A network based approach to drug repositioning identifies candidates for breast cancer and prostate cancer

The high cost and the long time required to bring drugs into commerce is driving efforts to repurpose FDA approved drugs—to find new uses for which they weren’t intended, and to thereby reduce the overall cost of commercialization, and shorten the lag between drug discovery and availability. In comparison to traditional drug repositioning, which relies on serendipitous clinical discoveries, computational methods can systemize the drug search and facilitate the drug development timeline even further. In this dissertation, I report on the development, testing and application of a promising new approach to drug repositioning. This novel computational drug repositioning method is based on mining a human functional linkage network for inversely correlated modules of drug and disease gene targets. Functional linkage network is an evidence-weighted network that provides a quantitative measure of the degree of functional association among any set of human genes. The method takes account of multiple information sources, including gene mutation, gene expression, and functional connectivity and proximity of within module genes. The method was used to identify candidates for treating breast and prostate cancer. We found that (i) the recall rate for FDA approved drugs for breast and (prostate) cancer is 20/20 (10/11), while the rates for drugs in clinical trials were 131/154 and (82/106); (ii) the Area Under the ROC Curve performance substantially exceeds that of two comparable previously published methods; (iii) preliminary in vitro studies indicate that 5/5 identified breast cancer candidates have therapeutic indices superior to that of Doxorubicin in Luminal-A (MCF7) and Triple-Negative (SUM149) breast cancer cell lines. I briefly discuss the biological plausibility of the candidates at a molecular level in the context of the biological processes that they mediate. In conclusion, our method provides a unique way of prioritizing disease causal genes and identifying drug candidates for repositioning, based on innovative computational method. The method appears to offer promise for the identification of multi-targeted drug candidates that can correct aberrant cellular functions. In particular the computational performance exceeded that of existing computational methods. The approach has the potential to provide a more efficient drug discovery pipeline

Polythiophenes comprising conjugated pendantstoward long-term air-stable inverted polymer solar cellswith high open circuit voltages

A series of polythiophenes (PTs) functionalized with bulky conjugated side chains comprising tert-butylsubstituted carbazole (tCz) as an electron donor pendant and bisbenzothiazolylvinyl (DBT) as anelectron acceptor pendant were synthesized via Stille copolymerization for polymer solar cell (PSC)applications. We use the descriptors PTtCz, PT(tCz)0.9(DBT)0.1, PT(tCz)0.64(DBT)0.36, PT(tCz)0.45(DBT)0.55,and PTDBT to identify each of these conjugated polymers, with the names denoting the compositionsof the bulky pendants. The tunable energy levels of the PTs were accomplished by incorporating bothtCz as a donor pendant and DBT as an acceptor pendant, while retaining the low-lying HOMO levels( 5.26 to 5.39 eV). Furthermore, lower bandgaps were observed for the DBT-derived PTs because ofstronger donor–p–acceptor characteristics and more efficient intramolecular charge transfer.Conventional PSCs were fabricated by spin-coating the blend of each PT and the fullerene derivative(PC71BM). The conventional PSC devices exhibited high open circuit voltages (Voc) of around 0.79–0.91 V. The power conversion efficiency (PCE) of the PSCs based on PTtCz : PC71BM (w/w ¼ 1 : 2.5)reached 2.48% with a Voc of 0.91 V, short circuit current (Jsc) of 6.58 (mA cm 2) and fill factor (FF) of41% under the illumination of AM1.5, 100 mW cm 2. Furthermore, a PTtCz/PC71BM-based inverted PSCwith ZnOx and MoO3 as an electron extraction layer and a hole extraction layer respectively was capableof retaining ca. 80% of its original efficiency after storage under ambient conditions (withoutencapsulation) for 1032 h, according to the ISOS-D-1 shelf protocol. The highly durable inverted PSCaccompanied by a large Voc value was achieved for the PT-type polymers

Ellagic Acid, the Active Compound of Phyllanthus urinaria, Exerts In Vivo Anti-Angiogenic Effect and Inhibits MMP-2 Activity

This study aimed to assess the potential anti-angiogenic mechanism of Phyllanthus urinaria (P. urinaria) and characterize the major compound in P. urinaria that exerts anti-angiogenic effect. The water extract of P. urinaria and Ellagic Acid were used to evaluate the anti-angiogenic effect in chorioallantoic membrane (CAM) in chicken embryo and human vascular endothelial cells (HUVECs). The matrix metalloproteinase-2 (MMP-2) activity was determined by gelatin zymography. The mRNA expressions of MMP-2, MMP-14 and tissue inhibitor of metalloproteinase-2 (TIMP-2) were analyzed by reverse transcription polymerase chain reaction (RT-PCR). Level of MMP-2 proteins in conditioned medium or cytosol was determined by western blot analysis. We confirmed that P. urinaria's in vivo anti-angiogenic effect was associated with a reduction in MMP-2 activity. Ellagic acid, one of the major polyphenolic components as identified in P. urinaria by high performance liquid chromatography mass spectrometry (HPLC/MS), exhibited the same anti-angiogenic effect in vivo. Both P. urinaria and Ellagic Acid inhibited MMP-2 activity in HUVECs with unchanged mRNA level. The mRNA expression levels of MMP-14 and TIMP-2 were not altered either. Results from comparing the change of MMP-2 protein levels in conditioned medium and cytosol of HUVECs after the P. urinaria or Ellagic Acid treatment revealed an inhibitory effect on the secretion of MMP-2 protein. This study concluded that Ellagic Acid is the active compound in P. urinaria to exhibit anti-angiogenic activity and to inhibit the secretion of MMP-2 protein from HUVECs

Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats

Puerarin, a major isoflavonoid derived from the Chinese medical herb Radix puerariae (kudzu root), has been reported to be useful in the treatment of various cardiovascular diseases. In the present study, we examined the detailed mechanisms underlying the inhibitory effects of puerarin on inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAO) in rats. Treatment of puerarin (25 and 50 mg/kg; intraperitoneally) 10 min before MCAO dose-dependently attenuated focal cerebral ischemia in rats. Administration of puerarin at 50 mg/kg, showed marked reduction in infarct size compared with that of control rats. MCAO-induced focal cerebral ischemia was associated with increases in hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), and active caspase-3 protein expressions as well as the mRNA expression of tumor necrosis factor-α (TNF-α) in ischemic regions. These expressions were markedly inhibited by the treatment of puerarin (50 mg/kg). In addition, puerarin (10~50 μM) concentration-dependently inhibited respiratory bursts in human neutrophils stimulated by formyl-Met-Leu-Phe. On the other hand, puerarin (20~500 μM) did not significantly inhibit the thiobarbituric acid-reactive substance reaction in rat brain homogenates. An electron spin resonance (ESR) method was conducted on the scavenging activity of puerarin on the free radicals formed. Puerarin (200 and 500 μM) did not reduce the ESR signal intensity of hydroxyl radical formation. In conclusion, we demonstrate that puerarin is a potent neuroprotective agent on MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both HIF-1α and TNF-α activation, followed by the inhibition of inflammatory responses (i.e., iNOS expression), apoptosis formation (active caspase-3), and neutrophil activation, resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, puerarin treatment may represent a novel approach to lowering the risk of or improving function in ischemia-reperfusion brain injury-related disorders

Cyclic nucleotides and mitogen-activated protein kinases: regulation of simvastatin in platelet activation

<p>Abstract</p> <p>Background</p> <p>3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been widely used to reduce cardiovascular risk. These statins (i.e., simvastatin) may exert other effects besides from their cholesterol-lowering actions, including inhibition of platelet activation. Platelet activation is relevant to a variety of coronary heart diseases. Although the inhibitory effect of simvastatin in platelet activation has been studied; the detailed signal transductions by which simvastatin inhibit platelet activation has not yet been completely resolved.</p> <p>Methods</p> <p>The aim of this study was to systematically examine the detailed mechanisms of simvastatin in preventing platelet activation. Platelet aggregation, flow cytometric analysis, immunoblotting, and electron spin resonance studies were used to assess the antiplatelet activity of simvastatin.</p> <p>Results</p> <p>Simvastatin (20-50 μM) exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin). Simvastatin inhibited collagen-stimulated platelet activation accompanied by [Ca²⁺]i mobilization, thromboxane A₂(TxA₂) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinases (i.e., p38 MAPK, JNKs) phosphorylation in washed platelets. Simvastatin obviously increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly increased NO release, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and endothelial nitric oxide synthase (eNOS) expression. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the simvastatin-mediated inhibitory effects on platelet aggregation, PLCγ2 and p38 MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP and eNOS phosphorylation.</p> <p>Conclusion</p> <p>The most important findings of this study demonstrate for the first time that inhibitory effect of simvastatin in platelet activation may involve activation of the cyclic AMP-eNOS/NO-cyclic GMP pathway, resulting in inhibition of the PLCγ2-PKC-p38 MAPK-TxA₂cascade, and finally inhibition of platelet aggregation.</p