Vitamin D Compounds PRI-2191 and PRI-2205 Enhance Anastrozole Activity in Human Breast Cancer Models

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D₃ metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24R)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)₂D₃ analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.     

Dihydrotanshinone,a Natural Diterpenoid,Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor

Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2′(3′)-O-(4-Benzoylbenzoyl)adenosine-5′-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1β, IL-6, TNF-α, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and/or counteracting the BRB dysfunctions elicited by HG conditions.     

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.     

D-limonene Inhibits Pentylenetetrazole-Induced Seizure via Adenosine A2A Receptor Modulation on GABAergic Neuronal Activity

Background: Epilepsy is a chronic neurological disorder characterized by the recurrence of seizures. One-third of patients with epilepsy may not respond to antiseizure drugs. Purpose: We aimed to examine whether D-limonene, a cyclic monoterpene, exhibited any antiseizure activity in the pentylenetetrazole (PTZ)-induced kindling mouse model and in vitro. Methods: PTZ kindling mouse model was established by administering PTZ (30 mg/kg) intraperitoneally to mice once every 48 h. We performed immunoblot blots, immunohistochemistry (IHC), and high-performance liquid chromatography (HPLC) analysis after the behavioral study. Results: An acute injection of PTZ (60 mg/kg) induced seizure in mice, while pretreatment with D-limonene inhibited PTZ-induced seizure. Repeated administration of PTZ (30 mg/kg) increased the seizure score gradually in mice, which was reduced in D-limonene (10 mg/kg)-pretreated group. In addition, D-limonene treatment increased glutamate decarboxylase-67 (GAD-67) expression in the hippocampus. Axonal sprouting of hippocampal neurons after kindling was inhibited by D-limonene pretreatment. Moreover, D-limonene reduced the expression levels of Neuronal PAS Domain Protein 4 (Npas4)-induced by PTZ. Furthermore, the adenosine A2A antagonist {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}SCH58261 and ZM241385 inhibited anticonvulsant activity and gamma-aminobutyric acid (GABA)ergic neurotransmission-induced by D-limonene. Conclusion: These results suggest that D-limonene exhibits anticonvulsant activity through modulation of adenosine A2A receptors on GABAergic neuronal function.     

CYLINDRICAL AND CONICAL FOLD GEOMETRIES IN THE CANTARELL STRUCTURE, SOUTHERN GULF OF MEXICO: IMPLICATIONS FOR HYDROCARBON EXPLORATION

The NW‐SE trending Cantarell structure in the Gulf of Campeche hosts the largest oilfield in Mexico. The oil occurs predominantly in latest Cretaceous – earliest Tertiary breccias with subsidiary reserves in Upper Jurassic (Oxfordian and Kimmeridgian) and Lower Cretaceous oolitic and partially dolomitized limestones, dolomites and shaly limestones. Cantarell has been interpreted both as a fold‐and‐thrust zone and as a dextral transpressional structure. Analysis of structure contours at 100m intervals, on the tops of the Tertiary breccia and the Kimmeridgian (Upper Jurassic) dolomite, indicates that the structure is an upright cylindrical fold with gently plunging conical terminations; there is also a conical portion in the central part of the structure. The axes of the central, NW and SE cones are subvertical. This geometry indicates that the two fold terminations and the central cone are aprons rather than points, with the NW and central cone axes intersecting the cylindrical fold axis at the point where the geometry switches from conical to cylindrical. The apical angle (i.e. the angle between the fold and cone axes) varies as follows: (i) in the NW cone, it is ～70° in the breccia and ～76° in the Kimmeridgian dolomite; (ii) in the central cone, it is ～77° in the breccia and ～73° in the Kimmeridgian dolomite; and (iii) in the SE cone, it is ～64° in the breccia and ～57° in the Kimmeridgian dolomite. This indicates that whereas the fold opens with depth in the NW cone, it tightens with depth in the central and SE cones. Assuming a parallel fold geometry, these apical angles indicate an increase in volume in the NW cone (i.e. larger hydrocarbon reservoirs), compared to the central and SE cones. Theoretical considerations indicate that the curvature increases dramatically towards the point of the cone. In the case of the Cantarell structure, the apices of the cones are located at the conical‐cylindrical fold junctions, where the highest curvature may have resulted in a higher degree of fracturing. The coincidence of maximum curvature and the intersection of the conical and cylindrical fold axes in the fold culminations with porous and permeable reservoir rocks may have made these locations favourable for the accumulation of hydrocarbons.     

深层及非生物成烃的催化机制

讨论了非生物成因烃的可能生成机制。通过对比分析,探讨了在地质条件下碳、氢经历费-托合成和由过渡金属催化产生烃的可能机制。     

塔河油田成藏期次的地球化学示踪研究

应用油藏地球化学的方法对塔河油田的成藏期次进行了探讨。塔河油田稠油正构烷烃分布完整,但色谱基线不同程度抬升;原油非烃和沥青质碳同位素偏轻,族组成碳同位素发生倒转;原油中普遍含有25-降藿烷。这些特征表明该区油藏经历了至少两期成藏过程,早期充注原油遭受生物降解作用后又受到高成熟原油充注。塔河油田天然气为典型的油型气,成熟度较高,为成熟—过成熟阶段产物,亦显示了两期充注的特征:早期充注的为典型的原油伴生气,充注时间与后期原油的充注时间相同;晚期充注的为高温裂解气,充注方向为自东向西。因此,塔河油田至少存在着3次油气充注过程。      

皮带秤秤架的响应特性曲线分析

介绍了皮带秤秤架响应特性曲线分析方法，对四种结构形式的秤架进行了响应特性曲线分析和比较，得出的结论是：悬浮式秤架的计量特性最好。     

焉耆盆地原油物理化学特征及油源对比研究

在焉耆盆地侏罗系三工河组和八道湾组均发现原油,目前关于侏罗系产层原油的油源问题存在不同的认识。对研究区原油的物理、化学性质进行系统的研究,认为侏罗系三工河组和八道湾组原油不仅在物理性质上有一定的差别,而且在地球化学组成及生物标记化合物上也有一定的差异,应具有不同的来源。侏罗系三工河组原油属于典型腐殖型干酪根成因,而侏罗系八道湾组原油除了具有腐殖型干酪根成因的某些特征外,还具有湖相泥岩生烃的特点。通过原油与各类源岩生物标志物进一步对比分析发现,侏罗系三工河组原油与西山窑、三工河组烃源岩及石炭系、三叠系烃源岩地球化学特征均存在明显差异,与侏罗系八道湾组烃源岩对比性较好。侏罗系八道湾组原油与八道湾组、三叠系源岩有一定相似性,因此认为八道湾组源岩为其主要源岩,三叠系源岩也有一定的贡献。目前勘探生产主要以八道湾组烃源岩为目标,下一步应加强对三叠系烃源岩贡献区带的勘探部署。