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mechanism action

Garrett D Morandi, Steve B Wiseman, Miao Guan, Xiaowei W Zhang, Jonathan W Martin, John P Giesy
Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface-mining oil sands industry in Alberta, Canada, and is acutely and chronically toxic to aquatic organisms. It is known that dissolved organic compounds in OSPW are responsible for most toxic effects, but knowledge of the specific mechanism(s) of toxicity, is limited. Using bioassay-based effects-directed analysis, the dissolved organic fraction of OSPW has previously been fractionated, ultimately producing refined samples of dissolved organic chemicals in OSPW, each with distinct chemical profiles...
August 8, 2017: Chemosphere
Khaled Horri, Sébastien Alfonso, Xavier Cousin, Catherine Munschy, Véronique Loizeau, Salima Aroua, Marie-Laure Bégout, Bruno Ernande
Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that have been shown to affect fish life-history traits such as reproductive success, growth and survival. At the individual level, their toxicity and underlying mechanisms of action have been studied through experimental exposure. However, the number of experimental studies approaching marine environmental situations is scarce, i.e., in most cases, individuals are exposed to either single congeners, or single types of molecules, or high concentrations, so that results can hardly be transposed to natural populations...
August 18, 2017: Science of the Total Environment
Yi-Jin Chen, Wen-Hung Wang, Wan-Yu Wu, Chia-Chi Hsu, Ling-Rung Wei, Sheng-Fan Wang, Ya-Wen Hsu, Chih-Chuang Liaw, Wan-Chi Tsai
OBJECTIVE: Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer. METHODS: Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study...
2017: PloS One
Janny A Villa-Pulgarín, Consuelo Gajate, Javier Botet, Alberto Jimenez, Nicole Justies, Rubén E Varela-M, Álvaro Cuesta-Marbán, Ingrid Müller, Manuel Modolell, José L Revuelta, Faustino Mollinedo
BACKGROUND: Leishmaniasis is the world's second deadliest parasitic disease after malaria, and current treatment of the different forms of this disease is far from satisfactory. Alkylphospholipid analogs (APLs) are a family of anticancer drugs that show antileishmanial activity, including the first oral drug (miltefosine) for leishmaniasis and drugs in preclinical/clinical oncology trials, but their precise mechanism of action remains to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the tumor cell apoptosis-inducer edelfosine was the most effective APL, as compared to miltefosine, perifosine and erucylphosphocholine, in killing Leishmania spp...
August 2017: PLoS Neglected Tropical Diseases
Juan Ramos-Treviño, Susana Bassol-Mayagoitia, Pablo Ruiz-Flores, Perla Karina Espino-Silva, Odila Saucedo-Cárdenas, Sheila Adela Villa-Cedillo, Martha P Nava-Hernández
The Sertoli cell plays a vital role during the spermatogenesis process and has been identified as one of the main targets of the toxic action of heavy metals on the seminiferous epithelium. In the present work, the effect of lead (Pb), Arsenic (As), and Cadmium (Cd) in primary cultures of Sertoli cells was analyzed by measuring the expression of the genes Cldn11, Ocln, and Gja1 that participate in the tight and gap junctions, which are responsible for maintaining the blood-testis barrier. Sertoli cells were isolated from the testes of Wistar rats...
August 22, 2017: DNA and Cell Biology
Roman Effenberg, Pavlína Turánek Knötigová, Daniel Zyka, Hana Čelechovská, Josef Mašek, Eliška Bartheldyová, Frantisek Hubatka, Štěpán Koudelka, Róbert Lukáč, Anna Kovalová, David Saman, Michal Křupka, Lucia Barkocziová, Petr Kosztyu, Marek Šebela, Ladislav Drož, Michal Hučko, Mária Kanásová, Andrew David Miller, Milan Raška, Miroslav Ledvina, Jaroslav Turanek
Apyrogenic fatty acyl analogues of muramyldipeptide (MDP) (abbreviated N-L18norAbuGMDP, N-B30norAbuGMDP, norAbuMDP-Lys(L18), norAbuMDP-Lys(B30), norAbuGMDP-Lys(L18), norAbuGMDP-Lys(B30), (B30)norAbuMDP, (L18)norAbuMDP) were designed and synthesized comprising the normuramyl-L-α-aminobutanoyl (norAbu) structural moiety. All new analogues show depressed pyrogenicity both as free compounds and in liposomal formulations when tested in vivo in rabbits (s.c. and i.v. application). The potency of analogues in selective activation of NOD2 and NLRP3 (inflammasome) receptors in vitro, but not NOD1, is demonstrated using transgenic cell-based detection systems...
August 22, 2017: Journal of Medicinal Chemistry
Panagiotis V S Vasileiou, Iordanis Mourouzis, Constantinos Pantos
Mitochondria have emerged as key players regarding cellular homeostasis not only due to their contribution regarding energy production through oxidative phosphorylation, but also due to their involvement in signaling, ion regulation, and programmed cell death. Indeed, current knowledge supports the notion that mitochondrial dysfunction is a hallmark in the pathogenesis of various diseases. Mitochondrial biogenesis and function require the coordinated action of two genomes: nuclear and mitochondrial. Unfortunately, both intrinsic and environmental genotoxic insults constantly threaten the integrity of nuclear as well as mitochondrial DNA...
August 22, 2017: International Journal of Molecular Sciences
Alberto Monteiro Dos Santos, Anderson Henrique Lima, Claudio Nahum Alves, Jeronimo Lameira
Enolpyruvyl transfer from phosphoenolpyruvate (PEP) to the hydroxyl group of shikimate-5-OH-3-phosphate (S3P) is catalyzed by 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase in a reaction that involves breaking the C-O bond of PEP. Catalysis involves an addition-elimination mechanism with the formation of a tetrahedral intermediate (THI). Experiments have elucidated the mechanism of THI formation and breakdown. However, the catalytic action of EPSP synthase and the individual roles of catalytic residues Asp313 and Glu341 remains unclear...
August 22, 2017: Journal of Physical Chemistry. B
M A Bodescu, F Rosenkötter, J Fritz
Melittin is a model system for the action of antimicrobial peptides which are potential candidates for novel antibiotics. We investigated the membrane lysis effect of melittin on phase-separated supported lipid bilayers (DOPC-DPPC) by atomic force microscopy. AFM images show that the peptide first forms defects at the interface between the two lipid phases and then degrades preferentially the liquid-phase DOPC-enriched domains. Vesicular structures of 10-20 nm radius were observed to form, suggesting a mixed carpet-toroidal model mechanism for the resolved action of melittin...
August 22, 2017: Soft Matter
Alexey V Shvetsov, Yana A Zabrodskaya, Peter A Nekrasov, Vladimir V Egorov
In this study we present molecular dynamics simulations of the antiviral drug triazavirine, that affects formation of amyloid-like fibrils of the model peptide (SI). According to our simulations, triazavirine is able to form linear supramolecular structures which can act as shields and prevent interactions between SI monomers. This model, as validated by simulations, provides an adequate explanation of triazavirine's mechanism of action as it pertains to SI peptide fibril formation.
August 22, 2017: Journal of Biomolecular Structure & Dynamics
Jacqueline R Mhizha-Murira, Avril Drummond, Olga A Klein, Roshan dasNair
OBJECTIVE: To determine the quantity and quality of description of cognitive rehabilitation for cognitive deficits in people with multiple sclerosis, using a variety of published checklists, and suggest ways of improving the reporting of these interventions. DATA SOURCES: A total of 10 electronic databases were searched, including MEDLINE, EMBASE, CINAHL and PsycINFO, from inception to May 2017. Grey literature databases, trial registers, reference lists and author citations were also searched...
August 1, 2017: Clinical Rehabilitation
Gareth R Willis, Stella Kourembanas, S Alex Mitsialis
With the advancements in antenatal steroid therapies and surfactant replacement, current clinical practices in neonatal intensive care units allow the survival of infants at very low gestational age. Despite these advances, there continues to be significant morbidity associated with extreme preterm birth that includes both short-term and long-term cardiorespiratory impairment. With no effective single therapy in preventing or treating developmental lung injuries, the need for new tools to treat and reduce risk of complications associated with extreme preterm birth is urgent...
2017: Methods in Molecular Biology
Juan C Mayo, Rosa M Sainz, Pedro González-Menéndez, David Hevia, Rafael Cernuda-Cernuda
Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors...
August 21, 2017: Cellular and Molecular Life Sciences: CMLS
Bo Xu, Dongxu Zhou, Li Ren, Steven Shulman, Xingan Zhang, Ming Xiong
BACKGROUND: This study was designed to investigate the pharmacokinetics and pharmacodynamics of dexmedetomidine in morbidly obese patients undergoing laparoscopic surgery. METHODS: Morbidly obese (body mass index ≥40 kg/m(2)) and normal weight patients scheduled for elective laparoscopic surgery were included (n = 8, each group). After baseline hemodynamic measurement, dexmedetomidine 1 μg/kg was administered over 10 min. General anesthesia was induced with propofol 1...
August 21, 2017: Journal of Anesthesia
Sabyasachi Dash, Muthukumar Balasubramaniam, Tanu Rana, Arthur Godino, Emily G Peck, Jeffery Shawn Goodwin, Fernando Villalta, Erin S Calipari, Eric J Nestler, Chandravanu Dash, Jui Pandhare
Cocaine exposure alters gene expression in the brain via methylation and acetylation of histones along with methylation of DNA. Recently, poly (ADP-ribose) polymerase-1 (PARP-1) catalyzed PARylation has been reported as an important regulator of cocaine-mediated gene expression. In this study, we report that the cellular microRNA "miR-125b" plays a key role for cocaine-induced PARP-1 expression. Acute and chronic cocaine exposure resulted in the downregulation of miR-125b concurrent with upregulation of PARP-1 in dopaminergic neuronal cells and nucleus accumbens (NAc) of mice but not in the medial prefrontal cortex (PFC) or ventral tegmental area (VTA)...
July 2017: ENeuro
James Coventon
OBJECTIVE: To summarise the contemporary literature regarding sorafenib and its effectiveness as a novel treatment in advanced osteosarcoma. BACKGROUND: Modern treatment has seen the cure rate of osteosarcoma increase to 65%. However, in patients who do not achieve remission, prognosis is poor, as there are no effective, consensual second line therapies. Sorafenib has emerged as a potentially viable drug to be used in this context. METHOD: A literature review was conducted evaluating articles pertaining to osteosarcoma and sorafenib...
September 2017: Journal of Bone Oncology
Xue Chen, Wei Zhao, Ye Yuan, Yan Bai, Yong Sun, Wenliang Zhu, Zhimin Du
Considering complicated microRNA (miRNA) biogenesis and action mechanisms, it was thought so high energy-consuming for a cell to afford simultaneous over-expression of many miRNAs. Thus it prompts that an alternative miRNA regulation pattern on protein-encoding genes must exist, which has characteristics of energy-saving and precise protein output. In this study, expression tendency of proteins encoded by miRNAs' target genes was evaluated in human organ scale, followed by quantitative assessment of miRNA synergism...
2017: PeerJ
J Kumar, I Reccia, T Kusano
BACKGROUND: Immunosuppressive therapies are important parts of renal transplantation. OBJECTIVE: To assess the present literature on the effectiveness of early introduction of mTOR inhibitors with or without calcineurin inhibitors (CNI) in renal transplant recipients in terms of renal functioning and graft survival. METHODS: The current literature was reviewed following PROSPERO approval, assessing the role of immunosuppressive agent, mTOR inhibitors as an alternative to CNI within 6 months of renal transplantation by searching PubMed, EMBASE, Cochrane, Crossref, and Scopus...
2017: International Journal of Organ Transplantation Medicine
Marija Smiljkovic, Danijela Stanisavljevic, Dejan Stojkovic, Isidora Petrovic, Jelena Marjanovic Vicentic, Jelena Popovic, Simona Golic Grdadolnik, Dejan Markovic, Snežana Sankovic-Babice, Jasmina Glamoclija, Milena Stevanovic, Marina Sokovic
Bioactive potential of apigenin derivative apigenin-7-O-glucoside related to its antifungal activity on Candida spp. and cytotoxic effect on colon cancer cells was studied and compared with bioactive potential of apigenin. Antifungal activity was tested on 14 different isolates of Candida spp. using membrane permeability assay, measuring inhibition of reactive oxidative species and inhibition of CYP51 C. albicans enzyme. Cytotoxic potential of apigenin-7-O-glucoside was tested on colon cancer HCT116 cells by measuring cell viability, apoptosis rate and apoptosis- and colon cancer-related gene expression...
2017: EXCLI journal
Rachel L Edwards, Robert C Brothers, Xu Wang, Maxim I Maron, Peter D Ziniel, Patricia S Tsang, Thomas E Kraft, Paul W Hruz, Kim C Williamson, Cynthia S Dowd, Audrey R Odom John
The emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme...
August 21, 2017: Scientific Reports
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