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Life (Basel, Switzerland) Oct 2023The aim of the study was to perform a comprehensive fundamental analysis of the factors of inflammation, oxidative stress, fibrosis, myocardial dysfunction, ischemia and...
The aim of the study was to perform a comprehensive fundamental analysis of the factors of inflammation, oxidative stress, fibrosis, myocardial dysfunction, ischemia and omega-3 index associated with postoperative atrial fibrillation (POAF) after coronary artery bypass graft (CABG) surgery in patients with coronary artery disease. The study involved 158 patients who were admitted to the hospital to undergo CABG surgery. Patients were divided into two groups: group 1 comprised 111 patients without POAF (82% males, median age-62.0 (56.0; 66.0) years), and group 2 comprised 47 patients with POAF (84.4% males, median age-65.0 (61.0; 70.0) years). POAF occurred 5.2 (2.0; 7.0) days after CABG. In all the patients, we evaluated laboratory tests before and 3-4 days after CABG. All the patients also underwent echocardiography. According to results of multifactorial regression analysis, the odds ratio of POAF development for left atrial diameter >41 mm was 4.3 (95% confidence interval (CI) 2.0-9.7, < 0.001), interleukin (IL)-6 postoperative levels >22.07 pg/mL-3.0 (95% CI 1.4-8.2, = 0.006), IL-8 postoperative levels >9.67 pg/mL-2.3 (95% CI 1.2-7.3, = 0.006), superoxide dismutase postoperative levels in plasma >1100.5 U/g-3.2 (95% CI 1.4-9.2, = 0.03), glutathione postoperative levels ≤0.194 micromole/g of hemoglobin-1.9 (95% CI 1.2-6.3, < 0.001), glutathione peroxidase postoperative levels ≤17.36 millimole/g of hemoglobin-2.2 (95% CI 1.1-8.2, < 0.001), glutathione reductase postoperative levels ≤2.99 millimole/g of hemoglobin-2.3 (95% CI, 1.1-5.7, < 0.001), malondialdehyde postoperative levels >1.25 micromole/g of hemoglobin-2.0 (95% CI, 1.2-7.9, < 0.001), NO postoperative levels in plasma >36.4 micromole/L-1.5 (95% CI, 1.1-5.9, < 0.001) and omega-3 index ≤1.59%-2.6 (95% CI 1.5-9.1, < 0.001). Our study showed that increased left atrial diameter, high postoperative levels of inflammatory factors, oxidative stress, fibrosis indicators and omega-3 index were associated with POAF in patients who underwent CABG.
PubMed: 37895417
DOI: 10.3390/life13102035 -
RSC Medicinal Chemistry Oct 2023Of the various WD40 family proteins, WDR5 is a particularly important multifunctional adaptor protein that can bind to several protein complexes to regulate gene...
Of the various WD40 family proteins, WDR5 is a particularly important multifunctional adaptor protein that can bind to several protein complexes to regulate gene activation, so it was considered as a promising epigenetic target in anti-cancer drug development. Despite many inhibitors having been discovered directing against the arginine-binding cavity in WDR5 called the WIN site, the side hydrophobic cavity called the WBM site receives rather scant attention. Herein, we aim to obtain novel WBM-targeted peptidic inhibitors with high potency and selectivity. We employed two improved biopanning approaches with a disulfide-constrained cyclic peptide phage library containing 7 randomized residues and identified several peptides with micromole binding activity by docking and binding assay. To further optimize the stability and activity, 9 thiol-reactive chemical linkers were utilized in the cyclization of the candidate peptide DH226027, which had good binding affinity. This study provides an effective method to discover potent peptides targeting protein-protein interactions and highlights a broader perspective of peptide-mimic drugs.
PubMed: 37859722
DOI: 10.1039/d3md00288h -
Nature Communications Sep 2023For decarbonization of ammonia production in industry, alternative methods by exploiting renewable energy sources have recently been explored. Nonetheless, they still...
For decarbonization of ammonia production in industry, alternative methods by exploiting renewable energy sources have recently been explored. Nonetheless, they still lack yield and efficiency to be industrially relevant. Here, we demonstrate an advanced approach of nitrogen fixation to synthesize ammonia at ambient conditions via laser-induced multiphoton dissociation of lithium oxide. Lithium oxide is dissociated under non-equilibrium multiphoton absorption and high temperatures under focused infrared light, and the generated zero-valent metal spontaneously fixes nitrogen and forms a lithium nitride, which upon subsequent hydrolysis generates ammonia. The highest ammonia yield rate of 30.9 micromoles per second per square centimeter is achieved at 25 °C and 1.0 bar nitrogen. This is two orders of magnitude higher than state-of-the-art ammonia synthesis at ambient conditions. The focused infrared light here is produced by a commercial simple CO laser, serving as a demonstration of potentially solar pumped lasers for nitrogen fixation and other high excitation chemistry. We anticipate such laser-involved technology will bring unprecedented opportunities to realize not only local ammonia production but also other new chemistries .
PubMed: 37704640
DOI: 10.1038/s41467-023-41441-0 -
Orphanet Journal of Rare Diseases Sep 2023Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in the OAT gene, encoding the enzyme ornithine...
BACKGROUND
Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in the OAT gene, encoding the enzyme ornithine δ-aminotransferase. Impaired enzymatic activity leads to systemic hyperornithinaemia, which in turn underlies progressive chorioretinal degeneration. In this study, we describe the clinical and molecular findings in a cohort of individuals with gyrate atrophy.
METHODS
Study participants were recruited through a tertiary UK clinical ophthalmic genetic service. All cases had a biochemical and molecular diagnosis of gyrate atrophy. Retrospective phenotypic and biochemical data were collected using electronic healthcare records.
RESULTS
18 affected individuals from 12 families (8 male, 10 female) met the study inclusion criteria. The median age at diagnosis was 8 years (range 10 months - 33 years) and all cases had hyperornithinaemia (median: 800 micromoles/L; range: 458-1244 micromoles/L). Common features at presentation included high myopia (10/18) and nyctalopia (5/18). Ophthalmic findings were present in all study participants who were above the age of 6 years. One third of patients had co-existing macular oedema and two thirds developed pre-senile cataracts. Compliance with dietary modifications was suboptimal in most cases. A subset of participants had extraocular features including a trend towards reduced fat-free mass and developmental delay.
CONCLUSIONS
Our findings highlight the importance of multidisciplinary care in families with gyrate atrophy. Secondary ophthalmic complications such as macular oedema and cataract formation are common. Management of affected individuals remains challenging due to the highly restrictive nature of the recommended diet and the limited evidence-base for current strategies.
Topics: Humans; Female; Male; Infant; Child; Gyrate Atrophy; Macular Edema; Retrospective Studies; Retina; Cataract
PubMed: 37667371
DOI: 10.1186/s13023-023-02840-0 -
Pediatric Nephrology (Berlin, Germany) Feb 2024Acute kidney injury (AKI) is a frequent complication of children admitted to the paediatric intensive care unit. One key management modality of AKI is the use of...
BACKGROUND
Acute kidney injury (AKI) is a frequent complication of children admitted to the paediatric intensive care unit. One key management modality of AKI is the use of diuretics to reduce fluid overload. Aminophylline, a drug that is well known for its use in the treatment of bronchial asthma, is also purported to have diuretic effects on the kidneys. This retrospective cohort study assesses the effect of aminophylline in critically ill children with AKI.
METHODS
A retrospective chart review of children admitted to the paediatric intensive care unit of the Red Cross War Memorial Children's Hospital (RCWMCH) with AKI who received aminophylline (from 2012 to June 2018) was carried out. Data captured and analyzed included demographics, underlying disease conditions, medications, urine output, fluid balance, and kidney function.
RESULTS
Data from thirty-four children were analyzed. Urine output increased from a median of 0.4 mls/kg/hr [IQR: 0.1, 1.1] at six hours prior to aminophylline administration to 0.6 mls/kg/hr [IQR: 0.2, 1.9] at six hours and 1.6 mls/kg/hr [IQR:0.2, 4.2] at twenty-four hours post aminophylline therapy. The median urine output significantly varied across the age groups over the 24-h time period post-aminophylline, with the most response in the neonates. There was no significant change in serum creatinine levels six hours post-aminophylline administration [109(IQR: 77, 227)-125.5(IQR: 82, 200) micromole/l] P-value = 0.135. However, there were significant age-related changes in creatinine levels at six hours post-aminophylline therapy.
CONCLUSIONS
Aminophylline increases urine output in critically ill children with AKI. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Child; Infant, Newborn; Humans; Aminophylline; Retrospective Studies; Critical Illness; Diuretics; Acute Kidney Injury; Kidney
PubMed: 37532898
DOI: 10.1007/s00467-023-06065-y -
Genes & Diseases Jul 2023Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of...
Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted.
PubMed: 37397523
DOI: 10.1016/j.gendis.2022.12.005 -
Rheumatology (Oxford, England) Jul 2023To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalizations for gout.
OBJECTIVE
To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalizations for gout.
METHODS
Using linked Clinical Practice Research Datalink and NHS Digital Hospital Episode Statistics data, we described the incidence and timing of hospitalizations for flares in people with index gout diagnoses in England from 2004-2020. Using Cox proportional hazards and propensity models, we investigated associations between ULT initiation, serum urate target attainment, colchicine prophylaxis, and the risk of hospitalizations for gout.
RESULTS
Of 292 270 people with incident gout, 7719 (2.64%) had one or more hospitalizations for gout, with an incidence rate of 4.64 hospitalizations per 1000 person-years (95% CI 4.54, 4.73). There was an associated increased risk of hospitalizations within the first 6 months after ULT initiation, when compared with people who did not initiate ULT [adjusted Hazard Ratio (aHR) 4.54; 95% CI 3.70, 5.58; P < 0.001]. Hospitalizations did not differ significantly between people prescribed vs not prescribed colchicine prophylaxis in fully adjusted models. From 12 months after initiation, ULT associated with a reduced risk of hospitalizations (aHR 0.77; 95% CI 0.71, 0.83; P < 0.001). In ULT initiators, attainment of a serum urate <360 micromol/l within 12 months of initiation associated with a reduced risk of hospitalizations (aHR 0.57; 95% CI 0.49, 0.67; P < 0.001) when compared with people initiating ULT but not attaining this target.
CONCLUSION
ULT associates with an increased risk of hospitalizations within the first 6 months of initiation but reduces hospitalizations in the long term, particularly when serum urate targets are achieved.
Topics: Humans; Uric Acid; Cohort Studies; Gout Suppressants; Gout; Hospitalization; Colchicine; England
PubMed: 36355461
DOI: 10.1093/rheumatology/keac638