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Current Neuropharmacology 2018Retinal ganglion cells (RGCs) are the nervous retinal elements which connect the visual receptors to the brain forming the nervous visual system. Functional and/or... (Review)
Review
BACKGROUND
Retinal ganglion cells (RGCs) are the nervous retinal elements which connect the visual receptors to the brain forming the nervous visual system. Functional and/or morphological involvement of RGCs occurs in several ocular and neurological disorders and therefore these cells are targeted in neuroprotective strategies. Cytidine 5-diphosphocholine or Citicoline is an endogenous compound that acts in the biosynthesis of phospholipids of cell membranes and increases neurotransmitters' levels in the Central Nervous System. Experimental studies suggested the neuromodulator effect and the protective role of Citicoline on RGCs. This review aims to present evidence of the effects of Citicoline in experimental models of RGCs degeneration and in human neurodegenerative disorders involving RGCs.
METHODS
All published papers containing experimental or clinical studies about the effects of Citicoline on RGCs morphology and function were reviewed.
RESULTS
In rodent retinal cultures and animal models, Citicoline induces antiapoptotic effects, increases the dopamine retinal level, and counteracts retinal nerve fibers layer thinning. Human studies in neurodegenerative visual pathologies such as glaucoma or non-arteritic ischemic neuropathy showed a reduction of the RGCs impairment after Citicoline administration. By reducing the RGCs' dysfunction, a better neural conduction along the post-retinal visual pathways with an improvement of the visual field defects was observed.
CONCLUSION
Citicoline, with a solid history of experimental and clinical studies, could be considered a very promising molecule for neuroprotective strategies in those pathologies (i.e. Glaucoma) in which morpho-functional changes of RGCc occurs.
Topics: Animals; Cytidine Diphosphate Choline; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Retinal Ganglion Cells
PubMed: 28676014
DOI: 10.2174/1570159X15666170703111729 -
Proceedings of the National Academy of... Jun 2023Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a...
Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a combination of femtosecond pulsed laser microirradiation at different wavelengths, quantitative imaging, and numerical modeling that yields a comprehensive picture of photon-mediated and free-electron-mediated DNA damage pathways in live cells. Laser irradiation was performed under highly standardized conditions at four wavelengths between 515 nm and 1,030 nm, enabling to study two-photon photochemical and free-electron-mediated DNA damage in situ. We quantitatively assessed cyclobutane pyrimidine dimer (CPD) and γH2AX-specific immunofluorescence signals to calibrate the damage threshold dose at these wavelengths and performed a comparative analysis of the recruitment of DNA repair factors xeroderma pigmentosum complementation group C (XPC) and Nijmegen breakage syndrome 1 (Nbs1). Our results show that two-photon-induced photochemical CPD generation dominates at 515 nm, while electron-mediated damage dominates at wavelengths ≥620 nm. The recruitment analysis revealed a cross talk between nucleotide excision and homologous recombination DNA repair pathways at 515 nm. Numerical simulations predicted electron densities and electron energy spectra, which govern the yield functions of a variety of direct electron-mediated DNA damage pathways and of indirect damage by OH radicals resulting from laser and electron interactions with water. Combining these data with information on free electron-DNA interactions gained in artificial systems, we provide a conceptual framework for the interpretation of the wavelength dependence of laser-induced DNA damage that may guide the selection of irradiation parameters in studies and applications that require the selective induction of DNA lesions.
Topics: Electrons; DNA Damage; Pyrimidine Dimers; DNA Repair; Lasers
PubMed: 37307476
DOI: 10.1073/pnas.2220132120 -
Digestive and Liver Disease : Official... Dec 2014Sofosbuvir is the first-in-class NS5B nucleotide analogues to be launched for hepatitis C virus (HCV) treatment. Its viral potency, pangenotypic activity and high... (Review)
Review
Sofosbuvir is the first-in-class NS5B nucleotide analogues to be launched for hepatitis C virus (HCV) treatment. Its viral potency, pangenotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Recent data demonstrated that sofosbuvir either with ribavirin alone or in combination with other direct-acting antivirals (DAAs) as daclatasvir, ledipasvir or simeprevir are able to cure HCV in at least 90% or over of patients. Treatment experienced genotype 3 population may remain the most difficult to treat population, but ongoing DAA combination studies will help to fill this gap. Safety profile of sofosbuvir or combination with other DAAs is good. Resistance to sofosbuvir did not appear as a significant issue. The rationale for using this class of drug and the available clinical data are reviewed.
Topics: Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Hepatitis D, Chronic; Humans; Interferons; Sofosbuvir; Treatment Outcome; Uridine Monophosphate
PubMed: 25453869
DOI: 10.1016/j.dld.2014.09.024 -
The Journal of Nutrition, Health & Aging 2023To investigate the relationship between Mediterranean diet (MedDiet) adherence and response to an exercise and health education program to prevent... (Randomized Controlled Trial)
Randomized Controlled Trial
Adherence to Mediterranean Diet and Response to an Exercise Program to Prevent Hospitalization-Associated Disability in Older Adults: A Secondary Analysis from a Randomized Controlled Trial.
OBJECTIVES
To investigate the relationship between Mediterranean diet (MedDiet) adherence and response to an exercise and health education program to prevent hospitalization-associated disability (HAD) in acutely hospitalized older adults.
DESIGN
Randomized controlled trial.
SETTING AND PARTICIPANTS
Secondary analysis of a subset of 109 participants from AGECAR-PLUS study with available data on MedDiet adherence (mean age 87, and range 75-98).
INTERVENTION
Participants were randomized into the control group (n = 46, usual care) or the intervention group (n = 63, supervised exercise and health education) at admission.
MEASUREMENTS
MedDiet adherence was measured with MEDAS and through urinary total polyphenols (UTP). Functional status was assessed with the Barthel Index.
RESULTS
At discharge, patients in the intervention group who had low levels of MedDiet or UTP showed an increase in functional status [adjusted mean (95% CI) = 77.8 (70.8-84.8) points, p = 0.005, and adjusted mean (95% CI) = 78.0 (68.3-87.7) points, p = 0.020, respectively].
CONCLUSION
Older individuals over age 75 with low MedDiet adherence were likely to benefit more from a physical exercise and health education intervention.
Topics: Humans; Aged; Aged, 80 and over; Diet, Mediterranean; Uridine Triphosphate; Exercise; Exercise Therapy; Hospitalization
PubMed: 37498097
DOI: 10.1007/s12603-023-1929-6 -
Hepatology (Baltimore, Md.) Dec 2023Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter...
BACKGROUND AND AIMS
Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter phase II pilot trial was carried out, evaluating the nucleotide analog sofosbuvir by treating nine chronically HEV-infected patients with sofosbuvir (Trial Number NCT03282474). During the study, antiviral therapy reduced virus RNA levels initially but did not lead to a sustained virologic response. Here, we characterize the changes in HEV intrahost populations during sofosbuvir treatment to identify the emergence of treatment-associated variants.
APPROACH AND RESULTS
We performed high-throughput sequencing on RNA-dependent RNA polymerase sequences to characterize viral population dynamics in study participants. Subsequently, we used an HEV-based reporter replicon system to investigate sofosbuvir sensitivity in high-frequency variants. Most patients had heterogenous HEV populations, suggesting high adaptability to treatment-related selection pressures. We identified numerous amino acid alterations emerging during treatment and found that the EC 50 of patient-derived replicon constructs was up to ~12-fold higher than the wild-type control, suggesting that variants associated with lower drug sensitivity were selected during sofosbuvir treatment. In particular, a single amino acid substitution (A1343V) in the finger domain of ORF1 could reduce susceptibility to sofosbuvir significantly in 8 of 9 patients.
CONCLUSIONS
In conclusion, viral population dynamics played a critical role during antiviral treatment. High population diversity during sofosbuvir treatment led to the selection of variants (especially A1343V) with lower sensitivity to the drug, uncovering a novel mechanism of resistance-associated variants during sofosbuvir treatment.
Topics: Humans; Sofosbuvir; Antiviral Agents; Hepatitis E; Sustained Virologic Response; Drug Therapy, Combination; Hepacivirus; Genotype; Treatment Outcome
PubMed: 37334496
DOI: 10.1097/HEP.0000000000000514 -
International Journal of Molecular... Oct 2022CTP synthase (CTPS) can form filamentous structures termed cytoophidia in cells in all three domains of life. In order to study the mesoscale structure of cytoophidia,...
CTP synthase (CTPS) can form filamentous structures termed cytoophidia in cells in all three domains of life. In order to study the mesoscale structure of cytoophidia, we perform fluorescence recovery after photobleaching (FRAP) and stimulated emission depletion (STED) microscopy in human cells. By using an EGFP dimeric tag as a tool to explore the physical properties of cytoophidia, we find that cytoophidia are dynamic and reticular. The reticular structure of CTPS cytoophidia may provide space for other components, such as IMPDH. In addition, we observe CTPS granules with tentacles.
Topics: Carbon-Nitrogen Ligases; Cytidine Triphosphate; Humans; Silanes
PubMed: 36233000
DOI: 10.3390/ijms231911698 -
Journal of Medicinal Chemistry Apr 2019Cluster of differentiation 73 (CD73) converts adenosine 5'-monophosphate to immunosuppressive adenosine, and its inhibition was proposed as a new strategy for cancer...
Cluster of differentiation 73 (CD73) converts adenosine 5'-monophosphate to immunosuppressive adenosine, and its inhibition was proposed as a new strategy for cancer treatment. We synthesized 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of purine and pyrimidine nucleosides, which represent nucleoside diphosphate analogues, and compared their CD73 inhibitory potencies. In the adenine series, most ribose modifications and 1-deaza and 3-deaza were detrimental, but 7-deaza was tolerated. Uracil substitution with N-methyl, but not larger groups, or 2-thio, was tolerated. 1,2-Diphosphono-ethyl modifications were not tolerated. N-(Aryl)alkyloxy-cytosine derivatives, especially with bulky benzyloxy substituents, showed increased potency. Among the most potent inhibitors were the 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of 5-fluorouridine (4l), N-benzoyl-cytidine (7f), N-[ O-(4-benzyloxy)]-cytidine (9h), and N-[ O-(4-naphth-2-ylmethyloxy)]-cytidine (9e) ( K values 5-10 nM at human CD73). Selected compounds tested at the two uridine diphosphate-activated P2Y receptor subtypes showed high CD73 selectivity, especially those with large nucleobase substituents. These nucleotide analogues are among the most potent CD73 inhibitors reported and may be considered for development as parenteral drugs.
Topics: 5'-Nucleotidase; Animals; Enzyme Inhibitors; GPI-Linked Proteins; Humans; Purine Nucleotides; Pyrimidine Nucleotides; Rats; Structure-Activity Relationship
PubMed: 30895781
DOI: 10.1021/acs.jmedchem.9b00164 -
Journal of Immunology (Baltimore, Md. :... Jun 2020deploys a unique immune evasion strategy wherein the lacto--neotetraose termini of lipooligosaccharide (LOS) are "capped" by a surface LOS sialyltransferase (Lst),...
deploys a unique immune evasion strategy wherein the lacto--neotetraose termini of lipooligosaccharide (LOS) are "capped" by a surface LOS sialyltransferase (Lst), using extracellular host-derived CMP-sialic acid (CMP-Neu5Ac in humans). LOS sialylation enhances complement resistance by recruiting factor H (FH; alternative complement pathway inhibitor) and also by limiting classical pathway activation. Sialylated LOS also engages inhibitory Siglecs on host leukocytes, dampening innate immunity. Previously, we showed that analogues of CMP-sialic acids (CMP-nonulosonates [CMP-NulOs]), such as CMP-Leg5,7Ac and CMP-Neu5Ac9N, are also substrates for Lst. Incorporation of Leg5,7Ac and Neu5Ac9N into LOS results in being fully serum sensitive. Importantly, intravaginal administration of CMP-Leg5,7Ac attenuated colonization of mouse vaginas. In this study, we characterize and develop additional candidate therapeutic CMP-NulOs. CMP-ketodeoxynonulosonate (CMP-Kdn) and CMP-Kdn7N, but not CMP-Neu4,5Ac, were substrates for Lst, further elucidating gonococcal Lst specificity. Lacto--neotetraose LOS capped with Kdn and Kdn7N bound FH to levels ∼60% of that seen with Neu5Ac and enabled gonococci to resist low (3.3%) but not higher (10%) concentrations of human complement. CMP-Kdn, CMP-Neu5Ac9N, and CMP-Leg5,7Ac administered intravaginally (10 μg/d) to -colonized mice were equally efficacious. Of the three CMP-NulOs above, CMP-Leg5,7Ac was the most pH and temperature stable. In addition, Leg5,7Ac-fed human cells did not display this NulO on their surface. Moreover, CMP-Leg5,7Ac was efficacious against several multidrug-resistant gonococci in mice with a humanized sialome ( mice) or humanized complement system (FH/C4b-binding protein transgenic mice). CMP-Leg5,7Ac and CMP-Kdn remain viable leads as topical preventive/therapeutic agents against the global threat of multidrug-resistant .
Topics: Animals; Cell Line, Tumor; Complement Factor H; Complement System Proteins; Cytidine Monophosphate; Cytidine Monophosphate N-Acetylneuraminic Acid; Drug Resistance, Multiple, Bacterial; Female; Gonorrhea; Humans; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Transgenic; Neisseria gonorrhoeae; Neuraminic Acids; Oligosaccharides; Sialic Acids; Sialyltransferases
PubMed: 32434942
DOI: 10.4049/jimmunol.1901398 -
Biotechnology Advances Oct 2023Glycosyltransferases catalyse the transfer of a glycosyl moiety from a donor to an acceptor. Members of this enzyme class are ubiquitous throughout all kingdoms of life... (Review)
Review
Glycosyltransferases catalyse the transfer of a glycosyl moiety from a donor to an acceptor. Members of this enzyme class are ubiquitous throughout all kingdoms of life and are involved in the biosynthesis of countless types of glycosides. Family 1 glycosyltransferases, also referred to as uridine diphosphate-dependent glycosyltransferases (UGTs), glycosylate small molecules such as secondary metabolites and xenobiotics. In plants, UGTs are recognised for their multiple functionalities ranging from roles in growth regulation and development, in protection against pathogens and abiotic stresses and in adaptation to changing environments. In this study, we review UGT-mediated glycosylation of phytohormones, endogenous secondary metabolites, and xenobiotics and contextualise the role this chemical modification plays in the response to biotic and abiotic stresses and plant fitness. Here, the potential advantages and drawbacks of altering the expression patterns of specific UGTs along with the heterologous expression of UGTs across plant species to improve stress tolerance in plants are discussed. We conclude that UGT-based genetic modification of plants could potentially enhance agricultural efficiency and take part in controlling the biological activity of xenobiotics in bioremediation strategies. However, more knowledge of the intricate interplay between UGTs in plants is needed to unlock the full potential of UGTs in crop resistance.
Topics: Glycosyltransferases; Uridine Diphosphate; Crop Protection; Xenobiotics; Glycosylation; Plants; Phylogeny
PubMed: 37268151
DOI: 10.1016/j.biotechadv.2023.108182 -
Bioorganic & Medicinal Chemistry Letters Aug 2021The G-coupled P2Y receptor (P2YR) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the...
The G-coupled P2Y receptor (P2YR) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2YR agonist and P2YR partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2YR agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2YR potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2YR, respectively. However, 3-alkyl (31-33, 37, 38), β-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2YR activation. Thus, we have identified new α,β-methylene bridged N-extended CDP analogues as P2YR agonists that are highly selective over the P2YR.
Topics: Diphosphonates; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrimidine Nucleotides; Receptors, Purinergic P2; Structure-Activity Relationship
PubMed: 34048882
DOI: 10.1016/j.bmcl.2021.128137