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Virology Sep 2023COVID-19 is a global health problem caused by SARS-CoV-2, which has led to over 600 million infections and 6 million deaths. Developing novel antiviral drugs is of...
COVID-19 is a global health problem caused by SARS-CoV-2, which has led to over 600 million infections and 6 million deaths. Developing novel antiviral drugs is of pivotal importance to slow down the epidemic swiftly. In this study, we identified five azo compounds as effective antiviral drugs to SARS-CoV-2, and mechanism study revealed their targets for impeding viral particles' ability to bind to host receptors. Direct Blue 53, which displayed the strongest inhibitory impact, inhibited five mutant strains at micromole. In vitro, mechanism study demonstrated Direct Blue 53 inhibited viral infection through interaction with the spike of SARS-CoV-2. And 25 mg/kg/d compound treatment showed 50% or 60% survival protection against lethal Delta or Omicron BA.2 infection in vivo. Taken together, our results demonstrate that azo compounds with dimethyl-biphenyl-diyl-bis(azo)bis structure may be promising anti-SARS-CoV-2 drug candidates, which provide practicable therapies with the aid of structural optimizations and further research.
Topics: Humans; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Antiviral Agents; Azo Compounds; Spike Glycoprotein, Coronavirus
PubMed: 37531695
DOI: 10.1016/j.virol.2023.07.006 -
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 -
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 -
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 -
Molecules (Basel, Switzerland) Mar 2023The development of new formulations can be driven by the knowledge of host-guest complexes using cyclodextrins which have the ability to include guest molecules within...
The development of new formulations can be driven by the knowledge of host-guest complexes using cyclodextrins which have the ability to include guest molecules within their hydrophobic cavities, improving the physicochemical properties of the guest. To rationally explore new pesticide formulations, the effects of cyclodextrins on the properties of such guest molecules need to be explored. Imidacloprid is a neonicotinoid systemic insecticide used worldwide. In this study, the inclusion complexes of Imidacloprid (IMI) with β-cyclodextrin (β-CD) were prepared in the solid state by co-precipitation and the physical mixing method, with a stoichiometry of 1:1 and 1:2 molar ratios. The obtained products, Imidacloprid:β-cyclodextrin inclusion complex (IMI:β-CD), were characterized in the solid state by Fourier transform-infrared (FT-IR) spectroscopy and X-ray powder diffractometry (XRD). In solution, the 1:1 stoichiometry for the inclusion complexes was established by the Job plot method, and the binding constant of IMI:β-CD was determined by UV-vis titration. The toxicity was determined in producers and primary consumers of the freshwater trophic chain, the green alga and the rotifer , respectively. The results indicated that Imidacloprid forms inclusion complexes with CDs showing improved physicochemical properties compared to free Imidacloprid. The formation of the inclusion complex reduced the chronic toxicity in rotifers when IMI concentrations were close to those of environmental concern (tenths/hundredths of micromoles/L). Therefore, CD inclusion complexes could provide important advantages to be considered for the future industrial production of new formulations.
Topics: Spectroscopy, Fourier Transform Infrared; beta-Cyclodextrins; Cyclodextrins; Neonicotinoids; X-Ray Diffraction; Calorimetry, Differential Scanning; Solubility
PubMed: 37049814
DOI: 10.3390/molecules28073049 -
RSC Advances Mar 2023Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1'-spiro-pyridine...
Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1'-spiro-pyridine derivatives were designed and synthesized based on an -(ethyl benzoate) moiety. The structure of the designed derivatives was confirmed by different spectroscopic techniques (FT-IR and NMR) and elemental analysis and then evaluated as antiproliferative against HepG-2 and Caco-2 cell lines compared with Doxorubicin. The spiro-pyridine derivatives 5, 7, and 8 exhibited a remarkably higher activity against Caco-2 cell lines than that of other derivatives. Additionally, these derivatives exhibited activation in the Bax and suppressed Bcl-2 expression with variable degrees. Interestingly, compound 7 showed the lowest cytotoxicity value on Caco-2 cells (IC = 7.83 ± 0.50 μM) compared with Doxorubicin (IC = 12.49 ± 1.10 μM). Additionally, this compound showed activation of the Bax gene (7.508-fold) and suppressed Bcl-2 (0.194-fold) compared to untreated Caco-2 cells, as revealed by the qRT-PCR technique. Moreover, compound 7 could inhibit EGFR and VEGFR-2 with sub-micromole values of 0.124 μM and 0.221 μM compared with Erlotinib (IC = 0.033 μM) and Sorafenib (IC = 0.043 μM), respectively. Further, cell cycle and apoptosis analysis demonstrated that compound 7 promoted apoptosis by increasing the apoptosis rate from 1.92 to 42.35% and the S cell accumulation ratio from 31.18 to 42.07% compared to untreated Caco-2 cells. Finally, the most active compound 7 showed good drug-likeness and toxicity profiles. Besides, molecular docking studies were performed to determine the binding mode, which is in agreement with the results.
PubMed: 37020892
DOI: 10.1039/d3ra00887h -
Antioxidants (Basel, Switzerland) Feb 2023Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal...
Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the hypothesis that oral melatonin supplementation in newborn infants undergoing surgery is effective in reducing perioperative oxidative stress. A total of twenty-three newborn infants requiring surgery were enrolled: 10 received a single dose of oral melatonin 0.5 mg/kg in the morning, before surgery (MEL group), and 13 newborns served as the control group (untreated group). Plasma concentrations of melatonin, Non-Protein-Bound Iron (NPBI), Advanced Oxidation Protein Products (AOPP), and F2-Isoprostanes (F2-IsoPs) were measured. Both in the pre- and postoperative period, melatonin concentrations were significantly higher in the MEL group than in the untreated group (preoperative: 1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL, < 0.0001; postoperative: 1465.20 ± 538.38 vs. 56.47 ± 37.18 pg/mL, < 0.0001). Melatonin significantly increased from the pre- to postoperative period in the untreated group (23.23 ± 17.71 vs. 56.47 ± 37.18 pg/mL; pg/mL = 0.006). In the MEL group, the mean blood concentrations of NPBI, F2-IsoPs, and AOPP significantly decreased from the pre- to the postoperative period (4.69 ± 3.85 vs. 1.65 ± 1.18 micromol/dL, = 0.049; 128.40 ± 92.30 vs. 50.25 ± 47.47 pg/mL, = 0.037 and 65.18 ± 15.50 vs. 43.98 ± 17.92 micromol/dL, = 0.022, respectively). Melatonin concentration increases physiologically from the pre- to the postoperative period, suggesting a defensive physiologic response to counteract oxidative stress. The administration of exogenous melatonin in newborn infants undergoing surgery reduces lipid and protein peroxidation in the postoperative period, showing a potential role in protecting babies from the deleterious consequences of oxidative stress.
PubMed: 36978811
DOI: 10.3390/antiox12030563 -
Cureus Feb 2023Introduction Vitiligo is an acquired pigmentary disorder clinically manifested by circumscribed depigmented macules and often associated with leucotrichia. Not much is...
Introduction Vitiligo is an acquired pigmentary disorder clinically manifested by circumscribed depigmented macules and often associated with leucotrichia. Not much is known about the biochemical abnormality occurring in vitiligo. Our study aims to determine whether serum homocysteine is raised in vitiligo patients and whether it can be used as a prognostic marker for vitiligo. Material and methods This study is a hospital-based, case-control, analytical study conducted on 70 patients of vitiligo patients. A total of 30 staff of the hospital served as control. Venous blood was withdrawn from the antecubital vein from all study participants using all aseptic precautions. Investigation of blood homocysteine levels was done in all the study participants. Scoring of vitiligo was done based on Vitiligo European Task Force (VETF) criteria which take into account body surface area, stage, and spread. Results Mean serum homocysteine level among vitiligo patients was 14.40± 5.80 micromoles/lit as compared to 10.33± 5.05 micromole/lit in control groups, and this difference was statistically significant (t-value = 3.19and p-value = 0.002). The correlation coefficient was statistically significant (correlation coefficient = 0.25 and p-value = 0.03) in between homocysteine level and stage of the disease. On multiple comparisons difference in serum homocysteine level of progressing category is significantly raised as compared to control, stable, and regressing categories. Conclusion The mean serum homocysteine level among all vitiligo patients was higher as compared to control groups. Moreover, the serum homocysteine level of active cases is significantly higher as compared to control, stable, and regressing categories. Also, serum homocysteine levels showed a positive correlation with the degree of depigmentation, i.e., stage of the disease.
PubMed: 36909125
DOI: 10.7759/cureus.34772