Nature is the best source of anti-inflammatory drugs: indexing natural products for their anti-inflammatory bioactivity

Objectives

The aim was to index natural products for less expensive preventive or curative anti-inflammatory therapeutic drugs.

Materials

A set of 441 anti-inflammatory drugs representing the active domain and 2892 natural products representing the inactive domain was used to construct a predictive model for bioactivity-indexing purposes.

Method

The model for indexing the natural products for potential anti-inflammatory activity was constructed using the iterative stochastic elimination algorithm (ISE). ISE is capable of differentiating between active and inactive anti-inflammatory molecules.

Results

By applying the prediction model to a mix set of (active/inactive) substances, we managed to capture 38% of the anti-inflammatory drugs in the top 1% of the screened set of chemicals, yielding enrichment factor of 38. Ten natural products that scored highly as potential anti-inflammatory drug candidates are disclosed. Searching the PubMed revealed that only three molecules (Moupinamide, Capsaicin, and Hypaphorine) out of the ten were tested and reported as anti-inflammatory. The other seven phytochemicals await evaluation for their anti-inflammatory activity in wet lab.

Conclusion

The proposed anti-inflammatory model can be utilized for the virtual screening of large chemical databases and for indexing natural products for potential anti-inflammatory activity.

     

O^6-甲基鸟嘌呤-DNA甲基转移酶基因多态性与新疆哈萨克族食管癌易感性关系的研究

目的 为探讨O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)基因多态性与新疆哈萨克族食管癌易感性的关系. 方法 运用病例-对照研究的方法,PCR-RFLP技术检测新疆哈萨克族食管癌51例及非癌对照109例的MGMT 84C>T和MGMT 135G>T单核苷酸多态(SNPs)的基因型. 结果 MGMT 84C>T位点的三种基因型CC,CT,TT,在哈萨克族食管癌中所占比例分别为76.5%(39/51) 、17.6%(9/51) 、5.9%(3/51),对照组分别为77.0%(84/109)、18.3%(20/109)、4.6%(5/109),两组间分布差异不显著(P=0.938,P>0.05);MGMT 135G>T位点的三种基因型GG,GT,TT,在哈萨克族食管癌中所占比例分别为90.2%(46/51)、7.8%(4/51)、2.0%(1/51),对照组分别为82.6%(90/109)、16.5%(18/109)、0.9%(1/109),两组间分布差异不显著(P=0.295,P>0.05);MGMT 84C>T位点和MGMT 135G>T位点联合分析,在食管癌组0突变等位基因与1-4突变等位基因所占比例分别为68.6%(35/51)、31.4%(16/51);对照组分别为:63.3%(69/109)、36.7%(40/109),两组间分布差异也不显著(P=0.511,P>0.05). 结论 MGMT 84C>T和MGMT 135G>T SNPs与哈萨克族食管癌易感性可能无关联.     

G-protein coupled and tyrosine kinase receptors: evidence that activation of the insulin-like growth factor I receptor is required for thrombin-induced mitogenesis of rat aortic smooth muscle cells.

IGF I is an ubiquitous peptide that activates a membrane tyrosine kinase receptor and has autocrine/paracrine effects on vascular smooth muscle cells. Thrombin activates a G-protein coupled receptor and is also a mitogen for vascular smooth muscle cells. To assess the potential role of IGF I as a mediator of thrombin's effects, we characterized expression of IGF I and of its receptor on vascular smooth muscle cells exposed to thrombin. Thrombin dose-dependently decreased IGF I mRNA levels and caused a delayed decrease in IGF I secretion from vascular smooth muscle cells. This effect was mimicked by the hexapeptide SF-FLRN (that functions as a tethered ligand) and was inhibited by hirudin. In contrast, thrombin doubled IGF I receptor density on vascular smooth muscle cells, without altering binding affinity (Kd). An anti-IGF I antiserum markedly reduced thrombin-induced DNA synthesis, whereas nonimmune serum and an anti-fibroblast growth factor antibody were without effect. Cell counts confirmed these results. Downregulation of IGF I receptors by antisense phosphorothioate oligonucleotides likewise markedly inhibited thrombin-induced DNA synthesis. These data demonstrate that a functional IGF I-IGF I receptor pathway is essential for thrombin-induced mitogenic signaling and support the concept of cross talk between G-protein coupled and tyrosine kinase receptors.     

Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart.

This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ET(A)-Rs/ET(B)-Rs, at the coronary endothelium (CE) and cardiomyocyte (CM) sites. It is carried out in normal and normotensive rats with streptozotocin-induced diabetes mellitus receiving different treatment modalities. Normal rats were divided into two groups, namely a placebo (N) and a losartan-treated (NL), and diabetic rats into four groups receiving placebo (D), insulin-treated (DI), losartan-treated (DL), and insulin/losartan-treated (DIL) respectively. Binding kinetics of ET-1 to ET(A)-Rs/ET(B)-Rs on CE and CMs were assessed in the above groups to try to explain the effect of therapeutic doses of an angiotensin II receptor subtype-1 blocker on the dynamics of this ligand and its receptor in insulin supplemented diabetic animals. Each group was divided into two subgroups: CHAPS-untreated and CHAPS-treated rat hearts perfused with [125I]ET-1 to respectively estimate ET-1 binding affinity (tau = 1/k-n) to its receptor subtype(s) on CE and CMs using mathematical modeling describing a 1:1 reversible binding stoichiometry. Heart perfusion results revealed that insulin treatment significantly decreased tau on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in tau value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized tau on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ET(A)-R density in all diabetic groups. However, significant decrease in ET(B)-R density was observed in all groups compared to the normal, and was reconfirmed by immunohistochemical analysis. In conclusion, coadministration of insulin and losartan in nonhypertensive animals suffering from diabetes type 1 may offer new cardiac protection benefits by improving coronary blood flow and cardiomyocyte contractility through modulating ET-1 receptor subtypes density and affinity at CE and CM sites.     

The expression of MUC mucin in cholangiocarcinoma

Cholangiocarcinoma (CC) is a highly malignant epithelial cancer of the biliary tract, the cellular and molecular pathogenesis of which remains unclear. Malignant transformation of glandular epithelial cells is associated with the altered expression of mucin. We investigated the type of mucins expressed in CC. Twenty-six patients with histologically confirmed CC were included in this study. The expression of mucin was studied by immunohistochemistry using antibodies to MUC1, MUC1 core, MUC2, MUC3, MUC4, MUC5AC, and MUC6. There was extensive (>50%) expression of mucin, mainly MUC1 in 11/25 and MUC5AC in 12/26 cases. In the case of MUC3, 6/26 cases expressed mucin extensively, whilst only 1/26 had MUC2, MUC4, and MUC6 expression. Well-differentiated tumors significantly expressed MUC3 extensively compared to poor or moderately differentiated tumors (p=0.003). Fifteen of 25 cases had metastatic disease. MUC1 was extensively expressed in 9/15 cases with metastatic disease. In contrast, MUC1 expression was present in 2/10 cases where metastases were absent. Hilar lesions were less likely to express MUC1, but this was not statistically significant. Fifteen of 25 cases had metastatic disease. Extensive MUC3 expression was significantly associated with well-differentiated tumors, whilst there was an approaching significance between the extensive expression of MUC1 and metastasis in cholangiocarcinoma.     

Is genetic polymorphism of ER-α, CYP1A1, and CYP1B1 a risk factor for uterine leiomyoma?

Introduction  

Uterine leiomyoma is the most common benign smooth muscle tumor.     

Neonatal mortality in Jordan: secondary analysis of Jordan Population and Family Health Survey (JPFHS) data

Objective: This study aimed to analyze the 2009 Jordan Population and Family Health Survey (JPFHS) data to determine the level, trend, and distribution of neonatal mortality (NNM) in Jordan and determine its associated factors.

Methods: Nationally representative data on NNM were extracted from the JPFHS data. Using multivariate analyses, the strength of associations between 12 clinical/sociodemographic variables and neonatal mortality were quantified after controlling for potential confounders.

Results: The weighted NNM rate for 2005–2009 period was 16 deaths per 1000 live births, with the early NNM rate and late NNM rates were 10 deaths per 1000 live births and six deaths per 1000 live births, respectively. Fluctuations of NNM according to year of birth and geographic variations were noted. Risk of NNM increased among male newborns, as mother’s education level decreased, in mothers 40–49 years old, in multiple gestations-low birth weight neonates, and as birth interval was <3 years.

Conclusions: The NNR rate for 2005–2009 period of 16 deaths per 1000 live births indicates that there are opportunities to decrease it. Risk factors of neonatal mortality with respect to predictors of death during first days of life and variables related to geographic variations require particular focus to improve the quality of obstetric and neonatal health services and to decrease neonatal mortality.