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https://www.readbyqxmd.com/read/28343223/sildenafil-enhances-quantity-of-immature-neurons-and-promotes-functional-recovery-in-the-developing-ischemic-mouse-brain
#1
Jonas Engels, Natalie Elting, Lisa Braun, Ivo Bendix, Josephine Herz, Ursula Felderhoff-Müser, Mark Dzietko
BACKGROUND: Hypoxic-ischemic (HI) injury to the developing brain occurs in 1 out of 1,000 live births and remains a major cause of significant morbidity and mortality. A large number of survivors suffer from long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after HI insult are not clearly understood, and preventive measures or clinical treatments are nonexistent or not sufficiently effective in the clinical setting...
March 25, 2017: Developmental Neuroscience
https://www.readbyqxmd.com/read/28341058/anti-fibrotic-effects-of-soluble-guanylate-cyclase-stimulators-and-activators-a-review-of-the-preclinical-evidence
#2
Peter Sandner, Johannes Peter Stasch
It is now well established that the NO-sGC-cGMP signal transduction system mediates many different physiological functions in almost every conceivable organ system; this has been best characterized in the cardiovascular system where NO-driven cGMP production exerts a plethora of cytoprotective and anti-atherogenic effects, including dilatation, inhibition of vascular smooth muscle proliferation, blockade of leukocyte recruitment, and anti-platelet activity. Accordingly, dysfunctional NO-sGC-cGMP mediated signaling is perceived as the underlying pathophysiological cause of many cardiovascular and non-cardiovascular diseases...
January 2017: Respiratory Medicine
https://www.readbyqxmd.com/read/28331244/a-novel-role-for-brain-natriuretic-peptide-inhibition-of-il-1%C3%AE-secretion-via-downregulation-of-nf-kb-erk-1-2-and-nalp3-asc-caspase-1-activation-in-human-thp-1-monocyte
#3
Letizia Mezzasoma, Cinzia Antognelli, Vincenzo Nicola Talesa
Interleukin-1β (IL-1β) is a pleiotropic cytokine and a crucial mediator of inflammatory and immune responses. IL-1β processing and release are tightly controlled by complex pathways such as NF-kB/ERK1/2, to produce pro-IL-1β, and NALP3/ASC/Caspase-1 inflammasome, to produce the active secreted protein. Dysregulation of both IL-1β and its related pathways is involved in inflammatory/autoimmune disorders and in a wide range of other diseases. Identifying molecules modulating their expression is a crucial need to develop new therapeutic agents...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28316997/sildenafil-can-affect-innate-and-adaptive-immune-system-in-both-experimental-animals-and-patients
#4
REVIEW
Monika Kniotek, Agnieszka Boguska
Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28315005/effect-of-nitric-oxide-on-renal-autoregulation-during-hypothermia-in-the-rat
#5
Lars Mikael Broman, Mattias Carlström, Örjan Källskog, Mats Wolgast
Hypothermia-induced reduction of metabolic rate is accompanied by depression of both glomerular perfusion and filtration. The present study investigated whether these changes are linked to changes in renal autoregulation and nitric oxide (NO) signalling. During hypothermia, renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced and urine production was increased, and this was linked with reduced plasma cGMP levels and increased renal vascular resistance. Although stimulation of NO production decreased vascular resistance, blood pressure and urine flow, intravenous infusion of the NO precursor L-arginine or the NO donor sodium nitroprusside did not alter RBF or GFR...
March 17, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28302718/a-unique-choanoflagellate-enzyme-rhodopsin-with-cyclic-nucleotide-phosphodiesterase-activity
#6
Kazuho Yoshida, Satoshi P Tsunoda, Leonid S Brown, Hideki Kandori
Photoactivated adenylyl cyclase (PAC) and guanylyl cyclase rhodopsin (Rh-GC) increase the concentrations of intracellular cyclic nucleotides upon illumination, serving as promising second-generation tools in optogenetics. To broaden arsenal of such tools, it is desirable to have light-activatable enzymes which can decrease cyclic nucleotide concentrations in cells. Here, we report on an unusual microbial rhodopsin which may be able to meet the demand. It is found in the choanoflagellate Salpingoeca rosetta and contains a C-terminal cyclic nucleotide phosphodiesterase (PDE) domain...
March 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28302516/impact-of-type-2-diabetes-on-vascular-reactivity-to-cgmp-generators-in-human-internal-thoracic-arteries
#7
Masashi Tawa, Takeshi Kinoshita, Tohru Asai, Tomoaki Suzuki, Takeshi Imamura, Tomio Okamura
OBJECTIVE: The balance between nitric oxide (NO)-sensitive and -insensitive forms of soluble guanylate cyclase (sGC) has been demonstrated to be disrupted in certain lifestyle-related diseases. However, it remains unclear whether type 2 diabetes results in a shift of sGC to the NO-insensitive form. This study addressed this issue in the human blood vessel. METHODS: Internal thoracic arteries were obtained from patients undergoing coronary artery bypass grafting...
March 14, 2017: Vascular Pharmacology
https://www.readbyqxmd.com/read/28299329/angiotensin-1-7-downregulates-diabetes-induced-cgmp-phosphodiesterase-activation-in-rat-corpus-cavernosum
#8
Gursev S Dhaunsi, Mariam Yousif, Batoul Makki, Saghir Akhtar, Ibrahim F Benter
Molecular mechanisms of the beneficial effects of angiotensin-(1-7), Ang-(1-7), in diabetes-related complications, including erectile dysfunction, remain unclear. We examined the effect of diabetes and/or Ang-(1-7) treatment on vascular reactivity and cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) in corpus cavernosum. Male Wistar rats were grouped as (1) control, (2) diabetic (streptozotocin, STZ, treated), (3) control + Ang-(1-7), and (4) diabetic + Ang-(1-7). Following 3 weeks of Ang-(1-7) treatment subsequent to induction of diabetes, rats were sacrificed...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28296282/sildenafil-reduces-neuroinflammation-in-cerebellum-restores-gabaergic-tone-and-improves-motor-in-coordination-in-rats-with-hepatic-encephalopathy
#9
Ana Agusti, Vicente Hernández-Rabaza, Tiziano Balzano, Lucas Taoro-Gonzalez, Andrea Ibañez-Grau, Andrea Cabrera-Pastor, Santos Fustero, Marta Llansola, Carmina Montoliu, Vicente Felipo
AIMS: Patients with liver disease may develop hepatic encephalopathy (HE), with cognitive impairment and motor in-coordination. Rats with HE due to portacaval shunts (PCS) show motor in-coordination. We hypothesized that in PCS rats: (i) Motor in-coordination would be due to enhanced GABAergic tone in cerebellum; (ii) increased GABAergic tone would be due to neuroinflammation; (iii) increasing cGMP would reduce neuroinflammation and GABAergic tone and restore motor coordination. To assess these hypotheses, we assessed if (i) treatment with sildenafil reduces neuroinflammation; (ii) reduced neuroinflammation is associated with reduced GABAergic tone and restored motor coordination...
March 11, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28292906/parasitophorous-vacuole-poration-precedes-its-rupture-and-rapid-host-erythrocyte-cytoskeleton-collapse-in-plasmodium-falciparum-egress
#10
Victoria L Hale, Jean M Watermeyer, Fiona Hackett, Gema Vizcay-Barrena, Christiaan van Ooij, James A Thomas, Matthew C Spink, Maria Harkiolaki, Elizabeth Duke, Roland A Fleck, Michael J Blackman, Helen R Saibil
In the asexual blood stages of malarial infection, merozoites invade erythrocytes and replicate within a parasitophorous vacuole to form daughter cells that eventually exit (egress) by sequential rupture of the vacuole and erythrocyte membranes. The current model is that PKG, a malarial cGMP-dependent protein kinase, triggers egress, activating malarial proteases and other effectors. Using selective inhibitors of either PKG or cysteine proteases to separately inhibit the sequential steps in membrane perforation, combined with video microscopy, electron tomography, electron energy loss spectroscopy, and soft X-ray tomography of mature intracellular Plasmodium falciparum parasites, we resolve intermediate steps in egress...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28289769/gene-therapy
#11
Barb Thorne, Ryan Takeya, Francesca Vitelli, Xin Swanson
Gene therapy refers to a rapidly growing field of medicine in which genes are introduced into the body to treat or prevent diseases. Although a variety of methods can be used to deliver the genetic materials into the target cells and tissues, modified viral vectors represent one of the more common delivery routes because of its transduction efficiency for therapeutic genes. Since the introduction of gene therapy concept in the 1970s, the field has advanced considerably with notable clinical successes being demonstrated in many clinical indications in which no standard treatment options are currently available...
March 14, 2017: Advances in Biochemical Engineering/biotechnology
https://www.readbyqxmd.com/read/28286139/de-novo-transcriptome-sequencing-and-analysis-of-the-juvenile-and-adult-stages-of-fasciola-gigantica
#12
Xiao-Xuan Zhang, Wei Cong, Hany M Elsheikha, Guo-Hua Liu, Jian-Gang Ma, Wei-Yi Huang, Quan Zhao, Xing-Quan Zhu
Fasciola gigantica is regarded as the major liver fluke causing fasciolosis in livestock in tropical countries. Despite the significant economic and public health impacts of F. gigantica there are few studies on the pathogenesis of this parasite and our understanding is further limited by the lack of genome and transcriptome information. In this study, de novo Illumina RNA sequencing (RNA-seq) was performed to obtain a comprehensive transcriptome profile of the juvenile (42days post infection) and adult stages of F...
March 9, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/28283839/selective-phosphodiesterase-2a-inhibitor-alleviates-radicular-inflammation-and-mechanical-allodynia-in-non-compressive-lumbar-disc-herniation-rats
#13
Jun-Nan Wang, Xue-Jun Zhao, Zhi-Hua Liu, Xu-Li Zhao, Tao Sun, Zhi-Jian Fu
PURPOSE: Phosphodiesterase inhibitors possess anti-inflammatory properties. In addition, some studies report that phosphodiesterase 2A (PDE2A) are highly expressed in the dorsal horn of the spinal cord. The present study aimed to investigate whether intrathecal administration of Bay 60-7550, a specific PDE2A inhibitor, could alleviate mechanical allodynia in non-compressive lumbar disc herniation (NCLDH) rats. METHODS: Rat NCLDH models by autologous nucleus pulposus implantation to dorsal root ganglion were established...
March 10, 2017: European Spine Journal
https://www.readbyqxmd.com/read/28283572/pdz-domain-dependent-regulation-of-nhe3-occurs-by-both-internal-class-ii-and-c-terminal-class-i-pdz-binding-motifs
#14
Boyoung Cha, Jianbo Yang, Varsha Singh, Nicholas C Zachos, Rafiquel I Sarker, Tian-E Chen, Molee Chakraborty, Chung-Ming Tse, Mark Donowitz
NHE3 directly binds NHERF family scaffolding proteins that are required for many aspects of NHE3 regulation. The NHERFs bind both to an internal region (aa. 586-660) of the NHE3 C-terminus and to the NHE3 C-terminal four amino acids. The internal NHERF binding region contains both putative Class I (-592SAV-) and Class II (-595CLDM-) PDZ binding motifs (PBM). Point mutagenesis showed that only the Class II motif contributes to NHERF binding. In this study, the roles in regulation of NHE3 activity of these two PBMs were investigated, revealing: 1) Interaction between these binding sites since mutation of either removed nearly all NHERF binding...
March 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28282490/gene-augmentation-therapy-for-a-missense-substitution-in-the-cgmp-binding-domain-of-ovine-cnga3-gene-restores-vision-in-day-blind-sheep
#15
Elisha Gootwine, Mazen Abu-Siam, Alexey Obolensky, Alex Rosov, Hen Honig, Tali Nitzan, Andrey Shirak, Raaya Ezra-Elia, Esther Yamin, Eyal Banin, Edward Averbukh, William W Hauswirth, Ron Ofri, Eyal Seroussi
Purpose: Applying CNGA3 gene augmentation therapy to cure a novel causative mutation underlying achromatopsia (ACHM) in sheep. Methods: Impaired vision that spontaneously appeared in newborn lambs was characterized by behavioral, electroretinographic (ERG), and histologic techniques. Deep-sequencing reads of an affected lamb and an unaffected lamb were compared within conserved genomic regions orthologous to human genes involved in similar visual impairment. Observed nonsynonymous amino acid substitutions were classified by their deleteriousness score...
March 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28279024/contribution-of-the-cyclic-nucleotide-gated-channel-subunit-cng-3-to-olfactory-plasticity-in-caenorhabditis-elegans
#16
Damien M O'Halloran, Svetlana Altshuler-Keylin, Xiao-Dong Zhang, Chao He, Christopher Morales-Phan, Yawei Yu, Julia A Kaye, Chantal Brueggemann, Tsung-Yu Chen, Noelle D L'Etoile
In Caenorhabditis elegans, the AWC neurons are thought to deploy a cGMP signaling cascade in the detection of and response to AWC sensed odors. Prolonged exposure to an AWC sensed odor in the absence of food leads to reversible decreases in the animal's attraction to that odor. This adaptation exhibits two stages referred to as short-term and long-term adaptation. Previously, the protein kinase G (PKG), EGL-4/PKG-1, was shown necessary for both stages of adaptation and phosphorylation of its target, the beta-type cyclic nucleotide gated (CNG) channel subunit, TAX-2, was implicated in the short term stage...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28274930/nitric-oxide-reduces-paracellular-resistance-in-rat-thick-ascending-limbs-by-increasing-na-and-cl-permeabilities
#17
Casandra Margarita Monzon, Rossana Occhipinti, Omar Pedro Pignataro, Jeffrey L Garvin
About 50% of the Na+ reabsorbed in thick ascending limbs traverses the paracellular pathway. Nitric oxide (NO) reduces the permselectivity of this pathway via cGMP, but its effects on absolute Na(+) (PNa(+)) and Cl(-) (PCl(-)) permeabilities are unknown. To address this, we measured the effect L-arginine (0.5mmol/L; NO synthase substrate) and cGMP (0.5mmol/L) on PNa(+) and PCl(-) calculated from transepithelial resistance (Rt) and PNa(+)/PCl(-) Rt was 7722±1554 ohm-cm in the control period and 6318±1757 ohm-cm after L-arginine treatment (p<0...
March 8, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28274638/development-of-a-self-assembling-protein-nanoparticle-vaccine-targeting-plasmodium-falciparum-circumsporozoite-protein-delivered-in-three-army-liposome-formulation-adjuvants
#18
Labdhi Seth, Karen M Bingham Ferlez, Stephen A Kaba, Derek M Musser, Sharareh Emadi, Gary R Matyas, Zoltan Beck, Carl R Alving, Peter Burkhard, David E Lanar
We have developed FMP014, a vaccine candidate against Plasmodium falciparum malaria, which is comprised of 60 identical monomer protein chains that form an icosahedral shaped self-assembling protein nanoparticle (SAPN). Each monomer contains selected P. falciparum Circumsporozoite Protein (PfCSP) CD4+ and CD8+ epitopes, universal TH epitopes, portions of the α-TSR domain, and 6 repeats of the NANP motifs of the PfCSP. Here we describe the conditions that are required for successful scale-up and cGMP manufacturing of FMP014 with a yield of ≈1...
March 5, 2017: Vaccine
https://www.readbyqxmd.com/read/28274265/reduced-cgmp-levels-in-csf-of-ad-patients-correlate-with-severity-of-dementia-and-current-depression
#19
Raphael Hesse, Ludwig Lausser, Pauline Gummert, Florian Schmid, Anke Wahler, Cathrin Schnack, Katja S Kroker, Markus Otto, Hayrettin Tumani, Hans A Kestler, Holger Rosenbrock, Christine A F von Arnim
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder, primarily affecting memory. That disorder is thought to be a consequence of neuronal network disturbances and synapse loss. Decline in cognitive function is associated with a high burden of neuropsychiatric symptoms (NPSs) such as depression. The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are essential second messengers that play a crucial role in memory processing as well as synaptic plasticity and are potential therapeutic targets...
March 9, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28273832/more-insight-into-bdnf-against-neurodegeneration-anti-apoptosis-anti-oxidation-and-suppression-of-autophagy
#20
REVIEW
Shang-Der Chen, Chia-Lin Wu, Wei-Chao Hwang, Ding-I Yang
In addition to its well-established neurotrophic action, brain-derived neurotrophic factor (BDNF) also possesses other neuroprotective effects including anti-apoptosis, anti-oxidation, and suppression of autophagy. We have shown before that BDNF triggers multiple mechanisms to confer neuronal resistance against 3-nitropropionic acid (3-NP)-induced mitochondrial dysfunction in primary rat cortical cultures. The beneficial effects of BDNF involve the induction of anti-oxidative thioredoxin with the resultant expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) as well as erythropoietin (EPO)-dependent stimulation of sonic hedgehog (SHH)...
March 3, 2017: International Journal of Molecular Sciences
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