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network pharmacology

Zhi-Dan Fan, Ya-Yuan Zhang, Yi-Hong Guo, Na Huang, Hui-Hui Ma, Hui Huang, Hai-Guo Yu
Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA). The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells. This study investigates the in vitro and in vivo effects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model. In CII-treated dendritic cells (DCs) and DC/CD4(+) T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1β, TGF-β1, IL-23p19 and IL-6)...
October 24, 2016: Scientific Reports
Pedro Casado, Maruan Hijazi, David Britton, Pedro R Cutillas
Signalling pathways driven by protein and lipid kinases are altered in most human diseases. Therefore, pharmacological inhibitors of cell signalling are one of the most intensively pursued therapeutic approaches for the treatment of diseases such as cancer, neurodegeneration and metabolic syndromes. Phosphoproteomics is a technique that measures the products of kinase activities and, with the appropriate bioinformatics techniques, the methodology can also provide measures of kinase pathway activation and network circuitry...
October 24, 2016: Proteomics
Sherie Ma, Craig M Smith, Anna Blasiak, Andrew L Gundlach
Relaxin-3 is a member of a superfamily of structurally-related peptides that includes relaxin and insulin-like peptide hormones. Soon after the discovery of the relaxin-3 gene, relaxin-3 was identified as an abundant neuropeptide in brain with a distinctive topographical distribution within a small number of GABA neuron populations that is well conserved across species. Relaxin-3 is thought to exert its biological actions through a single class-A GPCR - relaxin-family peptide receptor 3 (RXFP3). Class-A comprises GPCRs for relaxin-3 and insulin-like peptide-5 and other peptides such as orexin and the monoamine transmitters...
October 23, 2016: British Journal of Pharmacology
Maria Elena Giusepponi, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura, Laura Mattioli, Alan Hudson, Eleonora Diamanti, Fabio Del Bello, Mario Giannella, Valerio Mammoli, Corinne Dalila Paoletti, Alessandro Piergentili, Maria Pigini, Wilma Quaglia
Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including α2-adrenoceptors (α2-ARs) and I1- and I2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including α2-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I1-/I2-IBS or I1-/I2-IBS/α2-ARs...
October 13, 2016: ACS Medicinal Chemistry Letters
Junji Itou, Sunao Tanaka, Wenzhao Li, Atsuo Iida, Atsuko Sehara-Fujisawa, Fumiaki Sato, Masakazu Toi
During metastasis, cancer cell migration is enhanced. However, the mechanisms underlying this process remain elusive. Here, we addressed this issue by functionally analyzing the transcription factor Sal-like 4 (SALL4) in basal-like breast cancer cells. Loss-of-function studies of SALL4 showed that this transcription factor is required for the spindle-shaped morphology and the enhanced migration of cancer cells. SALL4 also up-regulated integrin gene expression. The impaired cell migration observed in SALL4 knockdown cells was restored by overexpression of integrin α6 and β1...
October 20, 2016: Biochimica et Biophysica Acta
Alejandro R Chade, John E Hall
Obesity is largely responsible for the growing incidence and prevalence of diabetes, cardiovascular and renal diseases. Current strategies to prevent and treat obesity and its consequences have been insufficient to reverse the ongoing trends. Lifestyle modification or pharmacological therapies often produce modest weight loss which is not sustained and recurrence of obesity is frequently observed, leading to progression of target organ damage in many obese subjects. Therefore, research efforts have focused not only on the factors that regulate energy balance, but also on understanding mechanisms of target organ injury in obesity...
October 22, 2016: American Journal of Nephrology
Pan Li, Bin Lv, Xiaoqing Jiang, Ting Wang, Xianghui Ma, Nianwei Chang, Xiaoying Wang, Xiumei Gao
ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu injection (SFI) is a commercial medicinal product approved by the China Food and Drug Administration that is widely used in the treatment of stroke and coronary heart disease. However, the material basis and the mechanism of SFI are not fully understood. AIM OF THE STUDY: With network pharmacology analysis, our research committed to identify the anti-inflammatory ingredients and mechanism of SFI by combining high-throughput screening...
October 19, 2016: Journal of Ethnopharmacology
Carolina Anazco, Alberto J Lopez-Jimenez, Mohamed Rafi, Lorenzo Vega-Montoto, Ming-Zhi Zhang, Billy G Hudson, Roberto M Vanacore
The 7S dodecamer is recognized as an important structural crosslinking domain of collagen IV networks that provide mechanical stability to basement membranes, a specialized form of extracellular matrix essential for the development and maintenance of tissue architecture. Although the 7S dodecamer is stabilized by covalent crosslinking, the molecular mechanism by which such crosslinks are formed has not been revealed. Here we aimed to identify the enzyme(s) that crosslinks the 7S dodecamer and characterize its expression in the kidney glomerulus...
October 21, 2016: Journal of Biological Chemistry
Francisca Sanchez-Jiménez, Almudena Pino-Ángeles, Rocio Rodríguez-López, María Morales, José Luis Urdiales
Human histidine decarboxylase (HDC) and dopa decarboxilase (DDC) are highly homologous enzymes responsible for the synthesis of biogenic amines (BA) like histamine, and serotonin and dopamine, respectively. The enzymes share many structural and functional analogies, while their product metabolisms also follow similar patterns that are confluent in some metabolic steps. They are involved in common physiological functions, such as neurotransmission, gastrointestinal track function, immunity, cell growth and cell differentiation...
October 18, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Sanna Rönkä, Anu Katainen
BACKGROUND: The non-medical use of prescription drugs is a growing phenomenon associated with increasing health-related harms. However, little is known about the drivers of this process among illicit drug users. Our aim is to show how the qualities of pharmaceutical drugs, pharmaceutical related knowledge, online communities sharing this knowledge and medical professionals mediate and transform the consumption behaviour related to pharmaceutical drugs. METHODS: The data consist of discussion threads from an online drug use forum...
October 18, 2016: International Journal on Drug Policy
Britta Wandschneider, Matthias J Koepp
Functional MRI studies have helped to elucidate underlying mechanisms in complex neurological and neuropsychiatric disorders. Disease processes often involve complex large-scale network interactions, extending beyond the presumed main disease focus. Given both the complexity of the clinical phenotype and the underlying dysfunctional brain circuits, so called pharmaco-fMRI (ph-MRI) studies probe pharmacological effects on functional neuro-anatomy, and can help to determine early treatment response, mechanisms of drug efficacy and side effects, and potentially advance CNS drug development...
2016: NeuroImage: Clinical
Jillian Iafrati, Arnaud Malvache, Cecilia Gonzalez Campo, M Juliana Orejarena, Olivier Lassalle, Lamine Bouamrane, Pascale Chavis
The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice...
October 21, 2016: Scientific Reports
Yang Yang, Jiaomiao Pei, Guozhen Gao, Zheng Yang, Shuzhong Guo, Bo Yue, Jianhua Qiu
We conducted a network meta-analysis in order to compare different strategies for managing melanoma patients. Electronic databases were searched for eligible randomized trials that compared different strategies in efficacy and tolerability. Five interventions were associated with a significant improvement in PFS over chemotherapy (all HR < 1): Ipilimumab, Tremelimumab, Nivolumab, Pembrolizumab 2 mg/kg and Ipilimumab + Nivolumab. Three interventions exhibited significantly improved OS results over chemotherapy (all HR < 1): Ipilimumab, Nivolumab and Ipilimumab + Chemotherapy...
October 13, 2016: Oncotarget
Erik Richter, Manuela Harms, Katharina Ventz, Rolf Nölker, Martin J Fraunholz, Jörg Mostertz, Falko Hochgräfe
Internalization of Staphylococcus aureus by non-professional phagocytic cells is a major suspected cause of persistent and difficult-to-treat infections, including pneumonia. In this study, we established an infection model with 16HBE14o- human bronchial epithelial cells and demonstrated internalization, escape from phagosomal clearance and intracellular replication of S. aureus HG001 within the first four hours post-infection. We used quantitative phosphoproteomics to identify characteristic signaling networks in the host at different infection stages...
October 20, 2016: Journal of Proteome Research
B Li, J Liu, Y Y Zhang, P Q Wang, Y N Yu, R X Kang, H L Wu, X X Zhang, Z Wang, Y Y Wang
Module-based methods have made much progress in deconstructing biological networks. However, it is a great challenge to quantitatively compare the topological structural variations of modules (allosteric modules [AMs]) under different situations. A total of 23, 42, and 15 coexpression modules were identified in baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA) in a global anti-ischemic mice network, respectively. Then, we integrated the methods of module-based consensus ratio (MCR) and modified Zsummary module statistic to validate 12 BA, 22 JA, and 8 UA on-modules based on comparing with vehicle...
October 19, 2016: CPT: Pharmacometrics & Systems Pharmacology
Chrysanthi Fergani, Victor Navarro
Reproductive function is driven by the hormonal interplay between the gonads and brain-pituitary axis. Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner, which is critical for the attainment and maintenance of fertility, however, GnRH neurons lack the ability to directly respond to most regulatory factors, and a hierarchical upstream neuronal network governs its secretion. We and others proposed a model in which Kiss1 neurons in the arcuate nucleus (ARC), so called KNDy neurons, release kisspeptin (a potent GnRH secretagogue) in a pulsatile manner to drive GnRH pulses under the coordinated autosynaptic action of its cotransmitters, the tachykinin neurokinin B (NKB, stimulatory) and dynorphin (inhibitory)...
October 17, 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
Langdong Chen, Diya Lv, Dongyao Wang, Xiaofei Chen, Zhenyu Zhu, Yan Cao, Yifeng Chai
Herbal medicines have long been widely used in the treatment of various complex diseases in China. However, the active constituents and therapeutic mechanisms of many herbal medicines remain undefined. Therefore, the identification of the active components and target proteins in these herbal medicines is a formidable task in herbal medicine research. In this study, we proposed a strategy, which integrates network pharmacology with biomedical analysis and surface plasmon resonance (SPR) to predict the active ingredients and potential targets of herbal medicine Sophora flavescens or Kushen in Chinese, and evaluate its anti-fibrosis activity...
October 18, 2016: Molecular BioSystems
Yutaka Imai
It has been confirmed that clinical significance of home blood pressure measurements (HBPM) is higher than clinic BP measurements and ambulatory BP monitoring. However, several drawbacks of HBPM have also been mentioned, e.g. selection and reporting biases, difficulties of calculation of multiple measurements, difficulties of onsite judgement of numerous recordings, etc. Recent devices for HBPM incorporate memory function. This function can overcome such drawbacks of HBPM. These memorized data can transmit, storage, retrieve, be arithmetic and control, be judged based on algorithm and be got feedback...
September 2016: Journal of Hypertension
Masahiro Nezu, Tomokazu Souma, Lei Yu, Hiroki Sekine, Takashi Moriguchi, Nobuyuki Takahashi, Sadayoshi Ito, Norio Suzuki, Masayuki Yamamoto
OBJECTIVE: Placental activation of the renin-angiotensin system (RAS) plays an important role in pathogenesis of preeclampsia. RAS induces reactive oxygen species (ROS) production by activating NADPH oxidases. Keap1-Nrf2 system is a critical regulator for cellular anti-oxidative stress response through controlling transcription of antioxidant genes. This study has explored the relationship between RAS-induced ROS signaling and Keap1-Nrf2 system in preeclampsia. DESIGN AND METHOD: To examine the contribution of Keap1-Nrf2 system to preeclampsia pathology, we generated transgenic mouse models of preeclampsia/pregnancy-associated hypertension (PAH mice), in which RAS is activated selectively in late pregnancy, under deficient, normal or active Nrf2 conditions...
September 2016: Journal of Hypertension
Jeganathan Manivannan, Manjunath Prashanth, Venkatesan Saravana Kumar, Manickaraj Shairam, Jayachandran Subburaj
Since there is no precise therapy for treating vascular calcification by directly targeting the vascular wall, we aim to unveil novel drug targets through mining the molecular effect of a high phosphate environment on vascular cells through computational methods. Here, we hypothesize that manipulation of the vascular pathogenic network by small molecule therapeutics predicted from prior knowledge might offer great promise. With this, we intend to understand the publicly available transcriptomic data of vascular smooth muscle cells and endothelial cells exposed to the high phosphate induced vascular calcification milieu and to re-examine the above published experiments for reasons different from those examined in the previous studies through multilevel systems biological understanding...
October 18, 2016: Molecular BioSystems
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