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Biochemical Pharmacology

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https://www.readbyqxmd.com/read/28912068/angiogenic-imbalance-and-diminished-matrix-metalloproteinase-2-and-9-underlie-regional-decreases-in-uteroplacental-vascularization-and-feto-placental-growth-in-hypertensive-pregnancy
#1
Carlos A Dias-Junior, Juanjuan Chen, Ning Cui, Charles L Chiang, Minglin Zhu, Zongli Ren, Jose S Possomato-Vieira, Raouf A Khalil
Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats...
September 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28912067/farnesoid-x-receptor-regulates-sult1e1-expression-through-inhibition-of-pgc1%C3%AE-binding-to-hnf4%C3%AE
#2
Shuai Wang, Xue Yuan, Danyi Lu, Lianxia Guo, Baojian Wu
Sulfotransferase 1E1 (SULT1E1, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Here we aimed to assess the effects of farnesoid X receptor (FXR) activation on SULT1E1 expression, and to determine the mechanism thereof. Treatment with specific FXR agonists (i.e., GW4064 and CDCA) significantly decreased both mRNA and protein levels of SULT1E1 in HepG2 cells. This was accompanied by a decrease in the enzymatic activity...
September 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28912066/the-camp-effectors-pka-and-epac-activate-endothelial-no-synthase-through-pi3k-akt-pathway-in-human-endothelial-cells
#3
Verónica García-Morales, María Luaces-Regueira, Manuel Campos-Toimil
3',5'-cyclic adenosine monophosphate (cAMP) exerts an endothelium-dependent vasorelaxant action by stimulating endothelial NO synthase (eNOS) activity, and the subsequent NO release, through cAMP protein kinase (PKA) and exchange protein directly activated by cAMP (Epac) activation in endothelial cells. We have here investigated the mechanism by which the cAMP-Epac/PKA pathway activates eNOS. cAMP-elevating agents (forskolin and dibutyryl-cAMP) and the joint activation of PKA (6-Bnz-cAMP) and Epac (8-pCPT-2'-O-Me-cAMP) increased cytoplasmic Ca(2+) concentration ([Ca(2+)]c) in ≤ 30% of fura-2-loaded isolated human umbilical vein endothelial cells (HUVEC)...
September 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28893617/therapeutic-potential-of-carbohydrates-as-regulators-of-macrophage-activation
#4
REVIEW
Mimmi L E Lundahl, Eoin M Scanlan, Ed C Lavelle
It is well established for a broad range of disease states, including cancer and Mycobacterium tuberculosis infection, that pathogenesis is bolstered by polarisation of macrophages towards an anti-inflammatory phenotype, known as M2. As these innate immune cells are relatively long-lived, their re-polarisation to pro-inflammatory, phagocytic and bactericidal "classically activated" M1 macrophages is an attractive therapeutic approach. On the other hand, there are scenarios where the resolving inflammation, wound healing and tissue remodelling properties of M2 macrophages are beneficial - for example the successful introduction of biomedical implants...
September 8, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28888950/the-two-faces-of-aldehyde-oxidase-oxidative-and-reductive-transformations-of-5-nitroquinoline
#5
Erickson M Paragas, Sara C Humphreys, Joshua Min, Carolyn A Joswig-Jones, Jeffrey P Jones
Aldehyde oxidase (AOX) is a cytosolic enzyme responsible for the metabolism of some drugs and drug candidates. AOX catalyzes the oxidative hydroxylation of substrates including several aliphatic and aromatic aldehydes, and nitrogen-containing heterocyclic compounds. AOX is also reported to catalyze the reductive metabolism of nitro-compounds, N-oxides, sulfoxides, isoxazoles, isothiazoles, nitrite and hydroxamic acids. These reductive transformations are not well understood and are generally believed to only occur at low oxygen concentrations...
September 6, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28888949/deficiency-of-n-acetyltransferase-increases-the-interactions-of-isoniazid-with-endobiotics-in-mouse-liver
#6
Pengcheng Wang, Amina I Shehu, Jie Lu, Rujuta H Joshi, Raman Venkataramanan, Kim S Sugamori, Denis M Grant, Xiao-Bo Zhong, Xiaochao Ma
Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2...
September 6, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28870526/drug-repurposing-strategy-against-trypanosoma-cruzi-infection-in-vitro-and-in-vivo-assessment-of-the-activity-of-metronidazole-in-mono-and-combined-therapy
#7
M R Simões-Silva, J S De Araújo, G M Oliveira, K C Demarque, R B Peres, I D'Almeida-Melo, D G J Batista, C F Da Silva, C Cardoso-Santos, P B Da Silva, M M Batista, M T Bahia, M N C Soeiro
Metronidazole (Mtz) is a commercial broad-spectrum nitroimidazolic derivative with relevant antimicrobial activity and relative safety profile. Therefore, it is fair to consider Mtz a candidate for drug repurposing for other neglected conditions such as Chagas disease (CD), a parasitic pathology caused by Trypanosoma cruzi. CD is treated only with benznidazole (Bz) and nifurtimox, both introduced in clinics decades ago despite important limitations, including low efficacy on the later disease stage (chronic form) and severe side effects...
September 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28867645/5-fluorouracil-induces-inflammation-and-oxidative-stress-in-the-major-salivary-glands-affecting-salivary-flow-and-saliva-composition
#8
Luana E Bomfin, Cíntia M Braga, Thais A Oliveira, Conceição S Martins, Danielle A Foschetti, Ana A Q A Santos, Deiziane V S Costa, Renata F C Leitão, Gerly A C Brito
This study aimed to elucidate the effect of 5-fluorouracil (5-FU) on the histological aspects of the major salivary glands, salivary flow and saliva composition using an established oral mucositis model in hamsters. Oral mucositis was induced by two intraperitoneal administrations of 5-FU in two consecutive days (60 and 40mg/kg), followed by cheek pouch mucosa scratch, on day 4. The Pilocarpine-stimulated salivary flow was measured 4 and 10days after the first 5-FU injection. Salivary glands were harvested for histopathological analysis, measurement of inflammatory cells, quantification of pro-inflammatory cytokines (TNF-α and IL-1β), investigation of cell death and cell proliferation...
September 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28865873/statin-therapy-exacerbates-alcohol-induced-constriction-of-cerebral-arteries-via-modulation-of-ethanol-induced-bk-channel-inhibition-in-vascular-smooth-muscle
#9
Maria N Simakova, Shivantika Bisen, Alex M Dopico, Anna N Bukiya
Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Middle cerebral arteries were pressurized in vitro at 60mmHg and AICAC was evoked by 50mM ethanol, that is within the range of blood alcohol detected in humans following moderate-to-heavy drinking. AICAC was evident in high CLR+atorvastatin group but not in high CLR diet+placebo...
September 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28859968/dipeptidyl-peptidase-4-independent-cardiac-dysfunction-links-saxagliptin-to-heart-failure
#10
Chintan N Koyani, Ewald Kolesnik, Gerald Wölkart, Niroj Shrestha, Susanne Scheruebel, Christopher Trummer, Klaus Zorn-Pauly, Astrid Hammer, Petra Lang, Helga Reicher, Heinrich Maechler, Klaus Groschner, Bernd Mayer, Peter P Rainer, Harald Sourij, Wolfgang Sattler, Ernst Malle, Brigitte Pelzmann, Dirk von Lewinski
Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca(2+)/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca(2+)-ATPase 2a axis and Na(+)-Ca(2+) exchanger function in Ca(2+) extrusion...
August 30, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28855087/fpr2-signaling-without-%C3%AE-arrestin-recruitment-alters-the-functional-repertoire-of-neutrophils
#11
Michael Gabl, Andre Holdfeldt, Martina Sundqvist, Jalal Lomei, Claes Dahlgren, Huamei Forsman
G-protein coupled receptor (GPCR) biased agonism or functional selectivity has become an essential concept in GPCR research over the last years. Receptor-specific biased agonists selectively trigger one signaling pathway over another and induce a restricted/directed functional response. In this study, we aimed to characterize the concept of biased agonism for FPR2, a member of the formyl peptide receptor (FPR) subfamily of GPCRs. We show that the earlier described FPR2-activating pepducin F2Pal10 is a biased FPR2 agonist...
August 30, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28859967/a-jak2-selective-inhibitor-potently-reverses-the-immune-suppression-by-modulating-the-tumor-microenvironment-for-cancer-immunotherapy
#12
Wei He, Yi Zhu, Ruoyu Mu, Jinzhi Xu, Xiaoyi Zhang, Chunming Wang, Qiu Li, Zhen Huang, Junfeng Zhang, Yi Pan, Jianlin Han, Lei Dong
Small molecule therapeutics can be potent tools for cancer immunotherapy. They may be devised to target the tumor associated macrophages (TAMs) and regulatory T cells (Treg), which are major immunosuppressive cells in the tumor microenvironment. The infiltration and functionalization of these cells, which essentially promote tumor development, are mediated by the hyper-activation of the Jak-STAT3 signaling pathway. Here, we demonstrated that compound 9#, a novel inhibitor of Jak2, could suppress Jak2-STAT3 signaling in macrophages (peritoneal macrophages and THP-1 cells) and direct the macrophages towards the pro-inflammatory (M1-like) phenotype...
August 28, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28859966/relative-distribution-and-biological-characterization-of-cxcl4l1-isoforms-in-platelets-from-healthy-donors
#13
Pieter Ruytinx, Rik Janssens, Nele Berghmans, Mieke Gouwy, Isabelle Ronsse, Sandra Liekens, Paul Proost, Jo Van Damme, Sofie Struyf
CXCL4L1, a platelet-derived ELR-negative CXC chemokine, is a powerful angiostatic and anti-tumoral chemokine. We developed a mass spectrometric assay for the detection of different natural CXCL4L1 isoforms. Using this assay, we identified 4 different CXCL4L1 isoforms in the supernatant of thrombin-stimulated platelets from healthy volunteers: the classical isoform CXCL4L1(1-70), CXCL4L1(-4-70), which probably arises through alternative signal peptide removal and two COOH-terminally truncated isoforms CXCL4L1(1-69) and CXCL4L1(-4-69)...
August 28, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28844929/distribution-properties-and-inhibitor-sensitivity-of-zebrafish-catechol-o-methyl-transferases-comt
#14
Svetlana Semenova, Stanislav Rozov, Pertti Panula
Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is an enzyme with multiple functions in vertebrates. COMT methylates and thus inactivates catecholamine neurotransmitters and metabolizes xenobiotic catechols. Gene polymorphism rs4680 that influences the enzymatic activity of COMT affects cognition and behavior in humans. The zebrafish is widely used as an experimental animal in many areas of biomedical research, but most aspects of COMT function in this species have remained uncharacterized. We hypothesized that both comt genes play essential roles in zebrafish...
August 24, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28843775/parathyroid-hormone-contributes-to-the-down-regulation-of-cytochrome-p450-3a-through-the-camp-pi3k-pkc-pka-nf-%C3%AE%C2%BAb-signaling-pathway-in-secondary-hyperparathyroidism
#15
Hiroshi Watanabe, Ryusei Sugimoto, Komei Ikegami, Yuki Enoki, Tadashi Imafuku, Rui Fujimura, Jing Bi, Kento Nishida, Yoshiaki Sakaguchi, Michiya Murata, Hitoshi Maeda, Kenshiro Hirata, Sachiko Jingami, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama
Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models...
August 24, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28837794/a-short-cross-linker-activates-human-p-glycoprotein-missing-a-catalytic-carboxylate
#16
Tip W Loo, David M Clarke
P-glycoprotein (P-gp) is an ATP-dependent drug pump that protects us from toxic agents and confers multidrug resistance. It has a tweezer-like structure with each arm consisting of a transmembrane domain (TMD) and a nucleotide-binding domain (NBD). Drug substrates bind to sites within the TMDs to activate ATPase activity by promoting a tweezer-like closing of the gap between the NBDs. The catalytic carboxylates may be critical for NBD movements because the E556Q(NBD1) or E1201Q(NBD2) mutation inhibited drug-stimulated ATPase activity...
August 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28837793/inducing-rat-brain-cyp2d-with-nicotine-increases-the-rate-of-codeine-tolerance-predicting-the-rate-of-tolerance-from-acute-analgesic-response
#17
Douglas M McMillan, Rachel F Tyndale
Repeated opioid administration produces analgesic tolerance, which may lead to dose escalation. Brain CYP2D metabolizes codeine to morphine, a bioactivation step required for codeine analgesia. Higher brain, but not liver, CYP2D is found in smokers and nicotine induces rat brain, but not liver, CYP2D expression and activity. Nicotine induction of rat brain CYP2D increases acute codeine conversion to morphine, and analgesia, however the role of brain CYP2D on the effects of repeated codeine exposure and tolerance is unknown...
August 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28827109/chromofungin-chr-chga47-66-is-downregulated-in-persons-with-active-ulcerative-colitis-and-suppresses-pro-inflammatory-macrophage-function-through-the-inhibition-of-nf-%C3%AE%C2%BAb-signaling
#18
Nour Eissa, Hayam Hussein, Laëtitia Kermarrec, Omar Elgazzar, Marie-Helene Metz-Boutigue, Charles N Bernstein, Jean-Eric Ghia
Chromogranin-A (CHGA) is a prohormone secreted by neuroendocrine cells and is a precursor of several bioactive peptides, which are implicated in different and distinctive biological and immune functions. Chromofungin (CHR: CHGA47-66) is a short peptide with antimicrobial effects and encodes from CHGA exon-IV. Inflammatory bowel disease (IBD) is characterized by alterations in the activation of pro-inflammatory pathways, pro-inflammatory macrophages (M1), and nuclear transcription factor kappa B (NF-κB) signaling leading to the perpetuation of the inflammatory process...
August 19, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28822784/a-novel-model-for-the-pharmacokinetic-studies-of-bevacizumab-and-etanercept-in-healthy-volunteers-and-patients
#19
Meizhen Li, Wei Qiang, Li Hu, Lei Wang, Zeneng Cheng
Therapeutic monoclonal antibodies (mAbs) have been successfully applied to treat various diseases and shown a promising prospect in medical treatment. MAbs have some unique characteristics comparing with small chemical drugs, and their pharmacokinetic (PK) properties are much more complex than those of small chemical drugs, whose eliminations are usually linear. In this study, a new model was established through taking into account the mechanisms of the elimination of mAbs. The proposed model was applied to the modeling and simulation of two kinds of mAbs, including bevacizumab and etanercept, in PK studies of healthy volunteers and eligible patients, and the classical linear compartment model was set as control...
August 16, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28822783/the-expression-induction-and-pharmacological-activity-of-cyp1a2-are-post-transcriptionally-regulated-by-microrna-hsa-mir-132-5p
#20
Yinting Chen, Linjuan Zeng, Yong Wang, William H Tolleson, Bridgett Knox, Si Chen, Zhen Ren, Lei Guo, Nan Mei, Feng Qian, Kaihong Huang, David Liu, Weida Tong, Dianke Yu, Baitang Ning
Cytochrome P450 1A2 (CYP1A2) is one of the most abundant and important drug metabolizing enzymes in human liver. However, little is known about the post-transcriptional regulation of CYP1A2, especially the mechanisms involving microRNAs (miRNAs). This study applied a systematic approach to investigate the post-transcriptional regulation of CYP1A2 by miRNAs. Candidate miRNAs targeting the 3'-untranslated region (3'-UTR) of CYP1A2 were screened in silico, resulting in the selection of sixty-two potential miRNAs for further analysis...
August 16, 2017: Biochemical Pharmacology
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