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International Journal of Molecular... Oct 2022Objective: The potential contribution of asymmetric dimethylarginine (ADMA) and high-sensitivity C reactive protein (hsCRP) to endothelial dysfunction in APS patients...
Objective: The potential contribution of asymmetric dimethylarginine (ADMA) and high-sensitivity C reactive protein (hsCRP) to endothelial dysfunction in APS patients has not been studied in detail, until now. The study involved 105 APS patients (59 diagnosed with primary APS (PAPS) and 46 APS associated with systemic lupus erythematosus (SAPS)) who were compared to 40 controls. Endothelial dysfunction was assessed by measurement of flow-mediated dilatation (FMD) and glyceryl trinitrate dilatation (NMD) of the brachial artery. ADMA (micromol/L) was analyzed by ELISA. Results: FMD in patients with APS was significantly lower than that of the controls (p < 0.001), with no difference between the PAPS and the SAPS groups. ADMA and hsCRP concentrations were significantly higher in the patient cohort than in the control group (p < 0.001, p = 0.006, respectively), as was the case with the SAPS group as compared to the PAPS group (p < 0.001, p = 0.022, respectively). FMD impairment correlated to ADMA (ρ 0.472, p < 0.001) and to hsCRP (ρ 0.181, p = 0.033). In the regression model, the ADMA concentration confirmed the strength of its association (B 0.518, SE 0.183, Wald 8.041, p = 0.005, Exp(B) 1.679, 95% CI 1.174−2.402) to FMD impairment. The synergistic probability model of ADMA and hsCRP caused FMD impairment when the positivity of β2GPIIgG was added. ADMA may be used as a simple and low-cost tool for verifying the presence of endothelial dysfunction in APS patients. According to the results of the study, we could presume that hsCRP, together with aPL, has a preparatory effect on the endothelium in causing endothelial dysfunction.
Topics: Humans; Antiphospholipid Syndrome; C-Reactive Protein; Vasodilation; Endothelium, Vascular; Nitroglycerin; Arginine; Biomarkers; Thrombosis; Dilatation, Pathologic
PubMed: 36293156
DOI: 10.3390/ijms232012309 -
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 -
Micromachines Dec 2022To verify the existence of plasma with the potential to kill tumor cells, this paper designed a novel helium (He) micro-plasma jet array device and detected the...
To verify the existence of plasma with the potential to kill tumor cells, this paper designed a novel helium (He) micro-plasma jet array device and detected the concentration of typical long-lived reactive oxygen and nitrogen species (RONS) with oxidative activity generated by it. The paper described a new He micro-plasma jet array device consisting of nine flexible quartz capillaries with an inner diameter of 75 μm arranged in a 3 × 3 array. Sterilized ultrapure water (up water) was first treated with the He micro-plasma jet array device to activate it to form enriched RONS micro-plasma-activated water (μ-PAW), and then μ-PAW was added to the cell culture medium (with cells) to observe the proliferation of human glioma cells. The concentration of long-lived RONS, such as nitrate (NO), was detected according to Beer-Lambert's law in combination with UV spectrophotometry as well as a color development method. The MTT Cell Proliferation and Cytotoxicity Assay Kit combined with the Hoechst Staining Kit were used to assess the proliferation status of the cells. The results showed that the range of RONS concentration variation could be controlled in the order of micromoles (µmol), while plasma-induced tumor cell death is apoptosis that does not affect the surrounding environment.
PubMed: 36557443
DOI: 10.3390/mi13122145 -
Cryo Letters 2023Cryopreservation of porcine oocytes is difficult compared with other species and immature oocytes particularly so compared to the meiotic stage.
BACKGROUND
Cryopreservation of porcine oocytes is difficult compared with other species and immature oocytes particularly so compared to the meiotic stage.
OBJECTIVE
To evaluate the efficacy of a pretreatment with 1 micromole per L paclitaxel (PTX, 30 min exposure) before vitrification to promote the maturation of porcine immature oocytes.
MATERIALS AND METHODS
Cumulus cell-enclosed oocytes (COs) aspirated from porcine ovaries were divided into three groups: i) non-pretreated with PTX and non-vitrified group (control group); ii) pretreated with PTX and vitrified group (PTX-V group); and iii) non-pretreated with PTX and vitrified group (nPTX-V group).
RESULTS
The nuclear maturation rate up to the preovulatory stage was significantly lower (P < 0.05) in the nPTX-V group than in the control group, but was similar in the PTX-V and control groups. No significant differences were observed in viability assessed by a normal CO morphology and the embryonic development of oocytes activated by the parthenogenetic stimulation between the PTX-V and control groups, but not the non-PTX-V group.
CONCLUSION
PTX may promote the maturation of vitrified porcine immature oocytes. Doi.org/10.54680/fr23510110812.
Topics: Female; Pregnancy; Swine; Animals; Vitrification; Cryopreservation; Oocytes; Embryonic Development; Paclitaxel
PubMed: 38032311
DOI: No ID Found -
Physiological Research Dec 2020Individual studies have suggested the utility of fractional exhaled nitric oxide (FeNO) measurement in detecting cough-variant asthma and eosinophilic bronchitis in...
Individual studies have suggested the utility of fractional exhaled nitric oxide (FeNO) measurement in detecting cough-variant asthma and eosinophilic bronchitis in patients with chronic cough. The aim of this study was to clarify a correlation of cough reflex sensitivity and fractional exhaled nitric oxide in asthmatic children. 25 children with asthma and 15 controls were submitted to cough reflex sensitivity measurement - capsaicin aerosol in doubling concentrations (from 0.61 to 1250 micromol/l) was inhaled by a single breath method. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Fractional exhaled nitric oxide (FeNO) measurement was included. Asthmatic children' (11 boys and 14 girls, mean age 9+/-1 years) and control group (unconfirmed diagnosis of asthma) (6 boys and 9 girls, mean age 8+/-1 years) were included into the study. FeNO vs. C2 in asthma (Spearman´s rank correlation: -0.146, p=0.49); FENO vs. C5 in asthma (Spearman´s rank correlation: -0.777, p=0.71). We found that there is no correlation between cough reflex sensitivity and fractional exhaled nitric oxide either in children with asthma or in the control group.
Topics: Asthma; Child; Cough; Exhalation; Female; Humans; Hypersensitivity; Male; Nitric Oxide; ROC Curve; Reflex; Respiratory Function Tests
PubMed: 33471545
DOI: 10.33549/physiolres.934601 -
International Journal of Sports... Aug 2023Mental fatigue causes decreases in aspects of athletes' performance. Elite coaches commonly undertake cognitively demanding tasks and are seemingly at similar risk of...
PURPOSE
Mental fatigue causes decreases in aspects of athletes' performance. Elite coaches commonly undertake cognitively demanding tasks and are seemingly at similar risk of subsequent performance impairment. However, elite sport coaches' experiences of mental fatigue, alongside other markers of psychobiological stress, have yet to be quantified.
METHODS
Three elite coaching and performance staff (2 women and 1 man) provided 100-mm visual analog scale ratings of mental fatigue, physical fatigue, readiness to perform, and salivary samples for later cortisol (sCort) and alpha-amylase (sAA) analysis. Data were obtained on the same morning each week across a 16-week preseason. Data were subset by individual coach for descriptive and repeated-measures correlational analyses.
RESULTS
Fluctuating mental fatigue was observed over the 16 weeks (min-max; coach 1 = 25-86 AU; coach 2 = 0-51 AU; and coach 3 = 15 - 76 AU). Elevated levels of mental fatigue were reported at multiple time points, with individual variability observed. sCort (in nanomoles per liter), sAA (in micromoles per liter), and sAA:sCort indicated that coaches experienced psychophysiological stress (min-max; coach 1 sCort = 8.42-17.31, sAA = 52.40-113.06, sAA:sCort = 3.20-12.80; coach 2 sCort = 4.20-9.70, sAA = 158.80-307.20, sAA:sCort = 21.10-61.70; and coach 3 sCort = 6.81-19.66, sAA = 86.55-495.85, sAA:sCort = 4.90-35.50). A significant inverse relationship between mental fatigue and readiness to perform (r = -.44 [-.64 to -.17], P = .002) was identified.
CONCLUSIONS
Elite sport coaches report elevated instances of mental fatigue during a preseason training period. Those involved in elite sports should act to understand the presence and potential subsequent impacts of staff mental fatigue and consider management or mitigation strategies. Optimization of the cognitive performance of coaches and performance staff presents as a potential source of competitive advantage.
Topics: Male; Humans; Female; Athletes; Mentoring; Athletic Performance; Mental Fatigue; Competitive Behavior
PubMed: 37311561
DOI: 10.1123/ijspp.2023-0033 -
Pediatric Critical Care Medicine : a... Sep 2020Up to 37% of children admitted to the PICU develop acute kidney injury as defined by Kidney Disease: Improving Global Outcomes criteria. We describe the prevalence of... (Observational Study)
Observational Study
OBJECTIVES
Up to 37% of children admitted to the PICU develop acute kidney injury as defined by Kidney Disease: Improving Global Outcomes criteria. We describe the prevalence of acute kidney injury in a mixed pediatric intensive care cohort using this criteria. As tools to stratify patients at risk of acute kidney injury on PICU admission are lacking, we explored the variables at admission and day 1 that might predict the development of acute kidney injury.
DESIGN
Single-center retrospective observational study.
SETTING
Thirty-six-bed surgical/medical tertiary PICU.
PATIENTS
Children from birth to less than or equal to 16 years old admitted between 2015 and 2018.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Clinical data were extracted from the PICU clinical information system. Patients with baseline creatinine at admission greater than 20 micromol/L above the calculated normal creatinine level were classified as "high risk of acute kidney injury." Models were created to predict acute kidney injury at admission and on day 1. Out of the 7,505 children admitted during the study period, 738 patients (9.8%) were classified as high risk of acute kidney injury at admission and 690 (9.2%) developed acute kidney injury during PICU admission. Compared to Kidney Disease: Improving Global Outcomes criteria as the reference standard, high risk of acute kidney injury had a lower sensitivity and higher specificity compared with renal angina index greater than or equal to 8 on day 1. For the admission model, the adjusted odds ratio of developing acute kidney injury for high risk of acute kidney injury was 4.2 (95% CI, 3.3-5.2). The adjusted odds ratio in the noncardiac cohort for high risk of acute kidney injury was 7.3 (95% CI, 5.5-9.7). For the day 1 model, odds ratios for high risk of acute kidney injury and renal angina index greater than or equal to 8 were 3.3 (95% CI, 2.6-4.2) and 3.1 (95% CI, 2.4-3.8), respectively.
CONCLUSIONS
The relationship between high risk of acute kidney injury and acute kidney injury needs further evaluation. High risk of acute kidney injury performed better in the noncardiac cohort.
Topics: Acute Kidney Injury; Adolescent; Child; Critical Care; Critical Illness; Humans; Infant; Intensive Care Units, Pediatric; Retrospective Studies; Risk Factors; Severity of Illness Index
PubMed: 32516223
DOI: 10.1097/PCC.0000000000002411 -
ESC Heart Failure Apr 2023Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac...
AIMS
Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac myofilaments, that is, direct activators of the myosin molecule and Ca sensitizers for patients with advanced HFrEF. Omecamtiv mecarbil (OM) is the first direct myosin activator with promising results in clinical studies. Here, we aimed to elucidate the cellular mechanisms of the positive inotropic effect of OM in a comparative in vitro investigation where Ca -sensitizing positive inotropic agents with distinct mechanisms of action [EMD 53998 (EMD), which also docks on the myosin molecule, and levosimendan (Levo), which binds to troponin C] were included.
METHODS
Enzymatically isolated canine cardiomyocytes with intact cell membranes were loaded with Fura-2AM, a Ca -sensitive, ratiometric, fluorescent dye. Changes in sarcomere length (SL) and intracellular Ca concentration were recorded in parallel at room temperature, whereas cardiomyocyte contractions were evoked by field stimulation at 0.1 Hz in the presence of different OM, EMD, or Levo concentrations.
RESULTS
SL was reduced by about 23% or 9% in the presence of 1 μM OM or 1 μM EMD in the absence of electrical stimulation, whereas 1 μM Levo had no effect on resting SL. Fractional sarcomere shortening was increased by 1 μM EMD or 1 μM Levo to about 152%, but only to about 128% in the presence of 0.03 μM OM. At higher OM concentrations, no significant increase in fractional sarcomere shortening could be recorded. Contraction durations largely increased, whereas the kinetics of contractions and relaxations decreased with increasing OM concentrations. One-micromole EMD or 1 μM Levo had no effects on contraction durations. One-micromole Levo, but not 1 μM EMD, accelerated the kinetics of cardiomyocyte contractions and relaxations. Ca transient amplitudes were unaffected by all treatments.
CONCLUSIONS
Our data revealed major distinctions between the cellular effects of myofilament targeted agents (OM, EMD, or Levo) depending on their target proteins and binding sites, although they were compatible with the involvement of Ca -sensitizing mechanisms for all three drugs. Significant part of the cardiotonic effect of OM relates to the prolongation of systolic contraction in combination with its Ca -sensitizing effect.
Topics: Animals; Dogs; Myocytes, Cardiac; Heart Failure; Stroke Volume; Simendan; Myosins
PubMed: 36722665
DOI: 10.1002/ehf2.14300 -
Cureus Nov 2021Introduction Increased levels of homocysteine (Hcy) may lead to endothelial damage and increase the risk of cardiovascular and renal malfunction. The current study aimed...
Introduction Increased levels of homocysteine (Hcy) may lead to endothelial damage and increase the risk of cardiovascular and renal malfunction. The current study aimed to evaluate the association of serum Hcy levels with gender, body mass index (BMI), duration of diabetes mellitus type 2 (DMT2), hemoglobin A1c (HbA1c), and blood pressure (BP). Methodology A prospective observational study was conducted at Hayatabad Medical Complex in Peshawar, Pakistan in the department of endocrinology from June 2020 to June 2021. All patients with diagnosed DMT2 above the age of 18 years were included in the study. Individuals with unconfirmed diagnoses with ages over 75 years were excluded from the study. All data including the patient's age, gender, and medical history were recorded. Height and weight were used to calculate the BMI. BP was examined thrice and a mean value was recorded for each patient. For laboratory investigation, a vial of 3 ml blood was extracted keeping sterile and aseptic conditions by a trained nurse. The sample was sent for the determination of HbA1c and serum Hcy levels. Measurement of serum Hcy was done by chemiluminescent microparticle immunoassay. All data were documented by the researchers on a predefined pro forma. Results A total of 188 patients with DMT2 were included in the study with a mean age ± SD of 54.65 ± 8.42 years. Normal (<15 micromoles per liter [mcmol/l]) serum Hcy levels were reported in 75 (39.89%) individuals, while in 47 (41.59%) individuals, there was severe (>100 mcmol/l) hyperhomocysteinemia. More than half of the patients, i.e. 157 (83.52%), had HbA1c of greater than 7%, which indicated poor glycemic control. The study revealed that the majority of the female patients, i.e. 37 (78.72%), had severe hyperhomocysteinemia (p<0.0001). Similarly, there was a direct correlation between HbA1c levels and serum Hcy. Severe hyperhomocysteinemia was found in over 80% of the patients with poor glycemic control, i.e. HbA1c >7% (p<0.0001). Furthermore, the duration of DMT2 and hypertension were both significantly associated with increased levels of Hcy with p-values of <0.0001 and <0.0001, respectively. However, no association was found between hyperhomocysteinemia and BMI. Conclusion The study revealed that increased levels of serum Hcy were associated with female gender, poor glycemic control (HbA1c >7%), BP, and duration of DMT2. However, the study failed to find an association between serum Hcy and BMI. It is recommended that patients with poor glycemic control or those with the duration of DMT2 of more than five years must be regularly checked for hyperhomocysteinemia and renal function tests. Large-scale and multi-center studies are required in order to determine the validity of these findings. The current study suggests that patients with diabetes mellitus and hypertension are likely to have increased levels of Hcy and, therefore, must be regularly screened for hyperhomocysteinemia.
PubMed: 34877198
DOI: 10.7759/cureus.19211 -
Bioorganic & Medicinal Chemistry Letters Aug 2020In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse...
In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC = 42 nM) in MT-4 cells, and sub-micromole (EC = 0.308 μM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC = 1.329 μM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.
Topics: Anti-HIV Agents; Cell Survival; Dose-Response Relationship, Drug; Drug Discovery; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Structure; Prodrugs; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured; gag Gene Products, Human Immunodeficiency Virus
PubMed: 32631509
DOI: 10.1016/j.bmcl.2020.127287