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Frontiers in Endocrinology 2023In this comprehensive review, we examine the main preclinical and clinical investigations assessing the effects of different forms of choline supplementation currently... (Review)
Review
In this comprehensive review, we examine the main preclinical and clinical investigations assessing the effects of different forms of choline supplementation currently available, including choline alfoscerate (CHNOP), also known as alpha-glycerophosphocholine (α-GPC, or GPC), choline bitartrate, lecithin, and citicoline, which are cholinergic compounds and precursors of acetylcholine. Extensively used as food supplements, they have been shown to represent an effective strategy for boosting memory and enhancing cognitive function.
Topics: Choline; Glycerylphosphorylcholine; Acetylcholine; Dietary Supplements; Cytidine Diphosphate Choline
PubMed: 36950691
DOI: 10.3389/fendo.2023.1148166 -
Revista de Neurologia Nov 2022This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3):... (Review)
Review
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
Topics: Humans; Cytidine Diphosphate Choline; Nootropic Agents; Stroke; Cognitive Dysfunction; Brain Injuries, Traumatic
PubMed: 36544369
DOI: 10.33588/rn.75s05.2022311 -
Nature Protocols Mar 2023The comet assay is a versatile method to detect nuclear DNA damage in individual eukaryotic cells, from yeast to human. The types of damage detected encompass DNA strand... (Review)
Review
The comet assay is a versatile method to detect nuclear DNA damage in individual eukaryotic cells, from yeast to human. The types of damage detected encompass DNA strand breaks and alkali-labile sites (e.g., apurinic/apyrimidinic sites), alkylated and oxidized nucleobases, DNA-DNA crosslinks, UV-induced cyclobutane pyrimidine dimers and some chemically induced DNA adducts. Depending on the specimen type, there are important modifications to the comet assay protocol to avoid the formation of additional DNA damage during the processing of samples and to ensure sufficient sensitivity to detect differences in damage levels between sample groups. Various applications of the comet assay have been validated by research groups in academia, industry and regulatory agencies, and its strengths are highlighted by the adoption of the comet assay as an in vivo test for genotoxicity in animal organs by the Organisation for Economic Co-operation and Development. The present document includes a series of consensus protocols that describe the application of the comet assay to a wide variety of cell types, species and types of DNA damage, thereby demonstrating its versatility.
Topics: Animals; Humans; Comet Assay; DNA Damage; Pyrimidine Dimers; Eukaryotic Cells; DNA
PubMed: 36707722
DOI: 10.1038/s41596-022-00754-y -
Journal of Applied Genetics Aug 2018Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus "cis" sequences that define exon-intron boundaries and... (Review)
Review
Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus "cis" sequences that define exon-intron boundaries and regulatory sequences recognized by splicing machinery. Point mutations at these consensus sequences can cause improper exon and intron recognition and may result in the formation of an aberrant transcript of the mutated gene. The splicing mutation may occur in both introns and exons and disrupt existing splice sites or splicing regulatory sequences (intronic and exonic splicing silencers and enhancers), create new ones, or activate the cryptic ones. Usually such mutations result in errors during the splicing process and may lead to improper intron removal and thus cause alterations of the open reading frame. Recent research has underlined the abundance and importance of splicing mutations in the etiology of inherited diseases. The application of modern techniques allowed to identify synonymous and nonsynonymous variants as well as deep intronic mutations that affected pre-mRNA splicing. The bioinformatic algorithms can be applied as a tool to assess the possible effect of the identified changes. However, it should be underlined that the results of such tests are only predictive, and the exact effect of the specific mutation should be verified in functional studies. This article summarizes the current knowledge about the "splicing mutations" and methods that help to identify such changes in clinical diagnosis.
Topics: Algorithms; Computational Biology; Computer Simulation; DNA Mutational Analysis; Exons; Genetic Diseases, Inborn; Humans; Introns; Mutation; Point Mutation; Pyrimidine Nucleotides; RNA Splice Sites; RNA Splicing
PubMed: 29680930
DOI: 10.1007/s13353-018-0444-7 -
Cell Nov 2021The cyclic pyrimidines 3',5'-cyclic cytidine monophosphate (cCMP) and 3',5'-cyclic uridine monophosphate (cUMP) have been reported in multiple organisms and cell types....
The cyclic pyrimidines 3',5'-cyclic cytidine monophosphate (cCMP) and 3',5'-cyclic uridine monophosphate (cUMP) have been reported in multiple organisms and cell types. As opposed to the cyclic nucleotides 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP), which are second messenger molecules with well-established regulatory roles across all domains of life, the biological role of cyclic pyrimidines has remained unclear. Here we report that cCMP and cUMP are second messengers functioning in bacterial immunity against viruses. We discovered a family of bacterial pyrimidine cyclase enzymes that specifically synthesize cCMP and cUMP following phage infection and demonstrate that these molecules activate immune effectors that execute an antiviral response. A crystal structure of a uridylate cyclase enzyme from this family explains the molecular mechanism of selectivity for pyrimidines as cyclization substrates. Defense systems encoding pyrimidine cyclases, denoted here Pycsar (pyrimidine cyclase system for antiphage resistance), are widespread in prokaryotes. Our results assign clear biological function to cCMP and cUMP as immunity signaling molecules in bacteria.
Topics: Amino Acid Sequence; Bacteria; Bacteriophages; Burkholderia; Cyclic CMP; Cyclization; Escherichia coli; Models, Molecular; Mutation; Nucleotides, Cyclic; Phosphorus-Oxygen Lyases; Pyrimidines; Uridine Monophosphate
PubMed: 34644530
DOI: 10.1016/j.cell.2021.09.031 -
Science (New York, N.Y.) Apr 2021Mutations in the or tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target...
Mutations in the or tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of -deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. -deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of -deficient cancers to PARPi therapy.
Topics: Antineoplastic Agents; Apoptosis; CRISPR-Cas Systems; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Replication; DNA, Neoplasm; Deoxycytidine Monophosphate; Deoxyuracil Nucleotides; Drug Resistance, Neoplasm; Genes, BRCA1; Humans; Hydrolysis; N-Glycosyl Hydrolases; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins; Synthetic Lethal Mutations; Thymidine; Uracil-DNA Glycosidase
PubMed: 33833118
DOI: 10.1126/science.abb4542 -
Nature Nov 2023Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge. Here we report a...
Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge. Here we report a therapeutic vulnerability in a sugar nucleotide biosynthetic pathway that can be exploited in cancer cells with only a limited impact on normal cells. A systematic examination of conditionally essential metabolic enzymes revealed that UXS1, a Golgi enzyme that converts one sugar nucleotide (UDP-glucuronic acid, UDPGA) to another (UDP-xylose), is essential only in cells that express high levels of the enzyme immediately upstream of it, UGDH. This conditional relationship exists because UXS1 is required to prevent excess accumulation of UDPGA, which is produced by UGDH. UXS1 not only clears away UDPGA but also limits its production through negative feedback on UGDH. Excess UDPGA disrupts Golgi morphology and function, which impedes the trafficking of surface receptors such as EGFR to the plasma membrane and diminishes the signalling capacity of cells. UGDH expression is elevated in several cancers, including lung adenocarcinoma, and is further enhanced during chemoresistant selection. As a result, these cancer cells are selectively dependent on UXS1 for UDPGA detoxification, revealing a potential weakness in tumours with high levels of UGDH.
Topics: Humans; Neoplasms; Signal Transduction; Uridine Diphosphate Glucuronic Acid; Uridine Diphosphate Xylose; Adenocarcinoma of Lung; Lung Neoplasms
PubMed: 37880368
DOI: 10.1038/s41586-023-06676-3 -
Nutrients Jan 2023Cognitive impairment is a staggering personal and societal burden; accordingly, there is a strong interest in potential strategies for its prevention and treatment.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cognitive impairment is a staggering personal and societal burden; accordingly, there is a strong interest in potential strategies for its prevention and treatment. Nutritional supplements have been extensively investigated, and citicoline seems to be a promising agent; its role in clinical practice, however, has not been established. We systematically reviewed studies on the effect of citicoline on cognitive performance.
METHODS
We searched the PubMed and Cochrane Library databases for articles published between 2010 and 2022. Relevant information was extracted and presented following the PRISMA recommendations. Data were pooled using the inverse-variance method with random effects models.
RESULTS
We selected seven studies including patients with mild cognitive impairment, Alzheimer's disease or post-stroke dementia. All the studies showed a positive effect of citicoline on cognitive functions. Six studies could be included in the meta-analysis. Overall, citicoline improved cognitive status, with pooled standardized mean differences ranging from 0.56 (95% CI: 0.37-0.75) to 1.57 (95% CI: 0.77-2.37) in different sensitivity analyses. The overall quality of the studies was poor.
DISCUSSION
Available data indicate that citicoline has positive effects on cognitive function. The general quality of the studies, however, is poor with significant risk of bias in favor of the intervention. Other: PubMed and the Cochrane Library.
Topics: Humans; Cytidine Diphosphate Choline; Alzheimer Disease; Cognitive Dysfunction; Cognition Disorders; Cognition
PubMed: 36678257
DOI: 10.3390/nu15020386 -
International Journal of Environmental... Sep 2022The presence of latent myofascial trigger points (MTrPs) in the gluteus medius is one of the possible causes of non-specific low back pain. Dry needling (DN) and... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of Dry Needling and Ischemic Trigger Point Compression in the Gluteus Medius in Patients with Non-Specific Low Back Pain: A Randomized Short-Term Clinical Trial.
BACKGROUND
The presence of latent myofascial trigger points (MTrPs) in the gluteus medius is one of the possible causes of non-specific low back pain. Dry needling (DN) and ischemic compression (IC) techniques may be useful for the treatment of these MTrPs.
METHODS
For this study, 80 participants were randomly divided into two groups: the dry needling group, who received a single session of DN to the gluteus medius muscle plus hyperalgesia ( = 40), and the IC group, who received a single session of IC to the gluteus medius muscle plus hyperalgesia ( = 40). Pain intensity, the pressure pain threshold (PPT), range of motion (ROM), and quality of life were assessed at baseline, immediately after treatment, after 48 h, and one week after treatment.
RESULTS
Statistically significant differences were shown between the two groups immediately after the intervention, showing a decrease in PPT ( < 0.05) in the DN group and an increase in PPT in the IC group. These values increased more and were better maintained at 48 h and after one week of treatment in the DN group than in the IC group. Quality of life improved in both groups, with greater improvement in the DN group than in the IC group.
CONCLUSIONS
IC could be more advisable than DN with respect to UDP and pain intensity in the most hyperalgesic latent MTrPs of the gluteus medius muscle in subjects with non-specific low back pain, immediately after treatment. DN may be more effective than IC in terms of PPT, pain intensity, and quality of life in treating latent plus hyperalgesic gluteus medius muscle MTrPs in subjects with non-specific low back pain after 48 h and after one week of treatment.
Topics: Dry Needling; Humans; Hyperalgesia; Low Back Pain; Quality of Life; Trigger Points; Uridine Diphosphate
PubMed: 36231767
DOI: 10.3390/ijerph191912468 -
Cold Spring Harbor Perspectives in... Jul 2021
Review
Topics: Animals; Humans; Nucleosides; Purine Nucleotides; Pyrimidine Nucleotides; Signal Transduction
PubMed: 34210662
DOI: 10.1101/cshperspect.a040592