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Journal of Nuclear Medicine : Official... Sep 2022Studies on colony-stimulating factor 1 receptor (CSF-1R) inhibition-induced microglia depletion indicated that inhibitor withdrawal allowed the renewal of the microglia...
Studies on colony-stimulating factor 1 receptor (CSF-1R) inhibition-induced microglia depletion indicated that inhibitor withdrawal allowed the renewal of the microglia compartment via repopulation and resolved the inflammatory imbalance. Therefore, we investigated for the first time (to our knowledge) the effects of microglia repopulation on inflammation and functional outcomes in an ischemic mouse model using translocator protein (TSPO)-PET/CT and MR imaging, ex vivo characterization, and behavioral tests. Eight C57BL/6 mice per group underwent a 30-min transient occlusion of the middle cerebral artery. The treatment group received CSF-1R inhibitor in 1,200 ppm PLX5622 chow (Plexxikon Inc.) from days 3 to 7 to induce microglia/macrophage depletion and then went back to a control diet to allow repopulation. The mice underwent T2-weighted MRI on day 1 after ischemia and F-labeled -diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (F-DPA-714) (TSPO) PET/CT on days 7, 14, 21, and 30. The percentage injected tracer dose per milliliter within the infarct, contralateral striatum, and spleen was assessed. Behavioral tests were performed to assess motor function recovery. Brains were harvested on days 14 and 35 after ischemia for ex vivo analyses (immunoreactivity and real-time quantitative polymerase chain reaction) of microglia- and macrophage-related markers. Repopulation significantly increased F-DPA-714 uptake within the infarct on days 14 ( < 0.001) and 21 ( = 0.002) after ischemia. On day 14, the ionized calcium binding adaptor molecule 1 (Iba-1)-positive cell population showed significantly higher expression of TSPO, CSF-1R, and CD68, in line with microglia repopulation. Gene expression analyses on day 14 indicated a significant increase in microglia-related markers ( and ) with repopulation, whereas peripheral cell recruitment-related gene expression decreased ( and ), indicative of peripheral recruitment during CSF-1R inhibition. Similarly, uncorrected spleen uptake was significantly higher on day 7 after ischemia with treatment ( = 0.001) and decreased after drug withdrawal. PLX5622-treated mice walked a longer distance ( < 0.001) and more quickly ( = 0.009), and showed greater forelimb strength ( < 0.001), than control mice on day 14. This study highlighted the potential of F-DPA-714 PET/CT imaging to track microglia and macrophage repopulation after short-term CSF-1R inhibition in stroke.
Topics: Acetamides; Animals; Calcium; Carrier Proteins; Fluorine Radioisotopes; Infarction; Macrophage Colony-Stimulating Factor; Mice; Mice, Inbred C57BL; Microglia; Organic Chemicals; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Pyrazoles; Pyrimidines; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Stroke
PubMed: 35115368
DOI: 10.2967/jnumed.121.263004 -
Drug Design, Development and Therapy 2019Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment... (Review)
Review
Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25-50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety.
Topics: Administration, Oral; Colitis, Ulcerative; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles
PubMed: 31819376
DOI: 10.2147/DDDT.S182891 -
Molecules (Basel, Switzerland) Mar 2020Pyrazolo[1,5-]pyrimidines -, - and - were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory...
Pyrazolo[1,5-]pyrimidines -, - and - were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-]pyrimidines showed that the pyrazolo[1,5-]pyrimidines (, , , , , , and ) displayed promising antimicrobial and immunomodulatory activities. Studying the in silico predicted physicochemical, pharmacokinetic, ADMET and drug-likeness properties for the pyrazolo[1,5-]pyrimidines -, - and - confirmed that most of the compounds (i) were within the range set by Lipinski's rule of five, (ii) show higher gastrointestinal absorption and inhibition of some CYP isoforms, and (iii) have a carcinogenicity test that was predicted as negative and hERG test that presented medium risk. Moreover, the molecular docking study demonstrated that the compounds , , , , , , and are potent inhibitors of 14-alpha demethylase, transpeptidase and alkaline phosphatase enzymes. This study could be valuable in the discovery of a new series of drugs.
Topics: 14-alpha Demethylase Inhibitors; Alkaline Phosphatase; Anti-Bacterial Agents; Anti-Infective Agents; Aspergillus; Caco-2 Cells; Candida albicans; Carcinogenicity Tests; Computer Simulation; Drug Design; Enterococcus faecalis; Escherichia coli; Fungi; Fusarium; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Molecular Docking Simulation; Molecular Structure; Peptidyl Transferases; Pseudomonas aeruginosa; Pyrazoles; Pyrimidines; Salmonella typhi; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 32245177
DOI: 10.3390/molecules25061431 -
Targeted Oncology May 2021Dysregulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin signaling is common in both indolent and aggressive forms of... (Review)
Review
Dysregulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin signaling is common in both indolent and aggressive forms of malignant lymphoma, for which several targeted therapies have been developed. Copanlisib is a highly selective and potent intravenous pan-class I PI3K inhibitor that has demonstrated durable objective responses and a manageable safety profile in heavily pre-treated patients with indolent lymphomas. As a result, copanlisib monotherapy received accelerated approval from the US Food and Drug Administration for the treatment of adults with relapsed follicular lymphoma who have received at least two systemic therapies, and breakthrough designation for patients with pre-treated relapsed or refractory marginal zone lymphoma. Hyperglycemia and hypertension are among the most frequently reported adverse events with copanlisib monotherapy, and are infusion-related, transient, and manageable with standard therapies. Mild diarrhea is also a common adverse event with copanlisib monotherapy; there is no evidence of worsening severity of diarrhea, or serious gastrointestinal toxicities such as colitis or severe liver enzyme elevations, which have been reported with orally administered PI3K inhibitors. The intravenous route of administration and intermittent dosing schedule of copanlisib may support a favorable tolerability profile over continually administered oral alternatives. Ongoing studies of copanlisib in combination with rituximab and standard-of-care chemotherapy in patients with relapsed indolent lymphoma have the potential to support the use of copanlisib in the second-line setting, providing a much-needed additional therapeutic option in this underserved patient population.
Topics: Humans; Lymphoma; Pyrimidines; Quinazolines
PubMed: 33687623
DOI: 10.1007/s11523-021-00802-9 -
Frontiers in Immunology 2022Pyrimidine metabolism is a hallmark of cancer and will soon become an essential part of cancer therapy. In the tumor microenvironment, cells reprogram pyrimidine...
Pyrimidine metabolism is a hallmark of cancer and will soon become an essential part of cancer therapy. In the tumor microenvironment, cells reprogram pyrimidine metabolism intrinsically and extracellularly, thereby promoting tumorigenesis. Metabolites in pyrimidine metabolism have a significant impact on promoting cancer advancement and modulating immune system responses. In preclinical studies and practical clinical applications, critical targets in pyrimidine metabolism are acted upon by drugs to exert promising therapeutic effects on tumors. However, the pyrimidine metabolism in breast cancer (BC) is still largely underexplored. In this study, 163 credible pyrimidine metabolism-related genes (PMGs) were retrieved, and their somatic mutations and expression levels were determined. In addition, by using The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, 12 PMGs related to the overall survival (OS) were determined using the univariate Cox regression analysis. Subsequently, by performing the LASSO Cox hazards regression analysis in the 12 PMGs in TCGA-BRCA dataset, we developed a prognosis nomogram using eight OS-related PMGs and then verified the same in the METABRIC, GSE96058, GSE20685, GSE42568 and GSE86166 data. Moreover, we validated relationships between the pyrimidine metabolism index (PMI) and the survival probability of patients, essential clinical parameters, including the TNM stage and the PAM50 subtypes. Next, we verified the predictive capability of the optimum model, including the signature, the PAM50 subtype, and age, using ROC analysis and calibration curve, and compared it with other single clinical factors for the predictive power of benefit using decision curve analysis. Finally, we investigated the potential effects of pyrimidine metabolism on immune checkpoints, tumor-infiltrating immune cells, and cytokine levels and determined the potential implications of pyrimidine metabolism in BC immunotherapy. In conclusion, our findings suggest that pyrimidine metabolism has underlying prognostic significance in BC and can facilitate a new management approach for patients with different prognoses and more precise immunotherapy.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Immunosuppressive Agents; Immunotherapy; Pyrimidines; Tumor Microenvironment
PubMed: 36524129
DOI: 10.3389/fimmu.2022.1056680 -
Angewandte Chemie (International Ed. in... Jun 2022Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that...
Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu and Mn . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules.
Topics: Aspartic Acid; Pyrimidines
PubMed: 35304939
DOI: 10.1002/anie.202117211 -
Journal of the American Chemical Society Oct 2022Given the ubiquity of heterocycles in biologically active molecules, transformations with the capacity to modify such molecular skeletons with modularity remain highly...
Given the ubiquity of heterocycles in biologically active molecules, transformations with the capacity to modify such molecular skeletons with modularity remain highly desirable. Ring expansions that enable interconversion of privileged heterocyclic motifs are especially interesting in this regard. As such, the known mechanisms for ring expansion and contraction determine the classes of heterocycle amenable to skeletal editing. Herein, we report a reaction that selectively cleaves the N-N bond of pyrazole and indazole cores to afford pyrimidines and quinazolines, respectively. This chlorodiazirine-mediated reaction provides a unified route to a related pair of heterocycles that are otherwise typically prepared by divergent approaches. Mechanistic experiments and DFT calculations support a pathway involving pyrazolium ylide fragmentation followed by cyclization of the ring-opened diazahexatriene intermediate to yield the new diazine core. Beyond enabling access to valuable heteroarenes from easily prepared starting materials, we demonstrate the synthetic utility of skeletal editing in the synthesis of a Rosuvastatin analog as well as in an aryl vector-adjusting direct scaffold hop.
Topics: Carbon; Quinazolines; Pyrimidines; Rosuvastatin Calcium; Indazoles
PubMed: 36240487
DOI: 10.1021/jacs.2c09616 -
Lipids in Health and Disease Nov 2022Chronic nonspecific low back pain (cNLBP) is a common health problem worldwide, affecting 65-80% of the population and greatly affecting people's quality of life and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic nonspecific low back pain (cNLBP) is a common health problem worldwide, affecting 65-80% of the population and greatly affecting people's quality of life and productivity. It also causes huge economic losses. Manual therapy (MT) and therapeutic exercise (TE) are effective treatment options for cNLBP physiotherapy-based treatment. However, the underlying mechanisms that promote cNLBP amelioration by MT or TE are incompletely understood.
METHODS
Seventeen recruited subjects were randomly divided into an MT group and a TE group. Subjects in the MT group performed muscular relaxation, myofascial release, and mobilization for 20 min during each treatment session. The treatment lasted for a total of six sessions, once every two days. Subjects in the TE group completed motor control and core stability exercises for 30 min during each treatment session. The motor control exercise included stretching of the trunk and extremity muscles through trunk and hip rotation and flexion training. Stabilization exercises consisted of the (1) bridge exercise, (2) single-leg-lift bridge exercise, (3) side bridge exercise, (4) two-point bird-dog position with an elevated contralateral leg and arm, (5) bear crawl exercise, and (6) dead bug exercise. The treatment lasted for a total of six sessions, with one session every two days. Serum samples were collected from subjects before and after physiotherapy-based treatment for lipidomic and metabolomic measurements.
RESULTS
Through lipidomic analysis, we found that the phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio decreased and the sphingomyelin/ceramide (SM/Cer) ratio increased in cNLBP patients after MT or TE treatment. In addition, eight metabolites enriched in pyrimidine and purine differed significantly in cNLBP patients who received MT treatment. A total of nine metabolites enriched in pyrimidine, tyrosine, and galactose pathways differed significantly in cNLBP patients after TE treatment during metabolomics analysis.
CONCLUSION
Our study was the first to elucidate the alterations in the lipidomics and metabolomics of cNLBP physiotherapy-based treatment and can expand our knowledge of cNLBP physiotherapy-based treatment.
Topics: Lipids; Low Back Pain; Physical Therapy Modalities; Pyrimidines; Quality of Life; Humans
PubMed: 36434687
DOI: 10.1186/s12944-022-01737-4 -
Nucleic Acids Research Aug 20235-Methylated cytosine is a frequent modification in eukaryotic RNA and DNA influencing mRNA stability and gene expression. Here we show that free 5-methylcytidine (5mC)...
5-Methylated cytosine is a frequent modification in eukaryotic RNA and DNA influencing mRNA stability and gene expression. Here we show that free 5-methylcytidine (5mC) and 5-methyl-2'-deoxycytidine are generated from nucleic acid turnover in Arabidopsis thaliana, and elucidate how these cytidines are degraded, which is unclear in eukaryotes. First CYTIDINE DEAMINASE produces 5-methyluridine (5mU) and thymidine which are subsequently hydrolyzed by NUCLEOSIDE HYDROLASE 1 (NSH1) to thymine and ribose or deoxyribose. Interestingly, far more thymine is generated from RNA than from DNA turnover, and most 5mU is directly released from RNA without a 5mC intermediate, since 5-methylated uridine (m5U) is an abundant RNA modification (m5U/U ∼1%) in Arabidopsis. We show that m5U is introduced mainly by tRNA-SPECIFIC METHYLTRANSFERASE 2A and 2B. Genetic disruption of 5mU degradation in the NSH1 mutant causes m5U to occur in mRNA and results in reduced seedling growth, which is aggravated by external 5mU supplementation, also leading to more m5U in all RNA species. Given the similarities between pyrimidine catabolism in plants, mammals and other eukaryotes, we hypothesize that the removal of 5mU is an important function of pyrimidine degradation in many organisms, which in plants serves to protect RNA from stochastic m5U modification.
Topics: Animals; RNA; Thymine; Uridine; Pyrimidines; Arabidopsis; DNA; Mammals
PubMed: 37334828
DOI: 10.1093/nar/gkad529 -
Molecules (Basel, Switzerland) Oct 2019A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the...
A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,β-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.
Topics: Acetates; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Neoplasms; Nitrogen; Pregnenolone; Pyrimidines; Steroids; Structure-Activity Relationship
PubMed: 31614780
DOI: 10.3390/molecules24203676