Deciphering the scalene association among type-2 diabetes mellitus, prostate cancer, and chronic myeloid leukemia via enrichment analysis of disease-gene network.

The potential biological relationship between type-2 diabetes mellitus (T2DM) has been focused in numerous studies. To investigate the molecular associations among T2DM, prostate cancer (PCa), and chronic myeloid leukemia (CML), using a biomolecular network enrichment analysis. We obtained a list of disease-related genes and constructed disease networks. Then, GO enrichment analysis was performed to identify the significant functions and pathways of overlapping modules in the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. More than 75% of these overlapping genes were found to be consistent with the findings of previous studies. In the three diseases, we found that Sarcoglycan delta (SGCD) and Rho family GTPase 3 (RND3) were the overlapping genes and identified negative regulation of apoptotic process and negative regulation of transcription from RNA polymerase II promoter RNA as the two overlapping biological functions. CML and PCa were the most closely related, with 34 overlapping genes, five overlapping modules, 27 overlapping biological functions, and nine overlapping pathways. There were 13 overlapping genes, one overlapping modules, four overlapping biological functions and one overlapping pathway (FoxO signaling pathway) were found in T2DM and CML.And T2DM and PCa were the least related pair in our study, with only six overlapping genes, five overlapping modules, and one overlapping biological function. SGCD and RND3 were the main gene-to-gene relationship among T2DM, CML, and PCa; apoptosis, development, and transcription from RNA polymerase II promote processes were the main functional connections among T2DM, CML, and PCa by network enrichment analysis. There is a "scalene" relationship among T2DM, CML, and PCa at gene, pathway, biological process, and module levels: CML and PCa were the most closely related, the second were T2DM and PCa, and T2DM and PCa were the least related pair in our study. Our study provides a new avenue for further studies on T2DM and cancers, which may promote the discovery and development of novel therapeutic and can be used to treat multiple diseases.

Entropy-based divergent and convergent modular pattern reveals additive and synergistic anticerebral ischemia mechanisms.

Module-based network analysis of diverse pharmacological mechanisms is critical to systematically understand combination therapies and disease outcomes. We first constructed drug-target ischemic networks in baicalin, jasminoidin, ursodeoxycholic acid, and their combinations baicalin and jasminoidin as well as jasminoidin and ursodeoxycholic acid groups and identified modules using the entropy-based clustering algorithm. The modules 11, 7, 4, 8 and 3 were identified as baicalin, jasminoidin, ursodeoxycholic acid, baicalin and jasminoidin and jasminoidin and ursodeoxycholic acid-emerged responsive modules, while 12, 8, 15, 17 and 9 were identified as disappeared responsive modules based on variation of topological similarity, respectively. No overlapping differential biological processes were enriched between baicalin and jasminoidin and jasminoidin and ursodeoxycholic acid pure emerged responsive modules, but two were enriched by their co-disappeared responsive modules including nucleotide-excision repair and epithelial structure maintenance. We found an additive effect of baicalin and jasminoidin in a divergent pattern and a synergistic effect of jasminoidin and ursodeoxycholic acid in a convergent pattern on "central hit strategy" of regulating inflammation against cerebral ischemia. The proposed module-based approach may provide us a holistic view to understand multiple pharmacological mechanisms associated with differential phenotypes from the standpoint of modular pharmacology.

Crosstalk between miRNAs and their regulated genes network in stroke.

In recent years, more and more studies focus on the roles of genes or miRNAs in stroke. However, the molecular mechanism connecting miRNAs and their targetgenes remains unclear. The aim of this study was to determine the differential regulation and correlations between miRNAs and their targetgenes in human stroke. Stroke-related miRNAs were obtained from the Human MicroRNA Disease Database (HMDD) and their targetgenes were generated from three independent sources. Kappa score was used to create the network and the functional modules. A total of 11 stroke-related miRNAs were identified from the HMDD and 441 overlapping targetgenes were extracted from the three databases. By network construction and GO analysis, 13 functional modules, 186 biological processes, and 21 pathways were found in the network, of which functional module 8 was the largest module, cellular-related process and phosphate-related process were the most important biological processes, and MAPK signaling pathway was the most significant pathway. In our study, all miRNAs regulate the stroke modular network by their targetgenes. After the validation of miRNAs, we found that miR-605 and miR-181d were highly expressed in the blood of stroke patients which never reported before may supply novel target for treatment.

In vitro experiment of allergic reactions induced by traditional Chinese medicine injections.

Allergic reactions caused by traditional Chinese medicine injections (TCMIs) become a greatest concern in the clinic application safety. The integral animal evaluation method commonly used in the preclinical evaluation for allergic reactions of TCMIs was not sensitive, specific, quick and objective in observation indexes. Therefore, more researchers have paid attention to the in vitro test method for evaluating allergic reactions induced by TCMIs. Currently, the methods for evaluating allergic reactions induced by TCMIs are mainly targeted at type I allergic reaction and anaphylactic reaction, with only a few in vitro methods for evaluating type II allergic reaction. In this paper, researchers summarized relevant literatures published about evaluation methods for allergic reactions induced by TCMIs in recent years.

Anti-tumor activities of active ingredients in Compound Kushen Injection.

Kushen (Radix Sophorae Flavescentis) has a long history of use for the treatment of tumors, inflammation and other diseases in traditional Chinese medicine. Compound Kushen Injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling (Rhizoma Smilacis Glabrae). The main principles of CKI are matrine (MT) and oxymatrine (OMT) that exhibit a variety of pharmacological activities, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrotic and cardiovascular protective effects. Recent evidence shows that these compounds also produce anti-cancer actions, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- and/or radiotherapy-induced toxicity when combined with chemotherapeutic drugs. In this review, we summarize recent progress in studying the anti-cancer activities of MT, OMT and CKI and their potential molecular targets, which provide clues and references for further study.

Sedative and hypnotic activity of N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2), an adenosine analog.

N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is an N(6)-substitued adenosine analog. Previous studies have shown that B2 binds to the adenosine A1 and A2A receptors with moderate affinity and produces protective effects on serum deprivation-induced cell damage. However, central nervous system effects of B2 have not been studied. We aimed to investigate the sedative and hypnotic effects and the mechanism of action of B2 in mice. Our behavioral studies showed that oral administration of B2 decreased spontaneous locomotor activity and potentiated the hypnotic effect of pentobarbital in mice. Sleep architecture analyses revealed that B2 decreased wakefulness and increased non-rapid eye movement (NREM) sleep in both normal mice and mice with caffeine-induced insomnia. Using immunohistochemistry, we showed that B2 increased c-Fos expression, a cellular marker for neuronal activity, in the ventrolateral preoptic (VLPO) area, a sleep center in the anterior hypothalamus. Altogether, these results indicate that oral administration of B2 produces sedative and hypnotic effects. Furthermore, the activation of VLPO neurons may be involved in the central depressant effects of B2.

Anticonvulsant activity of B2, an adenosine analog, on chemical convulsant-induced seizures.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N (6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is a N(6)-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP), pentylenetetrazol (PTZ), picrotoxin, kainite acid (KA), or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A1 and A2A receptors. Furthermore, DPCPX, a selective A1 receptor antagonist, but not SCH58261, a selective A2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy.

NHBA isolated from Gastrodia elata exerts sedative and hypnotic effects in sodium pentobarbital-treated mice.

The rhizomes of Gastrodia elata have been used for the treatment of insomnia in oriental countries. N6-(4-hydroxybenzyl) adenine riboside (NHBA) was originally isolated from G. elata. For the first time we report a detailed study on the effects and mechanisms of NHBA on its sedative and hypnotic activity. Adenosine, an endogenous sleep factor, regulates sleep-wake cycle via interacting with adenosine A1/A(2A) receptors. Using radioligand binding studies and cAMP accumulation assays, our results show that NHBA may be a functional ligand for the adenosine A1 and A(2A) receptors. NHBA significantly decreases spontaneous locomotor activity and potentiates the hypnotic effect of sodium pentobarbital in mice. Sleep architecture analyses reveal that NHBA significantly decreases wakefulness time and increases NREM sleep times. However, NHBA does not affect the amount of REM sleep. Pretreatment with the adenosine A1 receptor antagonist DPCPX or the A(2A) receptor antagonist SCH 58261 significantly reverses the increase in sleeping time induced by NHBA in sodium pentobarbital treated mice. Immunohistochemical studies show that NHBA increases c-Fos expression in GABAergic neurons of the ventrolateral preoptic area (VLPO), which suggests that NHBA activates the sleep center in the anterior hypothalamus. Altogether, these results indicate that NHBA produces significant sedative and hypnotic effects. Such effects might be mediated by the activation of adenosine A1/A(2A) receptors and stimulation of the sleep center VLPO.

A natural squamosamide derivative FLZ inhibits homocysteine-induced rat brain microvascular endothelial cells dysfunction.

Hyperhomocysteinemia is believed to induce endothelial dysfunction, which is an independent risk factor for atherosclerosis and vascular diseases. Compound FLZ is a novel synthetic squamosamide cyclic analog with several phenolic hydroxy groups, and exhibits strong anti-oxidative and neuroprotective activities in Alzheimer's and Parkinson's models. In the present study, we examined the actions of FLZ against homocysteine-induced injury to primary cultured rat brain microvascular endothelial cell (rBMECs). Cell survival was measured by MTT assay. Cell nuclei were observed by Hoechst 33342 staining. Senescent cells were detected by senescence-associated ß-galactosidase (SA-ß-gal) staining. Reactive oxygen species (ROS) were measured by 2',7'-dichlorofluorescein (DCF) fluorescent microscopy. Homocysteine-induced expression of NF-κB, p53, Noxa and Fas, and the release of mitochondrial cytochrome c, were measured by Western blotting. We found that FLZ treatment antagonized homocysteine-induced cell death and apoptosis and increased numbers of senescent cells. These changes were correlated with decreased ROS accumulation. FLZ treatment inhibited activation of NF-κB, the upregulation of p53, Noxa, and Fas, and blocked mitochondrial cytochrome c release. These data suggest that FLZ has a protective action against homocysteine-induced toxicity in rBMECs, suggesting that FLZ may have therapeutic potential for the prevention of cardiovascular diseases.

[Protective effect of new adenosine analog B2 against serum deprivation-induced PC12 cell injury].

This study is to investigate the effect of compound B2 on the damage of PC12 cells induced by serum deprivation and to explore its related mechanisms. The binding characteristics of B2 to rat striatum adenosine A2A receptor was studied by radioligand 3H-MSX-2 binding assay. Cell viability was detected by MTT assay. ROS formation was measured after DCFDA fluorescent staining. B2 has affinity to rat adenosine A2A receptor (K1 = 0.37 micromol x L(-1)). B2 remarkably increased PC12 cell survival rate in serum deprivation-induced PC12 cells. The percentage of serum deprivation-induced death of PC12 was 49.6%, and the treatment of B2 (0.1-100 micromol x L(-1)) increased the cell viability to 63.3%, 74.9%, 86.3% and 88.1%, respectively. Adenosine A2A receptor antagonist SCH 58261 could significantly block the protective effect of B2. The cell viability with 0.1 micromol x L(-1) SCH 58261 decreased by 16.1%, 24.0% and 19.8%, in the presence of B2 (0.1-10 micromol x L(-1)). Serum deprivation-induced ROS formation was 3.5 times more than that of control group, and treatment with B2 significantly and dose-dependently inhibited ROS over-formation. The protective effect of B2 may be related with adenosine A2A receptor. Decrease of serum-deprivation induced ROS formation may also be one of the mechanisms.