scholarly journals MiRNA therapeutics based on logic circuits of biological pathways

2019 ◽  
Vol 20 (S9) ◽  
Author(s):  
Valeria Boscaino ◽  
Antonino Fiannaca ◽  
Laura La Paglia ◽  
Massimo La Rosa ◽  
Riccardo Rizzo ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Circuit Simulation ◽  
Logic Gates ◽  
Digital Circuit ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Therapy Design ◽  
Mirna Therapeutics

Abstract Background In silico experiments, with the aid of computer simulation, speed up the process of in vitro or in vivo experiments. Cancer therapy design is often based on signalling pathway. MicroRNAs (miRNA) are small non-coding RNA molecules. In several kinds of diseases, including cancer, hepatitis and cardiovascular diseases, they are often deregulated, acting as oncogenes or tumor suppressors. miRNA therapeutics is based on two main kinds of molecules injection: miRNA mimics, which consists of injection of molecules that mimic the targeted miRNA, and antagomiR, which consists of injection of molecules inhibiting the targeted miRNA. Nowadays, the research is focused on miRNA therapeutics. This paper addresses cancer related signalling pathways to investigate miRNA therapeutics. Results In order to prove our approach, we present two different case studies: non-small cell lung cancer and melanoma. KEGG signalling pathways are modelled by a digital circuit. A logic value of 1 is linked to the expression of the corresponding gene. A logic value of 0 is linked to the absence (not expressed) gene. All possible relationships provided by a signalling pathway are modelled by logic gates. Mutations, derived according to the literature, are introduced and modelled as well. The modelling approach and analysis are widely discussed within the paper. MiRNA therapeutics is investigated by the digital circuit analysis. The most effective miRNA and combination of miRNAs, in terms of reduction of pathogenic conditions, are obtained. A discussion of obtained results in comparison with literature data is provided. Results are confirmed by existing data. Conclusions The proposed study is based on drug discovery and miRNA therapeutics and uses a digital circuit simulation of a cancer pathway. Using this simulation, the most effective combination of drugs and miRNAs for mutated cancer therapy design are obtained and these results were validated by the literature. The proposed modelling and analysis approach can be applied to each human disease, starting from the corresponding signalling pathway.

Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoA–Rho kinase and Akt signalling pathways in rats

2012 ◽  
Vol 90 (11) ◽  
pp. 1506-1515 ◽  
Author(s):  
Han-Ming Wang ◽  
Yun Wang ◽  
Ming Liu ◽  
Yang Bai ◽  
Xin-Hua Zhang ◽  
...  
Keyword(s):  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Small Gtpase ◽  
Signalling Pathway ◽  
Selective Serotonin ◽  
Signalling Pathways ◽  
Arterial Remodeling ◽  
Pulmonary Arterial

Activation of the small GTPase Ras homolog gene family member A (RhoA) and Rho-associated kinase (ROCK) are important in the pathogenesis of pulmonary arterial hypertension (PAH). Selective serotonin reuptake inhibitors inhibit activation of RhoA and ROCK in vitro, and ameliorate PAH and pulmonary arterial remodeling in vivo. However, little is known about whether the RhoA–ROCK signalling pathway is involved in the treatment of PAH with fluoxetine in vivo. The aim of the present study was to investigate the involvement of the RhoA–ROCK signalling pathway in the protective effect of the selective serotonin reuptake inhibitor fluoxetine against monocrotaline (MCT)-induced pulmonary arterial remodeling. MCT was applied to establish PAH in male Wistar rats. Fluoxetine was administered by gastric gavage once a day for 21 d. The results showed that MCT induced pulmonary arterial remodeling, raised the serotonylation and membrane translocation of RhoA in the lungs, and increased serotonin transporter (5-HTT), RhoA, and ROCK2 expression, and extracellular signal-regulated kinase (ERK) and Akt phosphorylation in the pulmonary arteries and the lungs. Fluoxetine markedly inhibited these MCT-induced changes. The findings suggest that fluoxetine inhibits MCT-induced pulmonary arterial remodeling in rats by inhibition of the RhoA–ROCK and Akt signalling pathways.

scholarly journals An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marisa Nacke ◽  
Emma Sandilands ◽  
Konstantina Nikolatou ◽  
Álvaro Román-Fernández ◽  
Susan Mason ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Cellular Responses ◽  
Signalling Pathways ◽  
External Signal ◽  
Phosphoinositide Metabolism ◽  
Invasion And Metastasis ◽  
3 Dimensional

AbstractThe signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.

scholarly journals Tumour-derived exosomal lncRNA-SOX2OT promotes bone metastasis of non-small cell lung cancer by targeting the miRNA-194-5p/RAC1 signalling axis in osteoclasts

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jianjiao Ni ◽  
Xiaofei Zhang ◽  
Juan Li ◽  
Zhiqin Zheng ◽  
Junhua Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Osteoclast Differentiation ◽  
Small Cell ◽  
Signalling Pathway ◽  
Small Cell Lung

AbstractBone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.

scholarly journals The Role of Herbal Bioactive Components in Mitochondria Function and Cancer Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Fangfang Tao ◽  
Yanrong Zhang ◽  
Zhiqian Zhang
Keyword(s):  
Cancer Therapy ◽  
Cancer Cell ◽  
Apoptotic Cell ◽  
Redox Status ◽  
Cancer Therapies ◽  
Bioactive Components ◽  
Atp Production

Mitochondria are highly dynamic double-membrane organelles which play a well-recognized role in ATP production, calcium homeostasis, oxidation-reduction (redox) status, apoptotic cell death, and inflammation. Dysfunction of mitochondria has long been observed in a number of human diseases, including cancer. Targeting mitochondria metabolism in tumors as a cancer therapeutic strategy has attracted much attention for researchers in recent years due to the essential role of mitochondria in cancer cell growth, apoptosis, and progression. On the other hand, a series of studies have indicated that traditional medicinal herbs, including traditional Chinese medicines (TCM), exert their potential anticancer effects as an effective adjunct treatment for alleviating the systemic side effects of conventional cancer therapies, for reducing the risk of recurrence and cancer mortality and for improving the quality of patients’ life. An amazing feature of these structurally diverse bioactive components is that majority of them target mitochondria to provoke cancer cell-specific death program. The aim of this review is to summarize the in vitro and in vivo studies about the role of these herbs, especially their bioactive compounds in the modulation of the disturbed mitochondrial function for cancer therapy.

A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade

2012 ◽  
Vol 123 (3) ◽  
pp. 147-159 ◽  
Author(s):  
Ting-Hsing Chao ◽  
Shih-Ya Tseng ◽  
Yi-Heng Li ◽  
Ping-Yen Liu ◽  
Chung-Lung Cho ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
No Production ◽  
Angiogenic Effect

Cilostazol is an anti-platelet agent with vasodilatory activity that acts by increasing intracellular concentrations of cAMP. Recent reports have suggested that cilostazol may promote angiogenesis. In the present study, we have investigated the effect of cilostazol in promoting angiogenesis and vasculogenesis in a hindlimb ischaemia model and have also examined its potential mechanism of action in vitro and in vivo. We found that cilostazol treatment significantly increased colony formation by human early EPCs (endothelial progenitor cells) through a mechanism involving the activation of cAMP/PKA (protein kinase A), PI3K (phosphoinositide 3-kinase)/Akt/eNOS (endothelial NO synthase) and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) signalling pathways. Cilostazol also enhanced proliferation, chemotaxis, NO production and vascular tube formation in HUVECs (human umbilical vein endothelial cells) through activation of multiple signalling pathways downstream of PI3K/Akt/eNOS. Cilostazol up-regulated VEGF (vascular endothelial growth factor)-A165 expression and secretion of VEGF-A in HUVECs through activation of the PI3K/Akt/eNOS pathway. In a mouse hindlimb ischaemia model, recovery of blood flow ratio (ipsilateral/contralateral) 14 days after surgery was significantly improved in cilostazol-treated mice (10 mg/kg of body weight) compared with vehicle-treated controls (0.63±0.07 and 0.43±0.05 respectively, P<0.05). Circulating CD34+ cells were also increased in cilostazol-treated mice (3614±670 compared with 2151±608 cells/ml, P<0.05). Expression of VEGF and phosphorylation of PI3K/Akt/eNOS and ERK/p38 MAPK in ischaemic muscles were significantly enhanced by cilostazol. Our data suggest that cilostazol produces a vasculo-angiogenic effect by up-regulating a broad signalling network that includes the ERK/p38 MAPK, VEGF-A165, PI3K/Akt/eNOS and cAMP/PKA pathways.

scholarly journals Protective Effect of Phillyrin on Lethal LPS-Induced Neutrophil Inflammation in Zebrafish

2017 ◽  
Vol 43 (5) ◽  
pp. 2074-2087 ◽  
Author(s):  
Liling Yang ◽  
Xiangjun Zhou ◽  
Weijuan Huang ◽  
Qin Fang ◽  
Jianlan Hu ◽  
...  
Keyword(s):  
Signalling Pathway ◽  
Dependent Manner ◽  
Zebrafish Model ◽  
Lps Challenge ◽  
Cell Counts ◽  
Tnf Α ◽  
Forsythia Suspensa ◽  
Anti Inflammatory

Background/Aims: Forsythia suspensa Vahl. (Oleaceae) fruits are widely used in traditional Chinese medicine to treat pneumonia, typhoid, dysentery, ulcers and oedema. Antibacterial and anti-inflammatory activities have been reported for phillyrin (PHN), the main ingredient in Forsythia suspensa Vahl fruits, in vitro. However, the underlying mechanisms in vivo remain poorly defined. In this study, we discovered that PHN exerted potent anti-inflammatory effects in lethal LPS-induced neutrophil inflammation by suppressing the MyD88-dependent signalling pathway in zebrafish. Methods: LPS-yolk microinjection was used to induce a lethal LPS-infected zebrafish model. The effect of PHN on the survival of zebrafish challenged with lethal LPS was evaluated using survival analysis. The effect of PHN on neutrophil inflammation grading in vivo was assessed by tracking neutrophils with a transgenic line. The effects of PHN on neutrophil production and migration were analysed by SB+ cell counts during consecutive hours after modelling. Additionally, key cytokines and members of the MyD88 signalling pathway that are involved in inflammatory response were detected using quantitative RT-PCR. To assess gene expression changes during consecutive hours after modelling, the IL-1β, IL-6, TNF-α, MyD88, TRIF, ERK1/2, JNK, IκBa and NF-κB expression levels were measured. Results: PHN could protect zebrafish against a lethal LPS challenge in a dose-dependent manner, as indicated by decreased neutrophil infltration, reduced tissue necrosis and increased survival rates. Up-regulated IL-1β, IL-6 and TNF-α expression also showed the same tendencies of depression by PHN. Critically, PHN significantly inhibited the LPS-induced activation of MyD88, IκBa, and NF-κB but did not affect the expression of ERK1/2 MAPKs or JNK MAPKs in LPS-stimulated zebrafish. Additionally, PHN regulated the MyD88/IκBα/NF-κB signalling pathway by controlling IκBα, IL-1β, IL-6, and TNF-α expression. Conclusion: This study provides a rationale for the clinical application of PHN as an anti-inflammatory agent.

scholarly journals Folate-Functionalized Mesoporous Hollow SnO2 Nanofibers as a Targeting Drug Carrier to Improve the Antitumor Effect of Paclitaxel for Liver Cancer Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-11
Author(s):  
Huiling Lv ◽  
Chao Wu ◽  
Xuan Liu ◽  
Andi Bai ◽  
Yue Cao ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Liver Cancer ◽  
Drug Carrier ◽  
In Vitro Release ◽  
Hollow Structure ◽  
Amorphous State ◽  
Outer Diameter ◽  
Drug Delivery Carrier

In this study, we prepared PTX-loaded mesoporous hollow SnO2 nanofibers conjugated with folic acid (SFNFP) for liver cancer therapy. According to SEM and TEM characterization, SFNF showed a mesoporous hollow structure. The average outer diameter was 200 nm, and the wall thickness was 50 nm. The DSC and XRD study showed that PTX in the channels of nanofibers was present in an amorphous state. The in vitro release experiments demonstrated that SFNF could efficiently improve the dissolution rate of PTX. Both in vitro cell experiments and in vivo antitumor experiments showed that SFNFP could efficiently inhibit the growth of liver cancer cells. Therefore, SFNF is a promising targeting antitumor drug delivery carrier.

Sign in / Sign up

Export Citation Format

Share Document