evidences regarding the effect of gabapentinoids on postoperative pain treatment. Methods: Medline, The Cochrane Library, EMBASE and CINHAL were searched for recent (2006-2009) randomized clinical trials (RCTs) of gabapentin-pregabalin for postoperative pain relief in adults. Quality of RCTs was evaluated according to Jadad method. Visual analogue scale (VAS), opioid consumption and side-effects (nausea, vomiting, dizziness and sedation) were considered the most important outcomes. Results: An overall of 22 gabapentin (1640 patients), 8 pregabalin (707 patients) RCTs and seven meta-analysis were involved in this review. Gabapentin provided better post-operative analgesia and rescue analgesics sparing than placebo in 6 of the 10 RCTs that administered only pre-emptive analgesia. Fourteen RCTs suggested that gabapentin did not reduce PONV when compared with placebo, clonidine or lornoxicam. Pregabalin provided better post-operative analgesia and rescue analgesics sparing than placebo in two of the three RCTs that evaluated the effects of pregabalin alone vs placebo. Four studies reported no pregabalin effects on preventing the PONV. Conclusion: Gabapentin and pregabalin reduce pain and opioid consumption after surgery in confront with placebo, but comparisons with other standard post-operative regimens are not sufficient. Gabapentin and pregabalin seem not to have any influence on the prevention of PONV.


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Emerging Drug Candidates of Dipeptidyl Peptidase IV (DPP IV) Inhibitor Class for the Treatment of Type 2 Diabetes
Rajesh Gupta, Sameer S. Walunj, Ranjeet K. Tokala, Kishore V.L. Parsa, Santosh Kumar Singh and Manojit Pal

Dipeptidyl peptidase IV (DPP IV) is a key regulator of insulin-stimulating hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus it is a promising target for the treatment of Type 2 Diabetes mellitus (T2DM). Inhibition of plasma DPP IV enzyme leads to enhanced endogenous GLP-1 and GIP activity, which ultimately results in the potentiation of insulin secretion by pancreatic β-cells and subsequent lowering of blood glucose levels, HbA[1c], glucagon secretion and liver glucose production. Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. These drugs have been approved as a once-daily oral monotherapy or as a combination therapy with current anti-diabetic agents like pioglitazone, glibenclamide, metformin etc. for the treatment of T2DM. Several other novel DPP IV inhibitors are in pipeline. The present review summarizes the latest preclinical and clinical trial data of different DPP IV inhibitors with a special emphasis on their DPP8/9 fold selectivity and therapeutic advantages over GLP-1 based approach.


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Clinical Development of Inhibitors of the Insulin-Like Growth Factor Receptor in Oncology
Zhijun Wang, Ranadheer Ravula, Mingju Cao, Moses Chow and Ying Huang

The insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumor cell survival and resistance to therapy. Ancillary evidence that targeting the IGF-IR may be useful in the treatment of cancer has been accumulating for almost two decades. Today, more than two dozen compounds have been developed and clinical trials are underway for at least 12 of those. The ability to pharmacologically control the IGF-IR pathway holds not only promising therapeutic implications but also the possibility to gather a better understanding of the role of the IGF axis in tumor initiation and progression. This review focuses on the preclinical rationale for targeting the IGF-IR and other components of the IGF-I system, early clinical results observed to date, biomarker approaches employed and the lessons from these early results for future study design. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence of receptor targeting. Instances of single-agent activity during phase I evaluations have been well documented and a recently reported randomized phase II study indicates that co-administration of an anti-IGF-IR antibody with chemotherapy improves objective response rate and progression-free survival in non-small cell lung cancer patients. These early results support ongoing research across a broad range of cancer indications.


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Interactions between Advanced Glycation End-Products (AGE) and Their Receptors in the Development and Progression of Diabetic Nephropathy - Are These Receptors Valid Therapeutic Targets
Karly C. Sourris and Josephine M. Forbes

Diabetes is a metabolic disorder characterised by chronic hyperglycaemia, hypertension, dyslipidaemia, microalbuminuria and inflammation. Moreover, there are a number of complications associated with this condition including retinopathy, neuropathy and nephropathy. Diabetic nephropathy, is the major cause of end-stage renal disease in Western societies affecting a substantial proportion (25-40%) of patients with diabetes. Advanced glycation end products (AGEs) have been identified as important modulators of the development and progression of diabetic nephropathy, through both receptor dependant and independent interactions. AGEs elicit their receptor mediated effects via their engagement with numerous receptors and binding proteins which are broadly thought to be either inflammatory (RAGE and AGE-R2) or clearance receptors (AGE-R1, AGE-R3, CD36, Scr-II, FEEL-1 and FEEL-2). Modulation of AGE receptor expression is an important potential therapeutic approach worth consideration as a treatment for diabetic nephropathy and likely applicable to other vascular complications.


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Should Adipokines Be Considered in the Choice of the Treatment of Obesity-Related Health Problems?
Vasilios G. Athyros, Konstantinos Tziomalos, Asterios Karagiannis, Panagiotis Anagnostis, Dimitri P. Mikhailidis, Gionata Fiorino, Serena Rovida, Carmen Correale, Alberto Malesci and Silvio Danese

White adipose tissue (WAT) is an important endocrine organ that secretes approximately 30 biologically active peptides and proteins, collectively termed "adipokines". These are either produced exclusively by WAT (mainly adiponectin, leptin and resistin) or also by other tissues [e.g. tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, plasminogen activator inhibitor (PAI)-1, angiotensinogen]. Adipokines play a central role in body homeostasis including the regulation of food intake and energy balance, insulin action, lipid and glucose metabolism, angiogenesis and vascular remodelling, regulation of blood pressure and coagulation. Excess WAT, especially visceral obesity, is linked to obesity-related health problems through insulin resistance (IR) [leading to type 2 diabetes mellitus (T2DM)] and systemic lowgrade inflammation [leading to cardiovascular disease (CVD)]. The adipokines are important mediators of these adverse effects. This review describes the role of proinflammatory adipokines in the pathogenesis of IR and of the chronic inflammatory state associated with visceral obesity. Moreover, it summarises treatment options for the normalisation of adipokine levels, which might confer an additional clinical benefit in the effort to prevent or treat obesity-related T2DM and CVD.


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Antioxidant Therapy in Critically Septic Patients
S. Rinaldi, F. Landucci and A.R. De Gaudio

Critical illness and particularly sepsis are associated with a significant redox imbalance resulting from an increased production of oxidant species and a decrease in endogenous antioxidant defences. In critical patients sources of oxidative stress include the mitochondrial respiratory electron transport chain, xanthine oxidase activation, the respiratory burst associated with neutrophil activation, and arachidonic acid metabolism. Several endogenous antioxidants have been identified including enzymes, like superoxide dismutases and glutathione peroxidase, vitamins and other molecules such as uric acid and bilirubin. Recent studies pointed out the correlations between oxidative stress, systemic inflammatory response and apoptosis. Prospective randomized clinical trials regarding antioxidant therapy in critical illness provide increasing evidence in support of selenium, glutamine and omega-3 fatty acids. In particular selenium seems to improve clinical outcome in terms of infections and organ failure, glutamine has been associated with a significant reduction in infectious complications and omega-3 fatty acids could be particularly efficacious in sepsis. Melatonin is a promising molecule that deserves the attention of future research, as well as vitamin C. Further studies should also try to establish the more beneficial combination of antioxidants, as well as the doses, and the timing of administration. When such problems will be resolved hopefully results about antioxidant therapy in critical illness will be more univocal and promising.


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Targeted Therapies for Prostate Cancer against the Prostate Specific Membrane Antigen
U. Elsasser-Beile, P. Buhler and P. Wolf

Prostate cancer is the most common cancer in men from Western industrialized countries and a significant proportion of patients progress to advanced metastatic disease, for which currently no curative treatment exists. Therefore, new therapeutic approaches need to be considered. Prostate specific membrane antigen (PSMA) is an integral, non-shed type 2 membrane protein that is highly and specifically expressed on prostate epithelial cells and strongly upregulated in prostate cancer. PSMA is also present in the neovasculature of other solid tumors. These findings have spurred the development of PSMA-targeted therapies and first-generation products have entered clinical testing. The proposed strategies range from targeted toxins and radionuclides to immunotherapeutic agents. The present review provides an overview of these approaches.


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Vascular microRNAs
Angelika Bonauer, Reinier A. Boon and Stefanie Dimmeler

MicroRNAs are endogenously expressed small non-coding RNAs that regulate gene expression on the posttranscriptional level. During the last years microRNAs have emerged as key regulators of several physiological and pathophysiological processes in the vascular wall. Endothelial cell functions and angiogenesis are critically regulated by microRNAs such as miR-126 and the miR-17-92 cluster in vitro and in vivo. Tumor angiogenesis is additionally controlled by miR-296 and miR-378. MicroRNAs also regulate smooth muscle cell phenotypes and control neointima formation and atherosclerosis. In this respect, miR-143 and miR-145 have been shown to play a crucial role. In this review, we summarize the role of microRNAs and their target genes in endothelial and smooth muscle cells and discuss their applicability as drug targets.