MECHANISTIC STUDIES OF DIFFERENT CLASSES OF BIOREDUCTIVE DRUGS: IN VITRO AND IN VIVO

1991 ◽  
pp. 76
Author(s):  
G.E. ADAMS ◽  
I.J. STRATFORD ◽  
E.M. FIELDEN ◽  
M.A. NAYLOR
Keyword(s):  
Mechanistic Studies ◽  
Bioreductive Drugs

scholarly journals Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1803 ◽  
Author(s):  
Amira Mbarek ◽  
Ghina Moussa ◽  
Jeanne Leblond Chain
Keyword(s):  
Cardiovascular Disease ◽  
Neurodegenerative Disorders ◽  
Therapeutic Agents ◽  
Mechanistic Studies ◽  
Molecular Tweezers ◽  
The Past ◽  
Pharmaceutical Applications ◽  
Controlled Motion

Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools.

scholarly journals Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Juan Carlos Espín ◽  
Mar Larrosa ◽  
María Teresa García-Conesa ◽  
Francisco Tomás-Barberán
Keyword(s):  
Health Effects ◽  
Ellagic Acid ◽  
Biological Effects ◽  
Biological Significance ◽  
Preliminary Evidence ◽  
Potential Contribution ◽  
Mechanistic Studies ◽  
Extensive Metabolism

The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2–20 μM. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based onin vitrotesting, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number ofin vivostudies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Bothin vivoand mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reachedin vivo.

1,3,2-Oxathiaphospholane approach to the synthesis of P-chiral stereodefined analogs of oligonucleotides and biologically relevant nucleoside polyphosphates

2008 ◽  
Vol 80 (8) ◽  
pp. 1859-1871 ◽  
Author(s):  
Barbara Nawrot ◽  
Beata Rębowska ◽  
Olga Michalak ◽  
Marek Bulkowski ◽  
Damian Błaziak ◽  
...  
Keyword(s):  
Nonbridging Oxygen ◽  
Mechanistic Studies ◽  
Sugar Phosphate ◽  
Chemical Methods ◽  
Biologically Relevant ◽  
In Vivo Experiments ◽  
Phosphate Backbone ◽  
Stereocontrolled Synthesis

Among the various classes of modified nucleotides and oligonucleotides, phosphorothioate analogs, in which the sugar-phosphate backbone is modified by the substitution of a sulfur atom for one of the nonbridging oxygen atoms, have been most extensively studied in both in vitro and in vivo experiments. However, this substitution induces P-chirality of the dinucleoside phosphorothioate moiety. Consequently, even short phosphorothioate oligonucleotides synthesized using standard chemical methods exist as mixtures of many diastereoisomers. In our laboratory, the oxathiaphospholane (OTP) method has been developed for a stereocontrolled synthesis of oligo(deoxyribonucleoside phosphorothioate)s. Recently, this approach has been extended to ribonucleoside derivatives, and stereodefined phosphorothioate diribonucleotides were incorporated into oligomers suitable for mechanistic studies on deoxyribozymes. Next, it was found that the OTP ring can be opened with nucleophiles as weak as the phosphate or pyrophosphate anion, giving rise to nucleoside α-thiopolyphosphates. Surprisingly, the reaction between nucleoside OTP and O,O-dialkyl H-phosphonate or O,O-dialkyl H-phosphonothioate led to nucleoside 5'-O-(α-thio-β-O,O-dialkyl-hypophosphate) or 5'-O-(α,β-dithio-β-O,O-dialkyl-hypophosphate), respectively, i.e., derivatives containing a direct P-P bond.

In vitro models of the human microbiota and microbiome

2017 ◽  
Vol 1 (4) ◽  
pp. 373-384 ◽  
Author(s):  
Julie A.K. McDonald
Keyword(s):  
Microbial Communities ◽  
Longitudinal Studies ◽  
New Technologies ◽  
Disease Status ◽  
Mechanistic Studies ◽  
Cross Sectional ◽  
Wide Range ◽  
Gut Fermentation

Gut microbiome studies have been gaining popularity over the years, especially with the development of new technologies (e.g. metataxonomics, metagenomics, metatranscriptomics, and metabonomics) that makes it easier for researchers to characterize the composition and functionality of these complex microbial communities. The goal of these studies is to identify a microorganism, group of microbes, or microbial metabolite which correlates with a disease state (e.g. inflammatory bowel disease, colorectal cancer, and obesity). Many of these are cross-sectional studies, where fecal samples from a group of diseased individuals are compared with those from a group of healthy individuals at a single time point. However, there are a wide range of variables that can affect the gut microbiota of humans which make mechanistic studies challenging. Longitudinal studies are required for research to more reliably correlate interventions or disease status to microbiota composition and functionality. However, longitudinal studies in humans and animals are difficult, expensive, and time-consuming. This review will discuss in vitro gut fermentation models and how they can be used to perform longitudinal studies that complement in vivo microbiome studies. Gut fermentation models support the growth of stable, reproducible, and diverse microbial communities in a tightly controlled environment set to mimic the conditions microbes encounter in the gastrointestinal tract. Gut fermentation models will make it easier for researchers to perform mechanistic studies and aid in the development of novel treatments that are both targeted and maintained over time.

Identification of a Novel N-Carbamoyl Glucuronide: In Vitro, In Vivo, and Mechanistic Studies

2009 ◽  
Vol 38 (3) ◽  
pp. 361-367 ◽  
Author(s):  
Mithat Gunduz ◽  
Upendra A. Argikar ◽  
Daniel Baeschlin ◽  
Suzie Ferreira ◽  
Vinayak Hosagrahara ◽  
...  
Keyword(s):  
Mechanistic Studies

scholarly journals Generation of hiPSC-Derived Functional Dopaminergic Neurons in Alginate-Based 3D Culture

2021 ◽  
Vol 9 ◽  
Author(s):  
Valentina Gilmozzi ◽  
Giovanna Gentile ◽  
Diana A. Riekschnitz ◽  
Michael Von Troyer ◽  
Alexandros A. Lavdas ◽  
...  
Keyword(s):  
Culture System ◽  
3D Culture ◽  
Patient Specific ◽  
Neuronal Cultures ◽  
Mechanistic Studies ◽  
Culture Methods ◽  
Cellular Environment ◽  
Hydrogel Matrix

Human induced pluripotent stem cells (hiPSCs) represent an unlimited cell source for the generation of patient-specific dopaminergic (DA) neurons, overcoming the hurdle of restricted accessibility to disease-affected tissue for mechanistic studies on Parkinson’s disease (PD). However, the complexity of the human brain is not fully recapitulated by existing monolayer culture methods. Neurons differentiated in a three dimensional (3D) in vitro culture system might better mimic the in vivo cellular environment for basic mechanistic studies and represent better predictors of drug responses in vivo. In this work we established a new in vitro cell culture system based on the microencapsulation of hiPSCs in small alginate/fibronectin beads and their differentiation to DA neurons. Optimization of hydrogel matrix concentrations and composition allowed a high viability of embedded hiPSCs. Neural differentiation competence and efficiency of DA neuronal generation were increased in the 3D cultures compared to a conventional 2D culture methodology. Additionally, electrophysiological parameters and metabolic switching profile confirmed increased functionality and an anticipated metabolic resetting of neurons grown in alginate scaffolds with respect to their 2D counterpart neurons. We also report long-term maintenance of neuronal cultures and preservation of the mature functional properties. Furthermore, our findings indicate that our 3D model system can recapitulate mitochondrial superoxide production as an important mitochondrial phenotype observed in neurons derived from PD patients, and that this phenotype might be detectable earlier during neuronal differentiation. Taken together, these results indicate that our alginate-based 3D culture system offers an advantageous strategy for the reliable and rapid derivation of mature and functional DA neurons from hiPSCs.

Fused pyrazine mono-N-oxides as bioreductive drugs III. Characterization of RB 90740 in vitro and in vivo

1995 ◽  
Vol 6 (2) ◽  
pp. 259-269 ◽  
Author(s):  
Matthew A Naylor ◽  
Gerald E Adams ◽  
Angela Haigh ◽  
Shirley Cole ◽  
Terence Jenner ◽  
...  
Keyword(s):  
Bioreductive Drugs

scholarly journals Evidence for the Existence of the Loop E Motif of Potato Spindle Tuber Viroid In Vivo

2006 ◽  
Vol 81 (4) ◽  
pp. 2074-2077 ◽  
Author(s):  
Ying Wang ◽  
Xuehua Zhong ◽  
Asuka Itaya ◽  
Biao Ding
Keyword(s):  
Direct Evidence ◽  
Biological Significance ◽  
Potato Spindle Tuber Viroid ◽  
Cross Linking ◽  
Mechanistic Studies ◽  
Base Pairing ◽  
Rna Motifs ◽  
Ligand Interactions

ABSTRACT RNA motifs comprising nucleotides that interact through non-Watson-Crick base pairing play critical roles in RNA functions, often by serving as the sites for RNA-RNA, RNA-protein, or RNA small ligand interactions. The structures of viral and viroid RNA motifs are studied commonly by in vitro, computational, and mutagenesis approaches. Demonstration of the in vivo existence of a motif will help establish its biological significance and promote mechanistic studies on its functions. By using UV cross-linking and primer extension, we have obtained direct evidence for the in vivo existence of the loop E motif of Potato spindle tuber viroid. We present our findings and discuss their biological implications.

Sign in / Sign up

Export Citation Format

Share Document