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American Journal of Obstetrics and... Jun 2024The principal fetal energy source is glucose provided by the placental transfer of maternal glucose. However, the placenta's glucose consumption exhibits considerable...
BACKGROUND
The principal fetal energy source is glucose provided by the placental transfer of maternal glucose. However, the placenta's glucose consumption exhibits considerable variation. Hexokinase is the first and one of the rate-limiting enzymes of glycolysis that phosphorylates glucose to glucose-6-phosphate. The role of placental hexokinase activity in human placental glucose metabolism is unknown.
OBJECTIVE
This study aimed to test the hypothesis that placental hexokinase activity is related to maternal body mass index, placental glucose uptake and consumption, and birthweight.
STUDY DESIGN
Overall, 67 healthy pregnant participants at term were included in this study at Oslo University Hospital, Oslo, Norway. Placental hexokinase activity was measured by using a colorimetric assay. The mass of glucose taken up by the uteroplacental unit and the fetus was obtained by measuring arteriovenous glucose differences combined with Doppler assessment of uterine and umbilical blood flow. Blood samples were obtained from the maternal radial artery, uterine vein, and umbilical artery and vein. The uteroplacental glucose consumption constituted the difference between uteroplacental and fetal glucose uptakes. The Spearman rank correlation was performed for statistical analyses to study the correlation of placental hexokinase activity (milliunit per milligram of protein) with prepregnancy body mass index, maternal glucose and insulin, birthweight, uteroplacental glucose uptake and consumption, and fetal glucose uptake (micromole per minute). Partial rank correlation analysis was performed when controlling for hours of fasting or placental weight.
RESULTS
Hexokinase activity was detectable in all placental tissue samples. The mean activity was 19.6 (standard deviation, 4.64) mU/mg protein. Placental hexokinase activity correlated positively with prepregnancy body mass index (Spearman rho=0.33; P=.006). On controlling for hours of fasting, hexokinase activity showed positive correlations with both maternal glucose (r=0.30; P=.01) and insulin (r=0.28; P=.02). Hexokinase activity was positively correlated with uteroplacental glucose uptake (Spearman rho=0.31; P=.01) and consumption (Spearman rho=0.28; P=.02). Hexokinase activity did not correlate with fetal glucose uptake. On controlling for placental weight, hexokinase activity showed a positive correlation with birthweight (r=0.31; P=.01).
CONCLUSION
Our findings suggest that placental hexokinase, being crucial for uteroplacental retention of glucose for disposition, is related to both maternal body mass index and birthweight independent of placental weight. Placental hexokinase may play a central role in the relationship between maternal glucose dysregulation and fetal growth. Thus, the current study supports the need to develop clinically useful tools to assess the metabolic properties of the placenta.
Topics: Humans; Female; Hexokinase; Pregnancy; Placenta; Body Mass Index; Birth Weight; Adult; Glucose; Blood Glucose; Infant, Newborn
PubMed: 37925123
DOI: 10.1016/j.ajog.2023.10.043 -
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 -
Cureus Jun 2023Background Placenta-mediated complications, such as preeclampsia, placental abruption, and fetal growth restriction, can indeed lead to significant maternal and...
Background Placenta-mediated complications, such as preeclampsia, placental abruption, and fetal growth restriction, can indeed lead to significant maternal and perinatal morbidity and mortality. Early detection and management of these conditions are crucial to ensuring optimal outcomes for both the mother and baby. However, there have been inconsistent correlations found between maternal homocysteine levels and placenta-related problems in various studies. Therefore, prospective research based on data pointing to a role for hyperhomocysteinemia in placenta-mediated complications will open doors for early detection and management of these complications. Thus, this study aims to determine if a higher risk of placenta-mediated problems is connected with a higher maternal plasma homocysteine content between 10 and 14 weeks of gestation. Methodology An observational prospective cohort study was conducted in the Department of Obstetrics and Gynecology, consisting of all the antenatal women between 10 and 14 weeks of gestation attending outpatient departments or inpatients admitted in labor rooms or wards having singleton pregnancies. Along with socio-demographic information and detailed history, a clinical examination was performed, and blood samples were collected to determine plasma homocysteine levels. Results As per the receiver operating characteristic curve (ROC curve), the cut-off value taken was <5 for the low level of serum homocysteine, 5 to 15 micromol/L for the normal value, and >15 micromol/L for a raised serum homocysteine level. The cutoff value for our study was 45 micromol/L with a sensitivity of 78.33%, a specificity of 91.67%, a positive predictive value of 90.38%, and a negative predictive value of 80.88% with a diagnostic accuracy of 85%. This means that, for most of the women included in the present study, those who developed placenta-mediated complications had serum blood homocysteine levels of 45 micromol/L or more at 10-14 weeks of gestation. Conclusion Women with high homocysteine levels in the late first trimester had more placenta-mediated complications, such as abruption, pre-eclampsia, restricted fetal growth, and recurrent pregnancy losses, compared to women with a normal level of homocysteine in the late first trimester. Therefore, measuring blood homocysteine levels in pregnancy may be helpful as a diagnostic test for the early detection of high-risk individuals for placenta-mediated complications.
PubMed: 37456448
DOI: 10.7759/cureus.40423 -
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 -
Cureus Apr 2023Background Placenta-mediated pregnancy complications (PMPCs) are a significant contributor to adverse maternal and fetal outcomes. Though the exact cause of the array of...
Background Placenta-mediated pregnancy complications (PMPCs) are a significant contributor to adverse maternal and fetal outcomes. Though the exact cause of the array of pregnancy-related vascular disorders is still unknown, increased maternal serum homocysteine (Hct) levels have been linked to the pathophysiology. Hyperhomocysteinemia (HHct) has been strongly linked with the risk of developing PMPCs such as preeclampsia (PE), fetal growth restriction (FGR), intrauterine fetal death (IUFD), preterm births and placental abruption. Methodology The present observational study was carried out on 810 low-risk antenatal women in their early second trimester (13-20 weeks gestation age) in the department of obstetrics and gynecology of a tertiary care rural hospital to identify the significance of abnormally raised maternal serum Hct level in developing PMPCs. Results Of the 810 participants studied, 224 (27.65%) had raised Hct levels whereas the rest of the 586 (72.35%) participants had normal Hct levels. The mean Hct level of raised homocysteine group (18.59 ± 2.46 micromol/L) was substantially raised than the normal Hct group (8.64 ± 3.1 micromol/L). It was observed that women with elevated serum Hct levels developed PMPCs significantly more than women with normal serum Hct levels (p-value <0.05). Among HHct subjects, 65.18% developed PE, 34.38% had FGR, 28.13% had a preterm delivery, 4.02% had abruptio placentae and 3.57% had IUFD. Conclusions The focus of the current study is on an easy and quick intervention such as assessing the often-ignored levels of Hct during pregnancy that can help predict and prevent PMPCs. It also highlights the necessity for well-thought-out large-scale studies and trials to further examine the phenomena, as pregnancy may be the only time when rural women will have the opportunity to receive advice and to be tested for HHct.
PubMed: 37187663
DOI: 10.7759/cureus.37461 -
RSC Advances Apr 2023A new series of 6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-]quinoxaline-2-ylidines 10a-f, 12, 14, 16, and 18 were designed, synthesized, and evaluated for their...
A new class of anti-proliferative activity and apoptotic inducer with molecular docking studies for a novel of 1,3-dithiolo[4,5-]quinoxaline derivatives hybrid with a sulfonamide moiety.
A new series of 6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-]quinoxaline-2-ylidines 10a-f, 12, 14, 16, and 18 were designed, synthesized, and evaluated for their anticancer activity. The structures of the novel compounds were systematically characterized by H NMR, C NMR, and elemental analysis. The synthesized derivatives were evaluated for their antiproliferative activity against three human cancer cell lines (HepG-2, HCT-116, and MCF-7) with more sensitivity to MCF-7. Moreover, three derivatives 10c, 10f, and 12 were the most promising candidates with sub-micromole values. These derivatives were further evaluated against MDA-MB-231, and the results displayed significant IC values ranging from 2.26 ± 0.1 to 10.46 ± 0.8 μM and showed low cellular cytotoxicity against WI-38. Surprisingly, the most active derivative 12 revealed sensitivity towards the breast cell lines MCF-7 (IC = 3.82 ± 0.2 μM) and MDA-MB-231 (IC = 2.26 ± 0.1 μM) compared with doxorubicin (IC = 4.17 ± 0.2 and 3.18 ± 0.1 M). Cell cycle analysis showed that compound 12 arrests and inhibits the growth of MCF-7 cells in the S phase with values of 48.16% compared with the untreated control 29.79% and exhibited a significantly higher apoptotic effect in MCF-7 with a value of 42.08% compared to control cell at 1.84%. Furthermore, compound 12 decreased Bcl-2 protein 0.368-fold and activation on pro-apoptotic genes Bax and P53 by 3.97 and 4.97 folds, respectively, in MCF-7 cells. Compound 12 exhibited higher inhibitory activity to EGFR, EGFR, and VEGFR-2 with IC values (0.19 ± 0.009, 0.026 ± 0.001, and 0.42 ± 0.021 μM) compared with erlotinib (IC = 0.037 ± 0.002 and 0.026 ± 0.001 μM) and sorafenib (IC = 0.035 ± 0.002 μM). Finally, ADMET prediction presented that 1,3-dithiolo[4,5-]quinoxaline derivative 12 obeys the Lipinski rule of five and the Veber rule with no PAINs alarms and moderately soluble properties. Additionally, toxicity prediction revealed that compound 12 demonstrated inactivity to hepatotoxic carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Moreover, molecular docking studies showed good binding affinity with lower binding energy inside the active site of Bcl-2 (PDB: 4AQ3), EGFR (PDB: 1M17), and VEGFR (PDB: 4ASD).
PubMed: 37101951
DOI: 10.1039/d3ra01635h