The series of 2-amino-7-propargyloxy-4H-chromene-3-carbonitriles 5a-t were synthesized from corresponding 2-amino-7-phydroxy-4H-chromene-3-carbonitriles 4a-t and propargyl bromide. Two procedures ...were used in these syntheses: K2CO3/acetone and NaH/DMF procedures with yields of 65–89% and 80–96%, respectively. 1H-1,2,3-Triazole-tethered 4H-chromene−d-glucose conjugates 7a-t were synthesized using click chemistry of propargyl ethers 5a-t and tetra-O-acetyl-β-d-glucopyranosyl azide. Cu@MOF-5 was the optimal catalyst for this chemistry. The yields of 1H-1,2,3-triazoles were 80–97.8%. All triazoles 7a-t were evaluated in vitro for anti-microorganism activities. Among tested compounds with MIC values of 1.56–6.25 μM, there were four compounds against B. subtilis, four compounds against S. aureus, and four compounds against S. epidermidis; five compounds against E. coli, four compounds against K. pneumoniae, five compounds against P. aeruginosa, and six compounds against S. typhimurium. Compounds 7c,7d,7f,7h, and 7r had MIC values of 1.56–6.25 μM for three clinical MRSA isolates. Some compounds had inhibitory activities against four fungi, including A. niger, A. flavus, C. albicans, and S. cerevisiae, with MIC values of 1.56–6.25 μM. Some 1H-1,2,3-triazoles had comparatively low toxicity against RAW 264.7 cells.
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•Novel 1H-1,2,3-triazole-tethered 4H-chromene−d-glucose conjugates by click chemistry.•Several triazoles were active for three strains of Gram-(+), four strains of Gram-(−) bacteria (MICs = 1.56–6.25 μM).•Some triazoles had activity against four strains of fungi with MICs of 1.56–6.25 μM.•7c,7d,7f,7h, 7r exerted anti-MRSA activities against all strains with MIC of 1.56–6.25 μM.•1H-1,2,3-Triazoles 7c,7d,7f,7h, 7r had comparatively low cytotoxicity against RAW 264.7 cells.
Fucoidans from brown macroalgae (brown seaweeds) have different structures and many interesting bioactivities. Fucoidans are classically extracted from brown seaweeds by hot acidic extraction. Here, ...we report a new targeted enzyme-assisted methodology for fucoidan extraction from brown seaweeds. This enzyme-assisted extraction protocol involves a one-step combined use of a commercial cellulase preparation (Cellic
CTec2) and an alginate lyase from
sp. (SALy), reaction at pH 6.0, 40 °C, removal of non-fucoidan polysaccharides by Ca
precipitation, and ethanol-precipitation of crude fucoidan. The workability of this method is demonstrated for fucoidan extraction from
subsp.
(basionym
) and
as compared with mild acidic extraction. The crude fucoidans resulting directly from the enzyme-assisted method contained considerable amounts of low molecular weight alginate, but this residual alginate was effectively removed by an additional ion-exchange chromatographic step to yield pure fucoidans (as confirmed by
H NMR). The fucoidan yields that were obtained by the enzymatic method were comparable to the chemically extracted yields for both
and
, but the molecular sizes of the fucoidans were significantly larger with enzyme-assisted extraction. The molecular weight distribution of the fucoidan fractions was 400 to 800 kDa for
and 300 to 800 kDa for
, whereas the molecular weights of the corresponding chemically extracted fucoidans from these seaweeds were 10-100 kDa and 50-100 kDa, respectively. Enzyme-assisted extraction represents a new gentle strategy for fucoidan extraction and it provides new opportunities for obtaining high yields of native fucoidan structures from brown macroalgae.
Abstract
Background
An endotracheal tube cuff pressure between 20 and 30 cmH2O is recommended to prevent ventilator-associated respiratory infection (VARI). We aimed to evaluate whether continuous ...cuff pressure control (CPC) was associated with reduced VARI incidence compared with intermittent CPC.
Methods
We conducted a multicenter open-label randomized controlled trial in intensive care unit (ICU) patients within 24 hours of intubation in Vietnam. Patients were randomly assigned 1:1 to receive either continuous CPC using an automated electronic device or intermittent CPC using a manually hand-held manometer. The primary endpoint was the occurrence of VARI, evaluated by an independent reviewer blinded to the CPC allocation.
Results
We randomized 600 patients; 597 received the intervention or control and were included in the intention to treat analysis. Compared with intermittent CPC, continuous CPC did not reduce the proportion of patients with at least one episode of VARI (74/296 25% vs 69/301 23%; odds ratio OR 1.13; 95% confidence interval CI .77–1.67. There were no significant differences between continuous and intermittent CPC concerning the proportion of microbiologically confirmed VARI (OR 1.40; 95% CI .94–2.10), the proportion of intubated days without antimicrobials (relative proportion RP 0.99; 95% CI .87–1.12), rate of ICU discharge (cause-specific hazard ratio HR 0.95; 95% CI .78–1.16), cost of ICU stay (difference in transformed mean DTM 0.02; 95% CI −.05 to .08, cost of ICU antimicrobials (DTM 0.02; 95% CI −.25 to .28), cost of hospital stay (DTM 0.02; 95% CI −.04 to .08), and ICU mortality risk (OR 0.96; 95% CI .67–1.38).
Conclusions
Maintaining CPC through an automated electronic device did not reduce VARI incidence.
Clinical Trial Registration
NCT02966392.
The results of this randomised controlled trial demonstrate that continuous endotracheal cuff pressure control using an electronic automated device does not reduce the occurrence of ventilator-associated respiratory infection (VARI) in intubated patients compared with intermittent control.
IL(interleukin)-6 is a multifunctional cytokine crucial for immunological, hematopoiesis, inflammation, and bone metabolism. Strikingly, IL-6 has been shown to significantly contribute to the ...initiation of cytokine storm—an acute systemic inflammatory syndrome in Covid-19 patients. Recent study has showed that blocking the IL-6 signaling pathway with an anti-IL-6 receptor monoclonal antibody (mAb) can reduce the severity of COVID-19 symptoms and enhance patient survival. However, the mAb has several drawbacks, such as high cost, potential immunogenicity, and invasive administration due to the large-molecule protein product. Instead, these issues could be mitigated using small molecule IL-6 inhibitors, but none are currently available. This study aimed to discover IL-6 inhibitors based on the PPI with a novel camelid Fab fragment, namely 68F2, in a crystal protein complex structure (PDB ID: 4ZS7). The pharmacophore models and molecular docking were used to screen compounds from DrugBank databases. The oral bioavailability of the top 24 ligands from the screening was predicted by the SwissAMDE tool. Subsequently, the selected molecules from docking and MD simulation illustrated a promising binding affinity in the formation of stable complexes at the active binding pocket of IL-6. Binding energies using the MM-PBSA technique were applied to the top 4 hit compounds. The result indicated that DB08402 and DB12903 could form strong interactions and build stable protein–ligand complexes with IL-6. These potential compounds may serve as a basis for further developing small molecule IL-6 inhibitors in the future.
Graphical abstract
In this study, MCM-41 mesoporous silica nanoparticles were successfully synthesized by the condensation of a tetraorthosilicate precursor on a template self-assembled by cetyltrimethylammonium ...bromide in alkaline. The small-angle x-ray diffraction patterns of MCM-41 indicate that silica nanoparticles possess hexagonal structures with a high degree of structural ordering. Transmission electron microscopy images show that the size of the MCM-41 particles is around 100-120 nm, and the pore sizes range from 2 nm to 4 nm. In addition, the specific surface area of MCM-41 obtained by Brunauer–Emmett–Teller analysis is as high as 987 m
2
.g
−1
and the pore size extracted from nitrogen physical adsorption isotherms is in accordance with the TEM result. Thermogravimetric analysis, Fourier-transform infrared spectroscopy, Zeta potential measurements and photoluminescence measurements show that 3-aminopropyltriethoxysilane (APTES) and doxorubicin were grafted and loaded successfully onto MCM-41 nanoparticles. An assay on fibroblasts, A549 and doxorubicin-resistant A549/DOX cells indicates that the prepared MCM41 grafting APTES nanoparticles are safe to normal cells and toxic to cancer cells
in vitro
.
Graphic abstract
Vietnam has a high thalassemia burden. We collected blood samples from 5880 pregnant Vietnamese women during prenatal health checks to assess thalassemia carrier frequency using combined ...gap-polymerase chain reaction (gap-PCR) and targeted next-generation sequencing (NGS). Thalassemia carriers were identified with prevalence of 13.13% (772), including 7.82% (460) carriers of α-thalassemia (α-thal), 5.31% (312) carriers of β-thalassemia (β-thal), and 0.63% (37) concurrent α-/β-thal carriers. Deletional mutations (368) accounted for 80.0% of α-thal carriers, of which, --
SEA
(Southeast Asian) (n = 254; 55.0%) was most prevalent, followed by the -α
3.7
(rightward) (n = 66; 14.0%) and -α
4.2
(leftward) (n = 45; 9.8%) deletions. Hb Westmead (HBA2: c.369C>G) (n = 53) and Hb Constant Spring (Hb CS or HBA2: c.427T>C) (in 28) are the two most common nondeletional α-globin variants, accounting for 11.5 and 6.0% of α-thal carriers. We detected 11 different β-thal genotypes. Hb E (HBB: c.79G>A) (in 211) accounted for 67.6% of β-thal carriers. The most common β-thal genotypes were associated with mutations at codon 17 (A>T) (HBB: c.52A>T), codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), and codon 71/72 (+A) (HBB: c.217_218insA) (prevalence 0.70%, 0.68%, and 0.2%, respectively). Based on mutation frequencies calculated in this study, estimates of 5021 babies in Vietnam are affected with clinically severe thalassemia annually. Our data suggest a higher thalassemia carrier frequency in Vietnam than previously reported. We established that combining NGS with gap-PCR creates an effective large-scale thalassemia screening method that can detect a broad range of mutations.
Fifteen steroids, including two new compounds, leptosteroid (1) and 5,6β-epoxygorgosterol (2), were isolated and structurally elucidated from the Vietnamese soft coral Sinularia leptoclados. Their ...cytotoxic effect against a panel of eight human cancer cell lines was evaluated using sulforhodamine B (SRB) method. Significant cytotoxicity against hepatoma cancer (HepG2, IC50=21.13±0.70 µM) and colon adenocarcinoma (SW480, IC50=28.65±1.53 µM) cell lines were observed for 1 and against acute leukemia (HL-60, IC50=20.53±2.26 µM) and SW480 (IC50=26.61±1.59 µM) for ergost-5-en-3β,7β-diol (8). In addition, 3β,7β-dihydroxyergosta-5,24(28)-diene (13) showed significant cytotoxic activity on all tested cell lines with IC50 values ranging from 13.45±1.81 to 29.01±3.21 µM.
Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with ...amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.
Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first 2 weeks - or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031.
Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (-0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference -0.005log10CFU/ml/day, 95% CI: -0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation.
High-dose tamoxifen does not increase the clearance rate of
from CSF. Novel, affordable therapies are needed.
The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.
β-thalassemia is an autosomal recessive disease with the reduction or absence in the production of β-globin chain in the hemoglobin, which is caused by mutations in the Hemoglobin subunit beta (HBB) ...gene. In Vietnam, the number of β-thalassemia carriers range from 1.5 to 25.0%, depending on ethnic and geographical areas, which is much higher than WHO's data worldwide (1.5%). Hence, preimplantation genetic diagnosis (PGD) plays a crucial role in reducing the rate of β-thalassemia affected patients/carriers. In this research, we report the feasibility and reliability of conducting PGD in combination with the use of short tandem repeat (STR) markers in facilitating the birth of healthy children. Six STRs, which were reported to closely linked with the HBB gene, were used on 15 couples of β-thalassemia carriers. With 231 embryos, 168 blastocysts were formed (formation rate of 72.73%), and 88 were biopsied and examined with STRs haplotyping and pedigree analysis. Thus, the results were verified by Sanger sequencing, as a definitive diagnosis. Consequently, 11 over 15 couples have achieved pregnancy of healthy or at least asymptomatic offspring. Only three couples failed to detect any signs of pregnancy such as increased Human Chorionic Gonadotropin (HCG) level, foetal sac, or heart; and one couple has not reached embryo transfer as they were proposed to continue with HLA-matching to screen for a potential umbilical cord blood donor sibling. Thus, these results have indicated that the combination of PGD with STRs analysis confirmed by Sanger sequencing has demonstrated to be a well-grounded and practical clinical strategy to improve the detection of β-thalassemia in the pregnancies of couples at-risk before embryo transfer, thus reducing β-thalassemia rate in the population.
Two new pyrrole oligoglycosides, plancipyrrosides A and B (1 and 2), were isolated from methanol extract of the Vietnamese starfish Acanthaster planci using various chromatographic procedures. Their ...structures were elucidated by spectroscopic methods including one and two dimensional (1D- and 2D)-NMR and Fourier transform ion cyclotron resonance (FT-ICR)-MS. The finding of 1 and 2 represents the third case of pyrrole oligoglycosides obtaining reported to date. Moreover, plancipyrroside B (2) exhibits a potent inhibitory effect on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells with IC50 of 5.94±0.34 µM, whereas plancipyrroside A (1) shows this inhibitory activity with IC50 of 16.61±1.85 µM.
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