(1) Background: Drug repositioning is an unconventional drug discovery approach to explore new therapeutic benefits of existing drugs. Currently, it emerges as a rapid avenue to alleviate the ...COVID-19 pandemic disease. (2) Methods: Herein, we tested the antiviral activity of anti-microbial and anti-inflammatory Food and Drug Administration (FDA)-approved drugs, commonly prescribed to relieve respiratory symptoms, against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the viral causative agent of the COVID-19 pandemic. (3) Results: Of these FDA-approved antimicrobial drugs, Azithromycin, Niclosamide, and Nitazoxanide showed a promising ability to hinder the replication of a SARS-CoV-2 isolate, with IC
of 0.32, 0.16, and 1.29 µM, respectively. We provided evidence that several antihistamine and anti-inflammatory drugs could partially reduce SARS-CoV-2 replication in vitro. Furthermore, this study showed that Azithromycin can selectively impair SARS-CoV-2 replication, but not the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). A virtual screening study illustrated that Azithromycin, Niclosamide, and Nitazoxanide bind to the main protease of SARS-CoV-2 (Protein data bank (PDB) ID: 6lu7) in binding mode similar to the reported co-crystalized ligand. Also, Niclosamide displayed hydrogen bond (HB) interaction with the key peptide moiety GLN: 493A of the spike glycoprotein active site. (4) Conclusions: The results suggest that Piroxicam should be prescribed in combination with Azithromycin for COVID-19 patients.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million ...infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (M
) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of
analyses, six terpenes demonstrated high potency as M
inhibitors with Δ
≤ -40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 M
than lopinavir over 100 ns with Δ
values of -51.9 vs. -33.6 kcal/mol, respectively. Protein-protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components
,
, and
. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target-function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further
and
testing.
The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for ...COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (M
) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target M
, a series of cembranoid diterpenes from the biologically active soft-coral genus
have been examined as SARS-CoV-2 M
inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as M
inhibitors with Δ
< -33.0 kcal/mol. Binding energy and structural analyses of the most potent
inhibitor, bislatumlide A (
), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that
has a higher binding affinity against M
than darunavir with Δ
values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for
; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that
has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of
as an antiviral agent against SARS-CoV-2.
Although the favourable role of T lymphocyte populations in different tumour types is established, that of B cells is still a matter of debate and needs further clarification. The presence of ...tumour-infiltrating B cells may represent an antibody response against breast tumour antigens. We used immunohistochemistry to investigate the density and localisation of B lymphocytes infiltrating 1470 breast tumours and to identify any prognostic significance and relationship to various clinicopathological factors. Higher numbers of CD20
+
cells were found in the stroma away from the carcinoma (mean 12 cells) compared with either intratumoural or adjacent stromal compartments (mean 1 cell). The majority of tumours showed a diffuse pattern of B cells rather than aggregates. There was a positive correlation between higher numbers of total CD20
+
B cells and higher tumour grade (
r
s
= 0.20,
P
< 0.001), ER and PgR negativity (
P
< 0.001), and basal phenotype (
P
< 0.001) subclass. In univariate survival analysis, higher total number of infiltrating CD20
+
cells, irrespective of location, was associated with significantly better BCSS (
P
= 0.037) and longer DFI (
P
= 0.001). In multivariate analysis, total CD20
+
B cell count (HR = 0.75, 95% CI = 0.58–0.96 for BCSS and HR = 0.72, 95% CI = 0.58–0.89, for DFI), tumour size, nodal stage, grade, vascular invasion, HER-2 status, and total CD8
+
T cell count were independently associated with outcome. This suggests that humoral immunity, in addition to the cell mediated immunity, may be important in breast cancer. This should be considered in breast cancer immunotherapy and vaccine strategies.
and
(Fabaceae) are well-known medicinal plants with valuable secondary metabolites and pharmacological properties. The flavonoid-rich fractions of
roots and
leaves were prepared using Diaion column ...chromatography, and the confirmation of flavonoid richness was confirmed using UPLC-ESI-MS profiling and total phenolics and flavonoids assays. UPLC-ESI-MS profiling of the flavonoid-rich fraction of
roots and
leaves resulted in the tentative identification of 32 and 23 compounds, respectively. Additionally, the wound healing potential of topical preparations of each fraction, individually and in combination (1:1) ointment and gel preparations, were investigated in vivo, supported by histopathological examinations and biomarker evaluations, as well as molecular docking studies for the major constituents. The topical application of
ointment and gel,
ointment and gel and combination preparations significantly increase the wound healing rate and the reduction of oxidative stress in the wound area via MDA reduction and the elevation of reduced GSH and SOD levels as compared to the wound and Nolaver
-treated groups. The molecular docking study revealed that that major compounds in
and
can efficiently bind to the active sites of three proteins related to wound healing: glycogen synthase kinase 3-
(GSK3-
), matrix metalloproteinases-8 (MMP-8) and nitric oxide synthase (iNOS). Consequently,
roots and
leaves may be a rich source of bioactive metabolites with antioxidant, anti-inflammatory and wound healing properties.
Hyperlipidemia is still the leading cause of heart disease in patients with hypertension. The purpose of this study is to make rosuvastatin calcium (ROS) and atenolol (AT) bilayer tablets to treat ...coexisting dyslipidemia and hypertension with a single product. ROS was chosen for the immediate-release layer of the constructed tablets, whereas AT was chosen for the sustained-release layer. The solid dispersion of ROS with sorbitol (1:3 w/w) was utilized in the immediate-release layer while hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium bicarbonate were incorporated into the floating sustained-release layer. The concentrations of HPMC and EC were optimized by employing 32 full factorial designs to sustain AT release. The bilayer tablets were prepared by the direct compression method. The immediate-release layer revealed that 92.34 ± 2.27% of ROS was released within 60 min at a pH of 1.2. The second sustained-release layer of the bilayer tablets exhibited delayed release of AT (96.65 ± 3.36% within 12 h) under the same conditions. The release of ROS and AT from the prepared tablets was found to obey the non-Fickian diffusion and mixed models (zero-order, Higuchi and Korsmeyer–Peppas), respectively. Preclinical studies using rabbit models investigated the impact of ROS/AT tablets on lipid profiles and blood pressure. A high-fat diet was used to induce obesity in rabbits. Bilayer ROS/AT tablets had a remarkable effect on decreasing the lipid profiles, slowing weight gain, and lowering blood pressure to normal levels when compared to the control group.
Breast carcinomas are often infiltrated by inflammatory cells, particularly macrophages and T lymphocytes, but the significance of these cells remains unclear. One possible role of these inflammatory ...cells is that they represent a cell-mediated immune response against the carcinoma. CD8(+) lymphocytes are a known crucial component of cell-mediated immunity. The purpose of this study was to explore the prognostic value of tumor-infiltrating CD8(+) cytotoxic lymphocytes in breast cancer. Tumor-infiltrating CD8(+) lymphocytes were assessed by immunohistochemical staining of tissue microarray cores from 1,334 unselected breast tumors from patients with long-term follow-up. The number of CD8(+) T cells was counted in tumor nests (intratumoral), in stroma adjacent to tumor cells, and in stroma distant to tumor cells, and their relationship with clinical outcome was determined. The total number of CD8(+) cells was positively correlated with tumor grade (r(s) = 0.20; P < .001) and inversely correlated with patient's age at diagnosis, estrogen receptor-alpha (ER-α), and progesterone receptor (PgR) expression (Mann-Whitney U test, P < .001). The total patient cohort was randomly divided into two separate training and validation sets before performing univariate survival analysis. Total number and distant stromal CD8(+) lymphocytes were associated with better patient survival (P = .041 and P < .001, respectively) in the training set. In multivariate analysis, total CD8(+) T-cell count was an independent prognostic factor in both training and validation sets. These results suggest that tumor-infiltrating CD8(+) T lymphocytes have antitumor activity as judged by their favorable effect on patients' survival and could potentially be exploited in the treatment of breast cancer.
To assess the level of medication adherence and to investigate predictors of medication adherence and blood pressure control among hypertensive patients attending primary healthcare clinics in ...Makkah, Saudi Arabia.
Hypertensive patients meeting the eligibility criteria were recruited from eight primary care clinics between January and May 2016 for this study. The patients completed Arabic version of Morisky Medication Adherence Scale (MMAS-8), an eight-item validated, self-reported measure to assess medication adherence. A structured data collection form was used to record patients' sociodemographic, medical and medication data.
Two hundred and four patients, of which 71.6% were females, participated in the study. Patients' mean age was 59.1 (SD 12.2). The mean number of medication used by patients was 4.4 (SD 1.89). More than half (110; 54%) of the patients were non-adherent to their medications (MMAS score < 6). Binary regression analysis showed that highly adherent patients (MMAS score = 8) were about five times (OR 4.91 95%CI: 1.85-12.93; P = 0.01) more likely to have controlled blood pressure compared to low adherent patients. Female gender (OR 0.40 95% CI: 0.20-0.80; P = 0.01), Age > 65 years (OR 2.0 95% CI: 1.0-4.2; P = 0.04), and being diabetic (OR 0.25 95% CI: 0.1-0.6; P = 0.04) were found to be independent predictors of medication adherence.
Medication adherence is alarmingly low among hypertensive patients attending primary care clinics in Saudi Arabia which may partly explain observed poor blood pressure control. There is a clear need to educate patients about the importance of medication adherence and its impact on improving clinical outcomes. Future research should identify barriers to medication adherence among Saudi hypertensive patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dye-sensitized solar cell (DSSC) provides credible alternative concept for inorganic solid-state photovoltaic devices. The conversion efficiency of DSSC is mainly based on the dye coated on the ...porous semiconductor TiO2 film. The use of natural dyes in solar cells is a promising development to this technology because it cuts down the high cost of noble metals and chemical synthesis. Therefore, this type of solar cell has attracted considerable attention from the academic and industrial communities. Numerous kinds of pigments, such as anthocyanin, carotenoid, chlorophyll, and flavonoid, extracted from various plant components, such as leaves, fruits, and flowers, have been tested as sensitizers. The photostability of the DSSC sensitizer material must be capable of undergoing many redox cycles without decomposition, and must also have the ability to carry attachment groups, such as phosphonate or carboxylate, to promptly graft it to the TiO2 oxide. This paper highlights and discusses the development of natural dye photosensitizers and the mechanisms affecting the dye stability.
This study aims to determine the influence of grafting and nano-silicon fertilizer on the growth and production of tomatoes (Solanumlycopersicum L.) under salinity conditions. A commercial tomato ...hybrid (cv. Strain B) was used as a scion and two tomato phenotypes were used as rootstocks: S. pimpinellifolium and Edkawy. The rootstock effect was evaluated by growing plants at two NaCl concentrations plus the control (0, 4000, and 8000 ppm NaCl). Nano-silicon foliar application (0.5 ppm) after 20, 28, and 36 days from transplanting was also used to mitigate salinity stress. Antioxidants, hormones, and proline were evaluated for a better understanding of the physiological changes induced by salinity and grafting. The results showed that grafting either on S. pimpinellifolium or Edkawy combined with nano-silicon application enhanced shoot and root growth, fruit yield, and fruit quality. The Edkawy rootstock was more effective than the S. pimpinellifolium rootstock in terms of counteracting the negative effect of salinity. Higher levels of mineral contents, GA3, ABA, and proline were detected in shoots that were subjected to grafting and nano-silicon application compared to the control treatment. This study indicates that grafting and nano-silicon application hold potential as alternative techniques to mitigate salt stress in commercial tomato cultivars.
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