2-Methoxyestradiol ameliorates doxorubicin-induced cardiotoxicity by regulating the expression of GLUT4 and CPT-1B in female rats.

The clinical usage of doxorubicin (DOX) is hampered due to cardiomyopathy. Studies reveal that estrogen (E2) modulates DOX-induced cardiotoxicity. Yet, the exact mechanism is unclear. The objective of the current study is to evaluate the influence of E2 and more specifically its metabolite 2-methoxyestradiol (2ME) on cardiac remodeling and the reprogramming of cardiac metabolism in rats subjected to DOX cardiotoxicity. Seventy-two female rats were divided into groups. Cardiotoxicity was induced by administering DOX (2.5 mg/kg three times weekly for 2 weeks). In some groups, the effect of endogenous E2 was abolished by ovariectomy (OVX) or by using the estrogen receptor (ER) blocker Fulvestrant (FULV). The effect of administering exogenous E2 or 2ME in the OVX group was studied. Furthermore, the influence of entacapone (COMT inhibitor) on induced cardiotoxicity was investigated. The evaluated cardiac parameters included ECG, histopathology, cardiac-related enzymes (creatine kinase isoenzyme-MB (CK-MB) and lactate dehydrogenase (LDH)), and lipid profile markers (total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL)). The expression levels of key metabolic enzymes (glucose transporter-4 (GLUT4) and carnitine palmitoyltransferase-1B (CPT-1B)) were assessed. Our results displayed that co-treatment of E2 and/or 2ME with DOX significantly reduced DOX-induced cardiomyopathy and enhanced the metabolism of the heart through the maintenance of GLUT4 and CPT-1B enzymes. On the other hand, co-treatment of DOX with OVX, entacapone, or FULV increased the toxic effect of DOX by further reducing these important metabolic enzymes. E2 and 2ME abrogate DOX-induced cardiomyopathy partly through modulation of GLUT 4 and CPT-1B enzymes.

The effects of dexmedetomidine on intraoperative neurophysiologic monitoring modalities during corrective scoliosis surgery in pediatric patients: A systematic review.

BACKGROUND: During scoliosis surgery, motor evoked potentials (MEP), and somatosensory evoked potentials (SSEP) have been reported to be affected by the use of higher doses of anesthetic agents. Dexmedetomidine, a sympatholytic agent, an alpha-2 receptor agonist, has been used as an adjunctive agent to lower anesthetic dose. However, there is conflicting evidence regarding the effects of dexmedetomidine on the intraoperative neurophysiological monitoring of MEP and SSEP during surgery, particularly among pediatric patients. OBJECTIVES: This systematic review aimed to determine whether, during spinal fusion surgery in pediatric patients with scoliosis, dexmedetomidine alters MEP amplitude or SSEP latency and amplitude and, if so, whether different doses of dexmedetomidine display different effects (PROSPERO registration number CRD42022300562). METHODS: We searched PubMed, Scopus, and Cochrane Library on January 1, 2022 and included randomized controlled trials, observational cohort and case-control studies and case series investigating dexmedetomidine in the population of interest and comparing against a standardized anesthesia regimen without dexmedetomidine or comparing multiple doses of dexmedetomidine. Animal and in vitro studies and conference abstracts were excluded. RESULTS: We found substantial heterogeneity in the risk of bias (per Cochrane-preferred tools) of the included articles (n = 5); results are summarized without meta-analysis. Articles with the lowest risk of bias indicated that dexmedetomidine was associated with MEP loss and that higher doses of dexmedetomidine increased risk. In contrast, articles reporting no association between dexmedetomidine and MEP loss suffered from higher risk of bias, including suspected or confirmed problems with confounding, outcome measurement, participant selection, results reporting, and lack of statistical transparency and power. CONCLUSION: Given the limitations of the studies available in the literature, it would be advisable to conduct rigorous randomized controlled trials with larger sample sizes to assess the effects of dexmedetomidine use of in scoliosis surgery in pediatric patients.

Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study.

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

The diagnostic and prognostic role of neutrophil-to-lymphocyte ratio in COVID-19: a systematic review and meta-analysis.

Background: The world urgently requires surrogate markers to diagnose COVID-19 and predict its progression. The severity is not easily predicted via currently used biomarkers. Critical COVID-19 patients need to be screened for hyperinflammation to improve mortality but expensive cytokine measurement is not routinely conducted in most laboratories. The neutrophil-to-lymphocyte ratio (NLR) is a novel biomarker in patients with various diseases. We evaluated the diagnostic and prognostic accuracy of the NLR in COVID-19 patients.Methods: We searched for relevant articles in seven databases. The quantitative analysis was conducted if at least two studies were evaluating the NLR role in COVID-19.Results: We included 8,120 individuals, including 7,482 COVID-19 patients, from 32 articles. Patients with COVID-19 had significantly higher levels of NLR compared to negative individuals. Advanced COVID-19 stages had significantly higher levels of NLR than earlier stages.Expert Opinion: We found significantly higher levels of NLR in advanced stages compared to earlier stages of COVID-19 with good accuracy to diagnose and predict the disease outcome, especially mortality prediction. A close evaluation of critical SARS-CoV-2 patients and efficient early management are essential measures to decrease mortality. NLR could help in assessing the resource allocation in severe COVID-19 patients even in restricted settings.

Clastogenic, anti-clastogenic profile and safety assessment of Camel urine towards the development of new drug target.

Camel Urine (CU) is composed of components that have antitumor properties and other therapeutic benefits. Regardless of short-term preliminary CU genotoxicity is reported, comprehensive genotoxic studies are limited. In this study, sensitive in vitro and in vivo genotoxic bioassays such as mitotic index (MI), chromosomal aberrations (CA), micronucleated polychromatic erythrocytes (MPE), and analysis of primary spermatocytes were employed. The adventitious roots of Allium cepa L. and mice (Mus musculus), as an experimental mammalian system, were employed to assess the MI and CA of CU induced by sodium nitrate and cyclophosphamide respectively. In contrast, other clastogenic assays were studied in mice (Mus musculus). Twenty-eight days of four repeated doses (2.5, 5, 25, and 50 mL/kg BW) of CU were tested and compared with three doses (10, 25, and 50 mg/kg BW) cyclophosphamide as a positive control and deionized water as the negative control. The results proved that cytological examination of CU was cytotoxic since a decrease in mitotic activity (16.8-1.1) was observed, since the significant reduction in cell proliferation in A. cepa L. and also in mice bone marrow cells. On the other hand, CU did not induce a clastogenic effect since no significant stickiness, fragment, multinucleoli were observed compared to the control group. Additionally, the data showed that CU decreased the CA when mice had received cyclophosphamide (25 mg BW) followed by CU doses. CU was found to be cytotoxic but no clastogenic effect. Furthermore, it possesses anticlastogenic properties. The observed results suggest that CU in whole or the metabolites present in CU could be a potent drug target. Further research is warranted to study the complete metabolites profiling and to study the molecular mechanisms.

Deep Hypothermic Circulatory Arrest in the Pediatric Population Undergoing Cardiac Surgery With Electroencephalography Monitoring: A Systematic Review and Meta-Analysis.

OBJECTIVE: Cardiac surgery for repair of congenital heart defects poses unique hazards to the developing brain. Deep hypothermic circulatory arrest (DHCA) is a simple and effective method for facilitating a bloodless surgical field during congenital heart defect repair. There are, however, some concerns that prolonged DHCA increases the risk of nervous system injury. The electroencephalogram (EEG) is used in adult and, to a lesser extent, pediatric cardiac procedures as a neuromonitoring method. The present study was performed to assess outcomes following DHCA with EEG monitoring in the pediatric population. DESIGN: In this systematic review and meta-analysis, the PubMed, Cochrane Central Register of Controlled Trials, Scopus, Institute of Science Index, and Embase databases were searched from inception for relevant articles. A fixed- or random-effects model, as appropriate, was used. SETTING: Surgical setting. PARTICIPANTS: Pediatric population (≤18 y old). INTERVENTIONS: DHCA (18°C) with EEG monitoring. MEASUREMENTS AND MAIN RESULTS: Nineteen articles with 1,267 pediatric patients ≤18 years were included. The event rate of clinical and EEG seizures among patients who underwent DHCA was 12.9% and 14.9%, respectively. Mortality was found to have a 6.3% prevalence. A longer duration of DHCA was associated with a higher risk of EEG seizure and neurologic abnormalities. In addition, seizures were associated with increased neurologic abnormalities and neurodevelopmental delay. CONCLUSIONS: EEG and neurologic abnormalities were common after DHCA. A longer duration of DHCA was found to lead to more EEG seizure and neurologic abnormalities. Moreover, EEG seizures were more common than clinical seizures. Seizures were found to be associated with increased neurologic abnormalities and neurodevelopmental delay.

The validity of central venous to arterial carbon dioxide difference to predict adequate fluid management during living donor liver transplantation. A prospective observational study.

BACKGROUND: To assess the validity of central and pulmonary veno-arterial CO2 gradients to predict fluid responsiveness and to guide fluid management during liver transplantation. METHODS: In adult recipients (ASA III to IV) scheduled for liver transplantation, intraoperative fluid management was guided by pulse pressure variations (PPV). PPV of ≥15% (Fluid Responding Status-FRS) indicated fluid resuscitation with 250 ml albumin 5% boluses repeated as required to restore PPV to < 15% (Fluid non-Responding Status-FnRS). Simultaneous blood samples from central venous and pulmonary artery catheters (PAC) were sent to calculate central venous to arterial CO2 gap [C(v-a) CO2 gap] and pulmonary venous to arterial CO2 gap [Pulm(p-a) CO2 gap]. CO and lactate were also measured. RESULTS: Sixty seven data points were recorded (20 FRS and 47 FnRS). The discriminative ability of central and pulmonary CO2 gaps between the two states (FRS and FnRS) was poor with AUC of ROC of 0.698 and 0.570 respectively. Central CO2 gap was significantly higher in FRS than FnRS (P = 0.016), with no difference in the pulmonary CO2 gap between both states. The central and Pulmonary CO2 gaps are weakly correlated to PPV [r = 0.291, (P = 0.017) and r = 0.367, (P = 0.002) respectively]. There was no correlation between both CO2 gaps and both CO and lactate. CONCLUSION: Central and the Pulmonary CO2 gaps cannot be used as valid tools to predict fluid responsiveness or to guide fluid management during liver transplantation. CO2 gaps also do not correlate well with the changes in PPV or CO. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03123172 . Registered on 31-march-2017.

Effect of ultrafiltration on extravascular lung water assessed by lung ultrasound in children undergoing cardiac surgery: a randomized prospective study.

BACKGROUND: Increased lung water and the resultant atelectasis are significant pulmonary complications after cardiopulmonary bypass (CPB) in children undergoing cardiac surgery; these complications are observed after CPB than after anaesthesia alone. Ultrafiltration has been shown to decrease total body water and postoperative blood loss and improve the alveolar to arterial oxygen gradient and pulmonary compliance. This study investigated whether conventional ultrafiltration during CPB in paediatric heart surgeries influences post-bypass extravascular lung water (EVLW) assessed by lung ultrasound (LUS). METHODS: This randomized controlled study included 60 patients with congenital heart disease (ASA II-III), aged 1 to 48 months, with a body weight > 3 kg. Conventional ultrafiltration targeting a haematocrit (HCT) level of 28% was performed on the ultrafiltration group, while the control group did not receive ultrafiltration. LUS scores were recorded at baseline and at the end of surgery. The PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen), urine output, and haemodynamic parameters were also recorded. RESULTS: LUS scores were comparable between the two groups both at baseline (p = 0.92) and at the end of surgery (p = 0.95); however, within the same group, the scores at the end of surgery significantly differed from their baseline values in both the ultrafiltration (p = 0.01) and non-ultrafiltration groups (p = 0.02). The baseline PaO2/FiO2 ratio was comparable between both groups. at the end of surgery, The PaO2/FiO2 ratio increased in the ultrafiltration group compared to that in the non-ultrafiltration group, albeit insignificant (p = 0.16). no correlation between the PaO2/FiO2 ratio and LUS score was found at baseline (r = - 0.21, p = 0.31). On the other hand, post-surgical measurements were negatively correlated (r = - 0.41, p = 0.045). CONCLUSION: Conventional ultrafiltration did not alter the EVLW when assessed by LUS and oxygenation state. Similarly, ultrafiltration did not affect the urea and creatinine levels, intensive care unit (ICU) stays, ventilation days, or mortality. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03146143 registered on 29-April-2017.

In vivo anticlastogenic effect of silymarin from milk thistle Silybum marianum L.

OBJECTIVE: Silymarin, extracted from the seeds of Silybum marianum L. (Milk thistle), is traditionally used for treating various illnesses such as diabetes, cancer, inflammation, hepatitis, liver cirrhosis, and renal problems. Acute cytotoxicity and genotoxicity studies have been reported with ambiguous outcomes; however, its relevant anticlastogenic potential is not yet evaluated. This study was aimed to evaluate in vivo subacute anticlastogenic properties of silymarin to validate its use as a medicinal agent. MATERIALS AND METHODS: Silymarin was isolated from seeds of milk thistle. Various genotoxicity bioassays of silymarin were performed using mice. First, the bone marrow cell proliferation was estimated by calculating mitotic index. Second, the chromosomal abnormalities in mice bone marrow cells were studied. Third, micronucleated polychromatic erythrocytes (MPE) test and in vivo activation of sister chromatid exchanges (SCEs) were carried out in mice bone marrow cells. Finally, primary spermatocytes were analyzed to estimate genotoxic effect of silymarin on germ cells. RESULTS: We found that silymarin is capable of inducing a significant increase (P ≤ 0.05) in cell proliferation of bone marrow cells. There is no increase in chromosomal aberrations following silymarin treatments. Results clearly showed that it significantly (P ≤ 0.05) decreased the MPE. Likewise, it was found to be a negative inducer of SCEs. It decreased in total abnormal metaphase, SCEs, MPE, and aberrant diakinesis. CONCLUSION: The results demonstrated that silymarin has a strong anticlastogenic activity upon mice genome in somatic and germ cells, indicating its safe use as a medicinal substance. Furthermore, it is not only safe but also has protective effect from clastogens.

Erratum to "Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases".

[This corrects the article DOI: 10.1155/2017/5316845.].

Perfused nonfunctioning renal allograft: Case report and review of the literature.

We report a case of very early postoperative iatrogenic dissection of common iliac artery (CIA), external iliac artery (EIA) causing acute ischemia of the right lower limb, and impairing the perfusion of a renal allograft. This was managed successfully by graft nephrectomy and interposition polytetrafluoroethylene grafting of the CIA and EIA with re-implantation of the kidney allograft and restoration of its perfusion and function, together with restoration of the lower limb circulation.

Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases.

The role of the extracellular matrix (ECM) in uterine fibroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stiffness and profoundly affect tumor progression. The aim of the current study was to investigate the relationship between ECM of UF, collagen and collagen cross-linking enzymes [lysyl hydroxylases (LH) and lysyl oxidases (LOX)], and the development and progression of UF. Our results indicated that hydroxyl lysine (Hyl) and HP cross-links are significantly higher in UF compared to the normal myometrial tissues accompanied by increased expression of LH (LH2b) and LOX. Also, increased resistance to matrix metalloproteinases (MMP) proteolytic degradation activity was observed. Furthermore, the extent of collagen cross-links was positively correlated with the expression of myofibroblast marker (α-SMA), growth-promoting markers (PCNA; pERK1/2; FAKpY397; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defines the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, differentiation, and resistance to MMP. These effects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF.

Leptin influences estrogen metabolism and increases DNA adduct formation in breast cancer cells.

OBJECTIVE: The elevated incidence of obesity has been paralleled with higher risks of breast cancer. High adiposity increases leptin secretion from adipose tissue, which in turn increases cancer cell proliferation. The interplay between leptin and estrogen is one of the mechanisms through which leptin influences breast carcinogenesis. An unbalanced estrogen metabolism increases the formations of catechol estrogen quinones, DNA adducts, and cancer mutations. This study aims to investigate the effect of leptin on some estrogen metabolic enzymes and DNA adduction in breast cancer cells. METHODS: High performance liquid chromatography (HPLC) was performed to analyze the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine. Reporter gene assay, real time reverse transcription polymerase chain reaction (real time RT-PCR), and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes: Cytochrome P-450 1B1 (CYP1B1), Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase1 (NQO1), and Catechol-O-methyl transferase (COMT). RESULTS: Leptin significantly increased the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine. Furthermore, leptin significantly upregulated CYP1B1 promoter activity and protein expression. The luciferase promoter activities of NQO1 and mRNA levels were significantly reduced. Moreover, leptin greatly reduced the reporter activities of the COMT-P1 and COMT-P2 promoters and diminished the protein expression of COMT. CONCLUSIONS: Leptin increases DNA adduct levels in breast cancer cells partly by affecting key genes and enzymes involved in estrogen metabolism. Thus, increased focus should be directed toward leptin and its effects on the estrogen metabolic pathway as an effective approach against breast cancer.

Effect of tumour necrosis factor-alpha on estrogen metabolic pathways in breast cancer cells.

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-ß estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer.