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https://www.readbyqxmd.com/read/29351565/sumo-targeting-of-a-stress-tolerant-ulp1-sumo-protease
#1
Jennifer Peek, Catherine Harvey, Dreux Gray, Danny Rosenberg, Likhitha Kolla, Reuben Levy-Myers, Rui Yin, Jonathan L McMurry, Oliver Kerscher
SUMO proteases of the SENP/Ulp family are master regulators of both sumoylation and desumoylation and regulate SUMO homeostasis in eukaryotic cells. SUMO conjugates rapidly increase in response to cellular stress, including nutrient starvation, hypoxia, osmotic stress, DNA damage, heat shock, and other proteotoxic stressors. Nevertheless, little is known about the regulation and targeting of SUMO proteases during stress. To this end we have undertaken a detailed comparison of the SUMO-binding activity of the budding yeast protein Ulp1 (ScUlp1) and its ortholog in the thermotolerant yeast Kluyveromyces marxianus, KmUlp1...
2018: PloS One
https://www.readbyqxmd.com/read/29351515/understanding-key-mechanisms-of-exercise-induced-cardiac-protection-to-mitigate-disease-current-knowledge-and-emerging-concepts
#2
Bianca C Bernardo, Jenny Y Y Ooi, Kate L Weeks, Natalie L Patterson, Julie R McMullen
The benefits of exercise on the heart are well recognized, and clinical studies have demonstrated that exercise is an intervention that can improve cardiac function in heart failure patients. This has led to significant research into understanding the key mechanisms responsible for exercise-induced cardiac protection. Here, we summarize molecular mechanisms that regulate exercise-induced cardiac myocyte growth and proliferation. We discuss in detail the effects of exercise on other cardiac cells, organelles, and systems that have received less or little attention and require further investigation...
January 1, 2018: Physiological Reviews
https://www.readbyqxmd.com/read/29351511/chemogenetic-tools-for-causal-cellular-and-neuronal-biology
#3
Deniz Atasoy, Scott M Sternson
Chemogenetic technologies enable selective pharmacological control of specific cell populations. An increasing number of approaches have been developed that modulate different signaling pathways. Selective pharmacological control over G protein-coupled receptor signaling, ion channel conductances, protein association, protein stability, and small molecule targeting allows modulation of cellular processes in distinct cell types. Here, we review these chemogenetic technologies and instances of their applications in complex tissues in vivo and ex vivo...
January 1, 2018: Physiological Reviews
https://www.readbyqxmd.com/read/29351497/screen-targeting-lung-and-prostate-cancer-oncogene-identifies-novel-inhibitors-of-rgs17-and-problematic-chemical-substructures
#4
Christopher R Bodle, Josephine H Schamp, Joseph B O'Brien, Michael P Hayes, Meng Wu, Jonathan A Doorn, David L Roman
Regulator of G protein signaling (RGS) proteins temporally regulate heterotrimeric G protein signaling cascades elicited by G protein-coupled receptor activation and thus are essential for cell homeostasis. The dysregulation of RGS protein expression has been linked to several pathologies, spurring discovery efforts to identify small-molecule inhibitors of these proteins. Presented here are the results of a high-throughput screening (HTS) campaign targeting RGS17, an RGS protein reported to be inappropriately upregulated in several cancers...
January 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29351482/suppression-of-gut-dysbiosis-reverses-western-diet-induced-vascular-dysfunction
#5
Micah L Battson, Dustin M Lee, Dillon K Jarrell, Shuofei Hou, Kayl E Ecton, Tiffany L Weir, Christopher L Gentile
OBJECTIVE: Vascular dysfunction represents a critical pre-clinical step in the development of cardiovascular disease. We examined the role of the gut microbiota in the development of obesity-related vascular dysfunction. Approach and Results. Male C57BL/6J mice were fed either a standard diet (SD) (n=12) or western diet (WD) (n=24) for 5m, after which time, WD mice were randomized to receive either un-supplemented drinking water or water containing a broad-spectrum antibiotic cocktail (WD+Abx) (n=12/group) for 2m...
December 26, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29351469/inhibition-of-mtor-protects-the-blood-brain-barrier-in-models-of-alzheimer-s-disease-and-vascular-cognitive-impairment
#6
Candice E Van Skike, Jordan B Jahrling, Angela B Olson, Naomi L Sayre, Stacy A Hussong, Zoltan I Ungvari, James D Lechleiter, Veronica Galvan
An intact blood-brain barrier (BBB) limits entry of pro-inflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD...
December 22, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29351449/personalized-medicine-in-cf-from-modulator-development-to-therapy-for-cystic-fibrosis-patients-with-rare-cftr-mutations
#7
Misak Harutyunyan, Yunjie Huang, Kyu-Shik Mun, Fanmuyi Yang, Kavisha Arora, Anjaparavanda P Naren
Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting approximately 1 in 3500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, over 2000 CFTR mutations have been identified and produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality...
December 14, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29351437/metabolic-reprogramming-in-the-pathogenesis-of-chronic-lung-diseases-including-bpd-copd-and-pulmonary-fibrosis
#8
Haifeng Zhao, Phyllis A Dennery, Hongwei Yao
The metabolism of nutrient substrates including glucose, glutamine and fatty acids provides acetyl-CoA for the tricarboxylic acid cycle to generate energy, and metabolites for the biosynthesis of biomolecules including nucleotides, proteins, and lipids. It has been shown that metabolism of glucose, fatty acid, and glutamine plays important roles in modulating cellular proliferation, differentiation, apoptosis, autophagy, senescence, and inflammatory responses. All these cellular processes contribute to the pathogenesis of chronic lung diseases, including bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis...
January 4, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29351409/pharmacological-activation-of-ppar%C3%AE-inhibits-hypoxia-induced-proliferation-through-a-caveolin-1-targeted-and-dependent-mechanism-in-pasmcs
#9
Kai Yang, Mingming Zhao, Junyi Huang, Chenting Zhang, Qiu Yu Zheng, Yuqin Chen, Haiyang Jiang, Wenju Lu, Jian Wang
Previously, we and others have demonstrated that activation of peroxisome proliferator- activated receptor γ (PPARγ) by specific pharmacological agonists inhibits the pathogenesis of chronic hypoxia-induced pulmonary hypertension (CHPH) by suppressing the proliferation and migration in distal pulmonary arterial smooth muscle cells (PASMCs). Moreover, these beneficial effects of PPARγ are mediated by targeting the intracellular calcium homeostasis and store-operated calcium channel (SOCC) proteins, including the main caveolae component caveolin-1...
January 3, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29351408/choroid-plexus-epithelial-cells-express-the-adhesion-protein-p-cadherin-at-cell-cell-contacts-and-syntaxin-4-in-the-luminal-membrane-domain
#10
Inga Baasch Christensen, Esben Nees Mogensen, Helle Hasager Damkier, Jeppe Praetorius
The choroid plexus epithelial cells (CPECs) belong to a small group of polarized cells, where the Na+,K+-ATPase is expressed in the luminal membrane. The basic polarity of the cells is, therefore, still debated. We investigated the subcellular distribution of an array of proteins known to play fundamental roles in either in establishing and maintaining basic cell polarity or the polarized delivery and recycling of plasma membrane proteins. Immunofluorescence histochemical analysis was applied to determine the subcellular localization of apical and basolateral membrane determinants...
January 10, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29351406/interleukin-6-promotes-a-sustained-loss-of-endothelial-barrier-function-via-janus-kinase-mediated-stat3-phosphorylation-and-de-novo-protein-synthesis
#11
Hiba Alsaffar, Nina Martino, Joshua P Garrett, Alejandro P Adam
Vascular leakage is a hallmark of the inflammatory response. Acute changes in endothelial permeability are due to post-translational changes in intercellular adhesion and cytoskeleton proteins. However, little is known about the mechanisms leading to long-term changes in vascular permeability. Here, we show that Interleukin-6 (IL-6) promotes an increase in endothelial monolayer permeability that lasts over 24 h and demonstrate that activation of Src and MEK/Erk pathways are required only for short-term increases in permeability, being dispensable after 2 h...
January 10, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29351405/acute-down-regulation-of-mir-199a-attenuates-sepsis-induced-acute-lung-injury-by-targeting-sirt1
#12
Yang Liu, Hao Guan, Ju-Lei Zhang, Zhao Zheng, Hong-Tao Wang, Ke Tao, Shi-Chao Han, Lin-Lin Su, Dahai Hu
MiR-199a is a novel gene regulator with an important role in inflammation and lung injury. However, its role in the pathogenesis of sepsis-induced acute respiratory distress syndrome (ARDS) is currently unknown. Our study explored the role of miR-199a in sepsis-induced ARDS and its mechanism of action. First, we found that LPS could up-regulate miR-199a in alveolar macrophages. Down-regulation of miR-199a inhibited the up-regulation of inflammatory cytokines in alveolar macrophages and induced the remission of histopathologic changes, the reduction of pro-inflammatory cytokines, and the up-regulation of apoptosis protein expression in an ARDS lung, showing a protective role for miR-199a...
January 10, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29351393/liver-tissue-metabolically-transformed-by-alcohol-induces-immune-recognition-of-liver-self-proteins-but-not-in-vivo-inflammation
#13
Michael J Duryee, Benjamin M Wiese, Jordan R Bowman, Jared D Vanlandingham, Lynell W Klassen, Geoffrey E Thiele, Carlos D Hunter, Daniel R Anderson, Ted R Mikuls, Geoffrey M Thiele
Precision cut liver slices (PCLSs) provide a novel model for studies in alcoholic liver disease (ALD). This is relevant, as in vivo ethanol exposure does not appear to generate significant liver damage in ethanol fed mice, except in the NIAAA binge model of ALD. Previous studies have shown that the two metabolites of ethanol consumption, malondialdhyde (MDA) and acetaldehyde (AA), combine to form (MAA), which has been correlated with the development and progression of ALD. In this study murine PCLSs were incubated with ethanol and examined for the production of MAA...
December 28, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29351391/the-bile-acids-deoxycholic-acid-and-ursodeoxycholic-acid-regulate-colonic-epithelial-wound-healing
#14
Magdalena S Mroz, Natalia K Lajczak, Bridie J Goggins, Simon Keely, Stephen Joseph Keely
The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although, bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) on epithelial restitution. Wound healing in T84 cell monolayers grown on transparent, permeable, supports was assessed over 48 hrs {plus minus} bile acids...
January 11, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29351389/proliferation-of-hepatic-stellate-cells-mediated-by-yap-and-taz-contributes-to-liver-repair-and-regeneration-after-liver-ischemia-reperfusion-injury
#15
Takanori Konishi, Rebecca M Schuster, Alex B Lentsch
Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key regulators of cell proliferation and organ size, however, their physiological contribution after liver injury has not been fully understood. In this study, we sought to determine the role of YAP and TAZ during liver recovery after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. After liver injury, there was marked activation and proliferation of hepatic stellate cells...
January 11, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29351374/fast-dynamic-docking-guided-by-adaptive-electrostatic-bias-the-md-binding-approach
#16
Andrea Spitaleri, Sergio Decherchi, Andrea Cavalli, Walter Rocchia
Engineering chemical entities to modify how pharmaceutical targets function, as it is done in drug design, requires a good understanding of molecular recognition and binding. In this context, the limitations of statically describing bimolecular recognition, as done in docking/scoring, call for insightful and efficient dynamical investigations. On the experimental side, the characterization of dynamical binding processes is still in its infancy. Thus, computer simulations, particularly molecular dynamics (MD), are compelled to play a prominent role, allowing a deeper comprehension of the binding process and its causes and thus a more informed compound selection, making more significant the computational contribution to drug discovery1...
January 19, 2018: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29351189/the-role-of-cadaverine-synthesis-on-pneumococcal-capsule-and-protein-expression
#17
Mary F Nakamya, Moses B Ayoola, Seongbin Park, Leslie A Shack, Edwin Swiatlo, Bindu Nanduri
Invasive infections caused by Streptococcus pneumoniae, a commensal in the nasopharynx, pose significant risk to human health. Limited serotype coverage by the available polysaccharide-based conjugate vaccines coupled with increasing incidence of antibiotic resistance complicates therapeutic strategies. Bacterial physiology and metabolism that allows pathogens to adapt to the host are a promising avenue for the discovery of novel therapeutics. Intracellular polyamine concentrations are tightly regulated by biosynthesis, transport and degradation...
January 19, 2018: Medical Sciences: Open Access Journal
https://www.readbyqxmd.com/read/29351144/cardiac-dysfunction-in-critical-illness
#18
Allison Dalton, Sajid Shahul
PURPOSE OF REVIEW: Sepsis and septic shock are prevalent conditions that are likely to increase in prevalence in the future. Given the high mortality and morbidity associated with sepsis and sepsis-induced cardiac dysfunction, we must continue to make advances in knowledge of the complex physiologic interactions and how we may target specific mediators for potential therapeutic options in the future. RECENT FINDINGS: Multiple biomarkers have been discovered, which when assayed in sepsis-induced cardiomyopathy predict morbidity and mortality...
January 17, 2018: Current Opinion in Anaesthesiology
https://www.readbyqxmd.com/read/29351125/central-inhibition-of-granulocyte-macrophage-colony-stimulating-factor-is-analgesic-in-experimental-neuropathic-pain
#19
Louise S C Nicol, Peter Thornton, Jon P Hatcher, Colin P Glover, Carl I Webster, Matthew Burrell, Kessia Hammett, Clare A Jones, Matthew A Sleeman, Andrew Billinton, Iain Chessell
With less than 50% of patients responding to the current standard of care and poor efficacy and selectivity of current treatments, neuropathic pain continues to be an area of considerable unmet medical need. Biological therapeutics such as monoclonal antibodies (mAbs) provide better intrinsic selectivity; however, delivery to the central nervous system (CNS) remains a challenge. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is well described in inflammation-induced pain, and early-phase clinical trials evaluating its antagonism have exemplified its importance as a peripheral pain target...
January 16, 2018: Pain
https://www.readbyqxmd.com/read/29351081/characterization-of-phosphate-transporter-s-and-understanding-their-role-in-leishmania-donovani-parasite
#20
K J Sindhu, Amit Kumar Kureel, Sheetal Saini, Smita Kumari, Pankaj Verma, Ambak Kumar Rai
Inorganic phosphate (Pi) is shown to be involved in excretion of methylglyoxal (MG) in the promastigote form of Leishmania donovani parasite. Absence of Pi leads to its accumulation inside the parasite. Accumulation of MG is toxic to the parasite and utilizes glyoxylase as well as excretory pathways for its detoxification. In addition, Pi is also reported to regulate activities of ectoenzymes and energy metabolism (glucose to pyruvate) etc. Thus, it is known to cumulatively affect the growth of Leishmania parasite...
March 26, 2018: Acta Parasitologica
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