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https://www.readbyqxmd.com/read/28088572/bcs-class-iv-drugs-highly-notorious-candidates-for-formulation-development
#1
REVIEW
Rohan Ghadi, Neha Dand
BCS class IV drugs (e.g., amphotericin B, furosemide, acetazolamide, ritonavir, paclitaxel) exhibit many characteristics that are problematic for effective oral and per oral delivery. Some of the problems associated include low aqueous solubility, poor permeability, erratic and poor absorption, inter and intra subject variability and significant positive food effect which leads to low and variable bioavailability. Also, most of the class IV drugs are substrate for P-glycoprotein (low permeability) and substrate for CYP3A4 (extensive pre systemic metabolism) which further potentiates the problem of poor therapeutic potential of these drugs...
January 11, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28087411/aspirin-prevents-tnf-%C3%AE-induced-endothelial-cell-dysfunction-by-regulating-the-nf-%C3%AE%C2%BAb-dependent-mir-155-enos-pathway-role-of-a-mir-155-enos-axis-in-preeclampsia
#2
Joohwan Kim, Kyu-Sun Lee, Ji-Hee Kim, Dong-Keon Lee, Minsik Park, Seunghwan Choi, Wonjin Park, Suji Kim, Yoon Kyoung Choi, Jong Yun Hwang, Jongseon Choe, Moo-Ho Won, Dooil Jeoung, Hansoo Lee, Sungwoo Ryoo, Kwon-Soo Ha, Young-Guen Kwon, Young-Myeong Kim
Preeclampsia is an inflammatory disease with endothelial cell dysfunction that occurs via decreased endothelial nitric oxide synthase/nitric oxide (eNOS/NO) activity. Aspirin reduces the incidence of hypertensive pregnancy complications. However, the underlying mechanism has not been clearly explained. Here, we found that tumor necrosis factor (TNF)-α, microRNA (miR)-155, and eNOS levels as well as endothelial redox phenotype were differentially regulated in preeclamptic patients, implying the involvement of TNF-α- and redox signal-mediated miR-155 biogenesis and eNOS downregulation in the pathogenesis of preeclampsia...
January 10, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28087360/the-synthetic-peptide-pnpp-19-induces-peripheral-antinociception-via-activation-of-no-cgmp-katp-pathway-role-of-enos-and-nnos
#3
A C N Freitas, G Silva, D F Pacheco, V Lemos, I D G Duarte, M E de Lima
BACKGROUND AND PURPOSE: The peptide PnPP-19, derived from the spider toxin PnTx2-6, potentiates erectile function by activating the nitrergic system. Since NO has been studied as an antinociceptive molecule and PnPP-19 is known to induce peripheral antinociception, we intended to evaluate whether PnPP-19 could induce peripheral antinociception through activation of this pathway. EXPERIMENTAL APPROACH: Nociceptive thresholds were measured by paw pressure test. PGE2 (2 μg/paw) was administered intraplantarly together with PnPP-19 and inhibitors/blockers of NOS, guanylyl cyclase and KATP channels...
January 10, 2017: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/28077315/inhibition-of-inos-alleviates-cognitive-deficits-and-depression-in-diabetic-mice-through-downregulating-the-no-sgc-cgmp-pkg-signal-pathway
#4
Xiao Yan Zhou, Fang Zhang, Chang Jiang Ying, Jing Chen, Ling Chen, Jing Dong, Yue Shi, Mang Tang, Xiao Tong Hu, Zhi Hua Pan, Na Na Xu, Kui Yang Zheng, Ren Xian Tang, Yuan Jian Song
Diabetes mellitus often results in a number of complications involving impaired brain function, including cognitive deficits and depression. However, the potential mechanisms for diabetes-related cognitive deficits and depression are not fully understood. Neurons in the hippocampal, cortical and amygdala functional regions are more susceptible to damage during hyperglycemia. Neuroprotection in the brain can rescue cognitive deficits and depression induced by hyperglycemia. This study investigated the potential mechanisms underlying diabetes-related congnitive deficits and depression, determined whether the inflammatory factor inducible nitric oxide synthase (iNOS) and the nitric oxide (NO)/soluble guanylyl cyclases (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway, play key roles in cognitive deficits and depression associated...
January 8, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28065754/mechanisms-involved-in-antinociception-induced-by-a-polysulfated-fraction-from-seaweed-gracilaria-cornea-in-the-temporomandibular-joint-of-rats
#5
Chistiane Oliveira Coura, Hellíada Vasconcelos Chaves, Danielle Rocha do Val, Lorena Vasconcelos Vieira, Felipe Dantas Silveira, Fernanda Maxcynne Lino Dos Santos Lopes, Francisco Isaac Fernandes Gomes, Annyta Fernandes Frota, Ricardo Basto Souza, Juliana Trindade Clemente-Napimoga, Mirna Marques Bezerra, Norma Maria Barros Benevides
Temporomandibular disorder is a common clinical condition involving pain in the temporomandibular joint (TMJ) region. This study assessed the antinociceptive effects of a polysulfated fraction from the red seaweed Gracilaria cornea (Gc-FI) on the formalin-induced TMJ hypernociception in rats and investigated the involvement of different mechanisms. Male Wistar rats were pretreated with injection (sc) of saline or Gc-FI 1h before intra- TMJ injection of formalin to evaluate the nociception. The results showed that pretreatment with Gc-FI significantly reduced formalin-induced nociceptive behavior...
January 5, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28065474/a-single-low-dose-of-a-cgmp-recombinant-bcg-vaccine-elicits-protective-t-cell-immunity-against-the-human-respiratory-syncytial-virus-infection-and-prevents-lung-pathology-in-mice
#6
Pablo F Céspedes, Emma Rey-Jurado, Janyra A Espinoza, Claudia A Rivera, Gisela Canedo-Marroquín, Susan M Bueno, Alexis M Kalergis
Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection...
January 5, 2017: Vaccine
https://www.readbyqxmd.com/read/28064475/administration-of-goji-lycium-chinense-mill-extracts-improves-erectile-function-in-old-aged-rat-model
#7
Hyong Woo Moon, Jung Woo Park, Kyu Won Lee, Hyun Cheol Jeong, Jin Bong Choi, Sae Woong Choi, Woong Jin Bae, Hyuk Jin Cho, U Syn Ha, Sung Hoo Hong, Jeong Ho Geum, Seong Bin Hong, Sae Woong Kim
PURPOSE: This study investigated the effect of goji (Lycium chinense Mill.) on erectile dysfunction in old-aged rats. MATERIALS AND METHODS: Twenty-four 18-month-old male Sprague-Dawley rats (defined as old-aged rats) were used. Treatment groups contained eight rats each: a control group, goji extract of 150 mg/kg/day group, and goji extract of 300 mg/kg/day group. Treatment was by orogastric tube once daily for 6 weeks. After 6 weeks of treatment, testes weight, serum testosterone, superoxide dismutase, nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-related parameters, intracavernous pressure/mean arterial pressure, and histological changes were examined...
December 22, 2016: World Journal of Men's Health
https://www.readbyqxmd.com/read/28064474/the-effect-of-alcohol-administration-on-the-corpus-cavernosum
#8
See Min Choi, Deok Ha Seo, Sin Woo Lee, Chunwoo Lee, Seong Uk Jeh, Sung Chul Kam, Jeong Seok Hwa, Ky Hyun Chung, Jae Seog Hyun
PURPOSE: We studied the effects of alcohol administration on the corpus cavernosum (CC) using an animal model. MATERIALS AND METHODS: CC sections and the aortic ring of rabbits were used in an organ bath study. After acute alcohol administration, changes in blood alcohol concentration and electrical stimulation induced intracavernosal pressure/mean arterial pressure (ICP/MAP) percentage were compared in rats. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the CC were measured using immunoassays...
December 22, 2016: World Journal of Men's Health
https://www.readbyqxmd.com/read/28062949/can-cyclic-nucleotide-phosphodiesterase-inhibitors-be-drugs-for-parkinson-s-disease
#9
REVIEW
Dominic Ngima Nthenge-Ngumbau, Kochupurackal P Mohanakumar
Parkinson's disease (PD) has no known cure; available therapies are only capable of offering temporary, symptomatic relief to the patients. Varied therapeutic strategies that are clinically used for PD are pharmacological therapies including dopamine replacement therapies (with or without adjuvant), postsynaptic dopamine receptor stimulation, dopamine catabolism inhibitors and also anticholinergics. Surgical therapies like deep brain stimulation and ablative surgical techniques are also employed. Phosphodiesterases (PDEs) are enzymes that degrade the phosphodiester bond in the second messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)...
January 6, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28062615/biochemistry-therapeutics-and-biomarker-implications-of-neprilysin-in-cardiorenal-disease
#10
REVIEW
Yang Chen, John C Burnett
BACKGROUND: Neprilysin (NEP) is a membrane-bound neutral endopeptidase that degrades a variety of bioactive peptides. The substrates include natriuretic peptides (NPs), which are important regulating mediators for cardiovascular and renal biology. Inhibition of NEP activity and exogenous NP administration thus have emerged as potential therapeutic strategies for treating cardiorenal diseases. More recently, B-type natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP), 3'-5' cyclic guanosine monophosphate (cGMP), and soluble NEP as biomarkers have also been investigated in heart failure (HF) trials and their predictive value are beginning to be recognized...
January 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28062305/involvement-of-second-messengers-in-the-signaling-pathway-of-vitellogenesis-inhibiting-hormone-and-their-effects-on-vitellogenin-mrna-expression-in-the-whiteleg-shrimp-litopenaeus-vannamei
#11
Sun-Hye Bae, Tomoyuki Okutsu, Naoaki Tsutsui, Bong Jung Kang, Hsiang-Yin Chen, Marcy N Wilder
We incubated fragments of Litopenaeus vannamei ovary to investigate second messengers involved in the regulation of vitellogenin (vg) mRNA levels. The use of 100 nM recombinant vitellogenesis-inhibiting hormone (VIH) (corresponding to recombinant L. vannamei sinus gland peptide-G: rLiv-SGP-G) significantly reduced vg mRNA expression in sub-adults after 8 h incubation to less than 20% of the control. The concentration of intracellular cyclic guanosine monophosphate (cGMP) increased 3.2-fold relative to the control after 2 h incubation with rLiv-SGP-G...
January 3, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28060997/effect-of-hypercholesterolemia-on-myocardial-function-ischemia-reperfusion-injury-and-cardioprotection-by-preconditioning-postconditioning-and-remote-conditioning
#12
REVIEW
Ioanna Andreadou, Efstathios K Iliodromitis, Antigone Lazou, Anikó Görbe, Zoltán Giricz, Rainer Schulz, Péter Ferdinandy
Hypercholesterolemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolemia affects global cardiac gene expression profile, among many other factors, increased myocardial oxidative stress, mitochondrial dysfunction and inflammation trigger apoptosis and this may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies revealed that hyperlcholesterolemia may interfere with the cardioprotective potential of conditioning mechanisms...
January 6, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28060942/white-cgmp-interaction-promotes-fast-locomotor-recovery-from-anoxia-in-adult-drosophila
#13
Chengfeng Xiao, R Meldrum Robertson
Increasing evidence indicates that the white (w) gene in Drosophila possesses extra-retinal functions in addition to its classical role in eye pigmentation. We have previously shown that w+ promotes fast and consistent locomotor recovery from anoxia, but how w+ modulates locomotor recovery is largely unknown. Here we show that in the absence of w+, several PDE mutants, especially cyclic guanosine monophosphate (cGMP)-specific PDE mutants, display wildtype-like fast locomotor recovery from anoxia, and that during the night time, locomotor recovery was light-sensitive in white-eyed mutant w1118, and light-insensitive in PDE mutants under w1118 background...
2017: PloS One
https://www.readbyqxmd.com/read/28057484/type-ii-cgmp-dependent-protein-kinase-negatively-regulates-fibroblast-growth-factor-signaling-by-phosphorylating-raf-1-at-serine-43-in-rat-chondrosarcoma-cells
#14
Norio Kamemura, Sara Murakami, Hiroaki Komatsu, Masahiro Sawanoi, Kenji Miyamoto, Kazumi Ishidoh, Koji Kishimoto, Akihiko Tsuji, Keizo Yuasa
Although type II cGMP-dependent protein kinase (PKGII) is a major downstream effector of cGMP in chondrocytes and attenuates the FGF receptor 3/ERK signaling pathway, its direct target proteins have not been fully explored. In the present study, we attempted to identify PKGII-targeted proteins, which are associated with the inhibition of FGF-induced MAPK activation. Although FGF2 stimulation induced the phosphorylation of ERK1/2, MEK1/2, and Raf-1 at Ser-338 in rat chondrosarcoma cells, pretreatment with a cell-permeable cGMP analog strongly inhibited their phosphorylation...
January 3, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28056744/nucleotide-second-messenger-signaling-as-a-target-for-the-control-of-bacterial-biofilm-formation
#15
Alberto J Martín-Rodríguez, Ute Römling
Bacterial biofilm formation and associated phenotypes are the major cause of chronic infection in humans. The major regulator of biofilm formation in Gram-negative and Gram-positive bacteria are nucleotide-based second messenger signaling pathways. Nucleotide-based signaling is a ubiquitous signal transduction mechanism in all domains of life that relay changes in the extracellular or intracellular milieu to protein or RNA effectors, leading to adaptive physiological responses. To date, six bona fide nucleotide signaling pathways, (p)ppGpp, cAMP, cGMP, c-di-AMP, c-di-GMP and cGAMP, have been characterized with respect to basic pathway modules and phenotypic and physiological output...
January 5, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28054671/natriuretic-peptide-type-c-induces-sperm-attraction-for-fertilization-in-mouse
#16
Nana Kong, Xiaoting Xu, Yu Zhang, Yakun Wang, Xiaoqiong Hao, Yu Zhao, Jie Qiao, Guoliang Xia, Meijia Zhang
Mammalian spermatozoa undergo selective movement along the isthmus of the oviduct to the ampulla during ovulation, which is a prerequisite for fertilization. The factor(s) that involves in selective spermatozoa movement is still unknown. In this study, we found that the oviductal epithelium in mouse ampulla expressed high levels of natriuretic peptide type C (NPPC) in the presence of ovulated oocyte-cumulus complexes (OCCs). Spermatozoa expressed NPPC receptor natriuretic peptide receptor 2 (NPR2, a guanylyl cyclase) on the midpiece of flagellum...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28052870/phosphodiesterase-5-inhibition-ameliorates-angiotensin-ii-dependent-hypertension-and-renal-vascular-dysfunction
#17
Manuel Thieme, Sema Hayriye Sivritas, Evanthia Mergia, Sebastian Alexander Potthoff, Guang Yang, Lydia Hering, Katharina Grave, Henning Hoch, Lars Christian Rump, Johannes Stegbauer
Changes in renal hemodynamics have a major impact on blood pressure (BP). Angiotensin (Ang) II has been shown to induce vascular dysfunction by interacting with phosphodiesterases (PDE)1 and PDE5. The predominant PDE isoform responsible for renal vascular dysfunction in hypertension is unknown. Here, we measured effects of PDE5-(sildenafil) or PDE1-(vinpocetine) inhibition on renal blood flow (RBF), BP and renal vascular function in normotensive and hypertensive mice. During acute short-term Ang II infusion, sildenafil decreased BP and increased RBF in C57BL/6 (WT) mice...
January 4, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28052251/interplay-between-obesity-induced-inflammation-and-cgmp-signaling-in-white-adipose-tissue
#18
Abhishek Sanyal, Jennifer Naumann, Linda Sarah Hoffmann, Agnieszka Chabowska-Kita, Anna Ehrlund, Andreas Schlitzer, Peter Arner, Matthias Blüher, Alexander Pfeifer
Current worldwide figures suggest that obesity is pandemic. Understanding the underlying molecular mechanisms would help develop viable anti-obesity therapies. Here, we assess the influence of obesity-induced inflammation on white adipocyte cyclic guanosine monophosphate (cGMP) signaling, which is beneficial for adipocyte differentiation and thermogenesis. We find that murine gonadal and not inguinal fat is prone to obesity-induced inflammation. Correspondingly, the cGMP cascade is dysregulated in gonadal but not in inguinal fat of obese mice...
January 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28042091/novel-pde10a-transcript-diversity-in-the-human-striatum-insights-into-gene-complexity-conservation-and-regulation
#19
Courtney M MacMullen, Mohammad Fallahi, Ronald L Davis
PDE10A is a cAMP/cGMP phosphodiesterase important in signal transduction within medium spiny neurons of the human striatum. This gene region has been associated with bipolar disorder via case-control and linkage studies. The three most studied human PDE10A isoforms differ in both their N-termini and trafficking within the cell with PDE10A2 found predominantly at the plasma membrane and PDE10A1 and PDE10A19 remaining primarily within the cytosol. RNA-sequencing and 5' RLM-RACE studies of the human putamen and caudate nucleus revealed 16 new exons and 12 novel transcripts of PDE10A, 3 of which are predicted to produce proteins with unique N-termini...
December 29, 2016: Gene
https://www.readbyqxmd.com/read/28033126/shear-stress-mediated-upregulation-of-gtp-cyclohydrolase-tetrahydrobiopterin-pathway-ameliorates-hypertension-related-decline-in-reendothelialization-capacity-of-endothelial-progenitor-cells
#20
Yong-Ping Bai, Songhua Xiao, Yong-Bo Tang, Zhi Tan, Hailin Tang, Zhi Ren, Haitao Zeng, Zhen Yang
OBJECTIVES: Guanosine triphosphate cyclohydrolase/tetrahydrobiopterin (GTPCH)/(BH4) pathway has been proved to regulate the function of endothelial progenitor cells (EPCs) in deoxycorticosterone acetate-salt hypertensive mice, indicating that GTPCH/BH4 pathway may be an important repair target for hypertension-related endothelial injury. Shear stress is an important nonpharmacologic strategy to modulate the function of EPCs. Here, we investigated the effects of laminar shear stress on the GTPCH/BH4 pathway and endothelial repair capacity of circulating EPCs in hypertension...
December 28, 2016: Journal of Hypertension
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