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11.
Leyi Gong Xiaochun Han Tania Silva Yun-Chou Tan Bindu Goyal Parch Tivitmahaisoon Alejandra Trejo Wylie Palmer Heather Hogg Alam Jahagir Muzaffar Alam Paul Wagner Karin Stein Lubov Filonova Brad Loe Ferenc Makra David Rotstein Lubica Rapatova David Goldstein 《Bioorganic & medicinal chemistry letters》2013,23(12):3565-3569
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties. 相似文献
12.
Arlette Santacruz Fernando M. Trejo Yolanda Sanz 《Obesity (Silver Spring, Md.)》2013,21(11):2310-2321
Objectives: To evaluate the effects of administration of Bifidobacterium pseudocatenulatum CECT 7765 on metabolic and immune alterations in obese mice. Design and Methods: Adult male wild‐type C57BL‐6 mice were fed a standard diet or high‐fat diet (HFD), supplemented or not with B. pseudocatenulatum CECT 7765 for 7 weeks. The assessments included biochemical and immunological parameters, insulin resistance, glucose tolerance, histology of liver, white‐adipose and intestinal tissues, immunocompetent cell functions, and microbiota‐related features. Results: B. pseudocatenulatum CECT 7765 reduced serum cholesterol, triglyceride, and glucose levels and decreased insulin resistance and improved glucose tolerance in obese mice. This strain reduced serum levels of leptin, interleukin (IL)‐6 and monocyte chemotactic protein‐1, while increased those of IL‐4 in HFD‐fed mice. B. pseudocatenulatum CECT7765 reduced liver steatosis and the number of larger adipocytes and number of fat micelles in enterocytes of obese mice. The strain also improved the function of macrophages and dendritic cells in relation to phagocytosis, cytokine production, and induction of T‐lymphocyte proliferation. The strain administration increased bifidobacteria and reduced enterobacteria and the inflammatory properties of the gut content in HFD‐fed mice. Conclusion: B. pseudocatenulatum CECT 7765 was shown to ameliorate both metabolic and immunological dysfunctions related to obesity in HFD‐fed mice. 相似文献
13.
Population genetic analysis and bioclimatic modeling in Agave striata in the Chihuahuan Desert indicate higher genetic variation and lower differentiation in drier and more variable environments 下载免费PDF全文
14.
Briva A Vadász I Lecuona E Welch LC Chen J Dada LA Trejo HE Dumasius V Azzam ZS Myrianthefs PM Batlle D Gruenbaum Y Sznajder JI 《PloS one》2007,2(11):e1238
Background
In patients with acute respiratory failure, gas exchange is impaired due to the accumulation of fluid in the lung airspaces. This life-threatening syndrome is treated with mechanical ventilation, which is adjusted to maintain gas exchange, but can be associated with the accumulation of carbon dioxide in the lung. Carbon dioxide (CO2) is a by-product of cellular energy utilization and its elimination is affected via alveolar epithelial cells. Signaling pathways sensitive to changes in CO2 levels were described in plants and neuronal mammalian cells. However, it has not been fully elucidated whether non-neuronal cells sense and respond to CO2. The Na,K-ATPase consumes ∼40% of the cellular metabolism to maintain cell homeostasis. Our study examines the effects of increased pCO2 on the epithelial Na,K-ATPase a major contributor to alveolar fluid reabsorption which is a marker of alveolar epithelial function.Principal Findings
We found that short-term increases in pCO2 impaired alveolar fluid reabsorption in rats. Also, we provide evidence that non-excitable, alveolar epithelial cells sense and respond to high levels of CO2, independently of extracellular and intracellular pH, by inhibiting Na,K-ATPase function, via activation of PKCζ which phosphorylates the Na,K-ATPase, causing it to endocytose from the plasma membrane into intracellular pools.Conclusions
Our data suggest that alveolar epithelial cells, through which CO2 is eliminated in mammals, are highly sensitive to hypercapnia. Elevated CO2 levels impair alveolar epithelial function, independently of pH, which is relevant in patients with lung diseases and altered alveolar gas exchange. 相似文献15.
Enrique Othn Hernndez Ana Lilia Roa-Espitia Juana Cruz Trejo Adela Mújica 《Molecular reproduction and development》1996,43(3):366-375
Annexins are a family of Ca2+-binding proteins involved in the exocytotic process. The presence and the role of annexins in mammalian spermatozoa have not been well established. Two annexin-like proteins were obtained from guinea pig testis, a doublet of Mr 31–33 kD (p31/33) and a protein of Mr 50 kD (p50). Both proteins were able to bind to erythrocyte ghosts in a Ca2+-dependent fashion. Polyclonal antibodies against p31/33 reacted with two major proteins, Mrs 50 kD (sp50) and 42 kD (sp42), from mature and immature guinea pig spermatozoa. p50 and sp50 are likely the native proteins from testis and spermatozoa, respectively, and they are seemingly related. By immunofluorescence, sp50 was only found in the apical acrosome region of immature and capacitated and noncapacitated spermatozoa, and its location was intracellular. In spermatozoa undergoing acrosome reaction, sp50 was detected in the whole acrosome, while in spermatozoa that had undergone acrosome reaction sp50 was not detected. However, in the protein pattern of acrosome reaction vesicles, anti-p31/33 antibody revealed diffuse bands of Mr 35–38 kD. sp50 was able to bind to plasma membrane fragments and acrosome outer membrane from demembranated sperm in a Ca2+-dependent fashion. The presence of sp50 in the acrosome region, its distribution throughout the acrosome membrane just before the acrosome reaction, and its ability to bind both plasma and outer acrosome membranes in a Ca2+-dependent manner suggest that sp50 may participate in the acrosome reaction mechanism in guinea pig spermatozoa. © 1996 Wiley-Liss, Inc. 相似文献
16.
MarcOlivier MartinGuay Michaël Belluau Benoit Ct Ira Tanya Handa Mark D. Jewell Rim Khlifa Alison D. Munson Maxime Rivest Joann K. Whalen David Rivest 《Ecology and evolution》2022,12(1)
- Soil C is the largest C pool in forest ecosystems that contributes to C sequestration and mitigates climate change. Tree diversity enhances forest productivity, so diversifying the tree species composition, notably in managed forests, could increase the quantity of organic matter being transferred to soils and alter other soil properties relevant to the C cycle.
- A ten‐year‐old tree diversity experiment was used to study the effects of tree identity and diversity (functional and taxonomic) on soils. Surface (0–10 cm) mineral soil was repeatedly measured for soil C concentration, C:N ratio, pH, moisture, and temperature in twenty‐four tree species mixtures and twelve corresponding monocultures (replicated in four blocks).
- Soil pH, moisture, and temperature responded to tree diversity and identity. Greater productivity in above‐ and below‐ground tree components did not increase soil C concentration. Soil pH increased and soil moisture decreased with functional diversity, more specifically, when species had different growth strategies and shade tolerances. Functional identity affected soil moisture and temperature, such that tree communities with more slow‐growing and shade‐tolerant species had greater soil moisture and temperature. Higher temperature was measured in communities with broadleaf‐deciduous species compared to communities with coniferous‐evergreen species.
- We conclude that long‐term soil C cycling in forest plantations will likely respond to changes in soil pH, moisture, and temperature that is mediated by tree species composition, since tree species affect these soil properties through their litter quality, water uptake, and physical control of soil microclimates.
17.
Olivia Molinar-Inglis Jacob M. Wozniak Neil J. Grimsey Lennis B. Ordua-Castillo Norton Cheng Ying Lin Monica L. Gonzalez Ramirez Cierra A. Birch John D. Lapek David J. Gonzalez JoAnn Trejo 《The Journal of biological chemistry》2022,298(4)
Endothelial dysfunction is a hallmark of inflammation and is mediated by inflammatory factors that signal through G protein–coupled receptors including protease-activated receptor-1 (PAR1). PAR1, a receptor for thrombin, signals via the small GTPase RhoA and myosin light chain intermediates to facilitate endothelial barrier permeability. PAR1 also induces endothelial barrier disruption through a p38 mitogen-activated protein kinase–dependent pathway, which does not integrate into the RhoA/MLC pathway; however, the PAR1-p38 signaling pathways that promote endothelial dysfunction remain poorly defined. To identify effectors of this pathway, we performed a global phosphoproteome analysis of thrombin signaling regulated by p38 in human cultured endothelial cells using multiplexed quantitative mass spectrometry. We identified 5491 unique phosphopeptides and 2317 phosphoproteins, four distinct dynamic phosphoproteome profiles of thrombin-p38 signaling, and an enrichment of biological functions associated with endothelial dysfunction, including modulators of endothelial barrier disruption and a subset of kinases predicted to regulate p38-dependent thrombin signaling. Using available antibodies to detect identified phosphosites of key p38-regulated proteins, we discovered that inhibition of p38 activity and siRNA-targeted depletion of the p38α isoform increased basal phosphorylation of extracellular signal–regulated protein kinase 1/2, resulting in amplified thrombin-stimulated extracellular signal–regulated protein kinase 1/2 phosphorylation that was dependent on PAR1. We also discovered a role for p38 in the phosphorylation of α-catenin, a component of adherens junctions, suggesting that this phosphorylation may function as an important regulatory process. Taken together, these studies define a rich array of thrombin- and p38-regulated candidate proteins that may serve important roles in endothelial dysfunction. 相似文献
18.
Inhibition of NF-kappaB activity by IkappaBbeta in association with kappaB-Ras 总被引:1,自引:0,他引:1 下载免费PDF全文
IkappaBbeta, one of the major IkappaB proteins, is only partially degraded in response to most extracellular signals. However, the molecular mechanism of this event is unknown. We show here that IkappaBbeta exists in at least two different forms: one that is bound to the NF-kappaB dimer and the other bound to both NF-kappaB and kappaB-Ras, a Ras-like small G protein. Removal of cellular kappaB-Ras enhances whereas excess kappaB-Ras blocks induced IkappaBbeta degradation. Remarkably, kappaB-Ras functions in both GDP- and GTP-bound states, and mutations of the conserved guanine-binding residues of kappaB-Ras abrogate its ability to block degradation of IkappaBbeta. kappaB-Ras also directly blocks the in vitro phosphorylation of IkappaBbeta by IKKbeta. These observations suggest that IkappaBbeta in the ternary complex is resistant to degradation by most signals. We suggest that specific signals, in addition to those that activate only IKK, are essential for the complete degradation of IkappaBbeta. 相似文献
19.
Wang Y Chang J Li YC Li YS Shyy JY Chien S 《American journal of physiology. Heart and circulatory physiology》2004,286(2):H685-H692
Vascular endothelial cells are continuously exposed to mechanical (e.g., shear stress) and chemical (e.g., growth factors) stimuli. It is important to elucidate the mechanisms by which cells perceive and integrate these different stimuli to regulate the downstream signaling pathways. We (50) have previously reported the shear-induced interplay between two membrane receptors, integrins and Flk-1. In the present study, we investigated the molecular mechanisms regulating the downstream IkappaB kinase (IKK) pathway in response to shear stress and VEGF. Both shear stress and VEGF induced a transient increase of IKK activity. These effects were inhibited by SU-1498, a specific Flk-1 inhibitor, and by a negative mutant of Casitas B-lineage lymphoma (Cbl) with tyrosine-to-phenylalanine mutations at sites 700, 731, and 774 (Cbl(nm)). Because Flk-1 and Cbl form a complex upon shearing or VEGF applications (50), these results suggest that shear stress and VEGF activate IKK via the receptor Flk-1 and its recruitment of the adapter protein Cbl. The inhibition of the shear- and VEGF-induced IKK activities by a negative mutant of Akt indicates that Akt acts upstream to IKK in response to shear stress and VEGF. Furthermore, SU-1498 and Cbl(-nm) abolished the shear- and VEGF-induced Akt activity, indicating that Akt acts at a level downstream to Flk-1 and Cbl. Therefore, our results indicate that the signaling events induced by shear stress and VEGF converge at the membrane receptor Flk-1 and that these stimuli share the Flk-1/Cbl/Akt pathway in activating IKK activation. 相似文献
20.