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Discovery of coumaric acid derivatives hinted by coastal marine source to seek for uric acid lowering agents.

ABSTRACT: In this work, a series of novel compounds Spartinin C1-C24 were screened, synthesised and evaluated for inhibiting xanthine oxidase thus lowering serum uric acid level. The backbones were derived from the components of coastal marine source Spartina alterniflora and marketed drugs. The top hits Spartinin C10 & C22 suggested high inhibition percentages (78.54 and 93.74) at 10 μM dosage, which were higher than the positive control Allopurinol. They were low cytotoxic onto human normal hepatocyte cells. Treatment with Spartinin C10 could lower the serum uric acid level to 440.0 μM in the hyperuricemic model mice (723.0 μM), comparable with Allopurinol (325.8 μM). Spartinin C10 was more appreciated than Allopurinol on other serum indexes. The preliminary pharmacokinetics evaluation indicated that the rapid absorption, metabolism and elimination of Spartinin C10 should be further improved. The discovery of pharmaceutical molecules from coastal marine source here might inspire the inter-disciplinary investigations on public health.

SUBMITTER: Yang YS

PROVIDER: S-EPMC9848256 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Discovery of coumaric acid derivatives hinted by coastal marine source to seek for uric acid lowering agents.

Yang Yu-Shun YS Wang Bin B Liu Junzhong J Li Qin Q Jiao Qin-Cai QC Qin Pei P

Journal of enzyme inhibition and medicinal chemistry 20231201 1

In this work, a series of novel compounds Spartinin C1-C24 were screened, synthesised and evaluated for inhibiting xanthine oxidase thus lowering serum uric acid level. The backbones were derived from the components of coastal marine source Spartina alterniflora and marketed drugs. The top hits Spartinin C10 & C22 suggested high inhibition percentages (78.54 and 93.74) at 10 μM dosage, which were higher than the positive control Allopurinol. They were low cytotoxic on ...[more]

PMID: 36629443

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Project description:ImportanceUric acid is a waste metabolite produced from the breakdown of purines, and elevated serum uric acid levels are associated with higher risk of hypertension, cardiovascular disease, and mortality and progression of chronic kidney disease (CKD). Treatment of hyperuricemia in patients with preexisting CKD has not been shown to improve kidney outcomes, but the associations of uric acid-lowering therapies with the development of new-onset kidney disease in patients with estimated glomerular filtration rate (eGFR) within reference range and no albuminuria is unclear.ObjectiveTo examine the association of initiating uric acid-lowering therapy with the incidence of CKD.Design, setting, and participantsThis cohort study included patients with eGFR of 60 mL/min/1.73 m2 or greater and no albuminuria treated at US Department of Veterans Affairs health care facilities from 2004 to 2019. Clinical trial emulation methods, including propensity score weighting, were used to minimize confounding. Data were analyzed from 2020 to 2022.ExposureNewly started uric acid-lowering therapy.Main outcomes and measuresThe main outcomes were incidences of eGFR less than 60 mL/min/1.73 m2, new-onset albuminuria, and end-stage kidney disease.ResultsA total of 269 651 patients were assessed (mean [SD] age, 57.4 [12.5] years; 252 171 [94%] men). Among these, 29 501 patients (10.9%) started uric acid-lowering therapy, and 240 150 patients (89.1%) did not. Baseline characteristics, including serum uric acid level, were similar among treated and untreated patients after propensity score weighting. In the overall cohort, uric acid-lowering therapy was associated with higher risk of both incident eGFR less than 60 mL/min/1.73 m2 (weighted subhazard ratio [SHR], 1.15 [95% CI, 1.10-1.20; P < .001) and incident albuminuria (SHR, 1.05 [95% CI, 1.01-1.09; P < .001) but was not associated with the risk of end-stage kidney disease (SHR, 0.96 [95% CI, 0.62-1.50]; P = .87). In subgroup analyses, the association of uric acid-lowering therapy with worse kidney outcomes was limited to patients with baseline serum uric acid levels of 8 mg/dL or less.Conclusions and relevanceThese findings suggest that in patients with kidney function within reference range, uric acid-lowering therapy was not associated with beneficial kidney outcomes and may be associated with potential harm in patients with less severely elevated serum uric acid levels.

Project description:We have looked at the transcriptional response of well characterised Synechococcus open ocean (WH8102) and coastal (CC9311) isolates to two DNA damaging agents, mitomycin C and ethidium bromide, using whole genome expression microarrays. The coastal strain, which was able to grow on higher concentrations of both chemicals, showed differential regulation of a larger proportion of its genome following M-bM-^@M-^Xtoxic shockM-bM-^@M-^Y treatment with each agent. Many of the orthologous genes in these strains, including those encoding sensor kinases, showed different transcriptional responses, with the CC9311 genes more likely to show significant changes for each tested treatment. While the overall response of each strain was considerably different, there were distinct transcriptional responses common to both strains observed for each DNA damaging agent, linked to the mode of action of each chemical. In both CC9311 and WH8102 there was evidence of SOS response induction under mitomycin C treatment, with genes encoding recA, the lexA repressor and umuC significantly upregulated in this experiment but not under ethidium bromide treatment. Conversely, ethidium bromide treatment tended to result in upregulation of the DNA-directed RNA polymerase genes, not observed following mitomycin C treatment. Interestingly, a large number of genes residing on putative genomic island regions of each genome also showed significant upregulation under one or both chemical treatments. In this series four conditions have been analyzed. These are 2 hour incubations (shock treatment) with ethidium bromide (EB, final conc 2ug/mL) and mitomycin C (MC, final conc 0.5 ug/mL) for Synechococcus sp. WH8102 and CC9311. For each slide, an experimental RNA sample was labeled with Cy3 or Cy5 and was hybridized with a reference RNA from a control sample (no addition of chemical agent) labeled with the other Cy dye. There are six slides per condition, each with at least two biological replicates and three technical replicates, including at least one flip-dye comparison. Each slide contains six replicate spots per gene.

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Discovery of coumaric acid derivatives hinted by coastal marine source to seek for uric acid lowering agents.

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Discovery of coumaric acid derivatives hinted by coastal marine source to seek for uric acid lowering agents.

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