Zingiber officinale Roscoe extract, Raphanus sativus L. extract, Rheum palmatum extract, Coptis chinensis extract, Glycyrrhiza uralensis extract (GUE), Potentilla discolor extract (PDE) and Taraxacum ...officinale extract (TOE) were screened for the green corrosion inhibitors of AZ91 alloy in saline environment. The experiment results demonstrated that GUE, PDE and TOE can significantly enhance the corrosion resistance of AZ91 alloy by 73.4, 87.6 and 84.6%, respectively. Surface characterization using FTIR, UV-Vis and XPS revealed that the organic compounds of GUE, PDE and TOE can interact with the alloy surface to form a protective physisorbed film, effectively mitigating the corrosion process of AZ91 alloy. The present results may be helpful to discover the new green inhibitors with high inhibition efficiency for AZ91 alloy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The risk of drug-induced liver injury (DILI) poses a major challenge for development of natural products derived from traditional Chinese medicines (NP-TCMs). It is urgent to find a new method for ...the safety assessment of the NP-TCMs. Recent study has reported an in vitro/in silico method to estimate the acceptable daily intake of hepatotoxic compounds using support vector machine (SVM) classifier and physiologically based pharmacokinetic (PBPK) modeling. However, this method is not suitable for estimating the dosing schedule of compounds which are administered in multiple daily doses. Thus, in this study, the method mentioned above was in particular optimized, and used to estimate the hepatotoxic plasma concentrations of 17 NP-TCMs. Additionally, the oral dosing schedules of the triptolide, emodin, matrine and oxymatrine were also predicted by the SVM classifier and PBPK modeling. The optimization included that: (1) in vitro cytotoxicity data of 28 training set compounds was optimized using benchmark concentrations (BMC) modeling; (2) AUC of the training set compound was used as the in vivo metric instead of
C
max
to better reflect the total daily exposure of compounds which are administered in multiple daily doses; (3) using the mean AUC in plasma as in vivo metric and BMC value as in vitro metric could achieve the better toxicity separation index (0.962 vs. 0.938); (4) The TSI for
C
max
and BMC values was 0.985 calculated in this study, and the results indicated that BMC modeling improved the separation performance. This optimized in vitro–in vivo extrapolation (IVIVE) workflow could extrapolate in vitro BMC to blood concentrations and the oral dosing schedule which are corresponding to certain risk of hepatotoxicity. The estimated safe dosing schedule of oxymatrine by this optimized method was close to the clinical recommended dosing regimen. The results indicate that the optimized method could be used to predict the dosing schedule of compounds administered in multiple daily doses, and our optimized workflow could be helpful for the safety assessment as well as the research and development on NP-TCMs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The worldwide outbreak of carbapenem-resistant
(CRKP) has become an urgent public health problem. High mortality and lack of effective treatments further pose new challenges to control this ...infection. However, studies about the evaluation of available antibiotics for CRKP infection are limited. The present study aimed to compare the efficacy of polymyxin B versus ceftazidime-avibactam (CAZ/AVI) in Chinese patients with CRKP infections and to identify risk factors affecting 7-day bacterial eradication and 28-day all-cause mortality.
From January 8, 2018, to July 6, 2020, a total of 115 adult CRKP infected patients from two tertiary teaching hospitals in Shanghai, China were enrolled based on the inclusion and exclusion criteria. By reviewing electronic medical records of these patients, demographic and clinical data were extracted. The selected patients were divided into polymyxin B and CAZ/AVI groups according to primary antibiotic exposure to compare therapeutic effects. Binary logistic and cox's regression analysis were performed to identify risk factors for 7-day bacterial eradication and all-cause mortality.
One hundred and five patients were treated with polymyxin B (67.8%) or CAZ/AVI (32.2%). Patients in the CAZ/AVI group had significantly lower rates of 28-day mortality (8.1 vs 29.5%,
= 0.013), higher microbiological eradication and 28-day clinical success. Multivariate analysis showed that Charlson comorbidity index (≥3) and prior antibiotic use within 90 days were independent risk factors for poor microbiological eradication. Cox's regression analysis indicated that the length of hospitalization after CRKP infection and baseline creatinine clearance negatively affected 28-day mortality.
CAZ/AVI was more effective than polymyxin B and appeared to be a promising drug for CRKP infection, especially for critically ill patients.
Diabetic retinopathy (DR), a neurovascular disease, is one of the leading causes of blindness in working-age adults. Long noncoding RNAs (lncRNAs) have attracted attention as indicators for DR. This ...study aimed to characterize the role of lncRNA human testis development-related gene 1 (TDRG1) and its modulation of vascular endothelial growth factor (VEGF) in deteriorating DR.
Tissue samples were obtained from patients with epiretinal membranes (EMs) or proliferative DR, and human retinal microvascular endothelial cells (HRECs) were cultured with high-glucose medium to mimic DR as the
model. The expression of lncRNA TDRG1 and VEGF was determined by immunofluorescence staining, Western blotting, and RT-qPCR. Transfection of small-interfering RNA was conducted to knock down target gene expression. HREC functions were evaluated by cell viability, fluorescein isothiocyanate (FITC)-dextran extravasation, migration, and tube formation assays under different conditions.
LncRNA TDRG1 and VEGF were found to be co-expressed and significantly upregulated in fibrovascular membranes (FVMs) from DR patients compared to those from EM patients. In the
model, hyperglycemic treatment markedly increased the expression of lncRNA TDRG1 and VEGF at the mRNA and protein levels, which promoted cell proliferation and migration, enhanced permeability, and disrupted tube formation of HRECs. However, knockdown of lncRNA TDRG1 or VEGF notably decreased the expression of VEGF and reversed the impaired functions of high-glucose-treated HRECs.
LncRNA TDRG1 promoted microvascular cell dysfunction
upregulating VEGF in the progression of DR and may serve as a potential therapeutic target in DR treatment.
The presentation and progression of Parkinson’s disease (PD) are not uniform, but the presence of rapid eye movement sleep behavior disorder (RBD) in PD patients may indicate a worse prognosis than ...isolated PD. Increasing evidence suggests that patients with comorbid PD and RBD (PD-RBD) are more likely to develop cognitive impairment (CI) than those with isolated PD; however, the predictors of CI in PD-RBD patients are not well understood. This study aimed to develop a prognostic model for predicting mild cognitive impairment (MCI) in PD-RBD patients. The data of PD-RBD patients were extracted from the Parkinson’s Progression Markers Initiative study (PPMI), and the sample was randomly divided into a training set (
n
= 96) and a validation set (
n
= 24). PD-MCI as defined by the level II Movement Disorder Society (MDS) diagnostic criteria was the outcome of interest. The demographic features, clinical assessments, dopamine transporter (DAT) imaging data, cerebrospinal fluid (CSF) analyses and genetic data of PD patients were considered candidate predictors. We found that performance on the University of Pennsylvania Smell Identification Test (UPSIT), the mean signal and asymmetry index of the putamen on DAT imaging, p-tau/α-syn and p-tau in CSF, and rs55785911 genotype were predictors of PD-MCI in PD-RBD patients. A C-index of 0.81 was obtained with this model, and a C-index of 0.73 was obtained in the validation set. Favorable results of calibrations and decision curve analysis demonstrated the efficacy and feasibility of this model. In conclusion, we developed a prognostic model for predicting MCI in PD-RBD patients; the model displayed good discrimination and calibration and may be a convenient tool for clinical application. Larger samples and external validation sets are needed to validate this model.
This study aimed to investigate the effects of long-term home quarantine on the mental health of people during the COVID-19 epidemic in Shanghai. We conducted an online questionnaire survey on March ...26 2020 and collected data on demographics, level of physical activity (PA), and mental health status of the participants. We assessed the mental health status using the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Scale (GAD-7), whereas PA was assessed using International Physical Activity Questionnaire Short Form (IPAQ-SF). Of all 2,409 valid samples, participants reported performing a total of 2015.20 metabolic equivalent of task (MET)-minutes/week of total PA before the outbreak period and 1720.29 MET-minutes/week of total PA during the outbreak period (
< 0.001). Participants who spent a longer time at home reported to have a better performance on the PHQ-9 (
= 0.087) and GAD-7 (
< 0.001). A high level of PA was considered an protective factor against depression (OR = 0.755, 95% CI 0.603-0.944,
< 0.001). Additionally, a high level of PA had a preventative effect on anxiety (OR = 0.741, 95% CI 0.568-0.967,
< 0.001), and a longer working period during the outbreak was shown to be a risk factor for anxiety (11-29 days, OR 1.455, 95% CI 1.110-1.909; 30-60 days OR 1.619, 95% CI 1.227-2.316). Home confinement during the pandemic might not have a negative effect on mental health provided that people engage in more PA indoors. This study encourages interventions for mental health problems through physical exercise.
Pneumocystis jirovecii pneumonia and invasive pulmonary aspergillosis are both life‐threatening opportunistic fungal infections. There are only few reports of coinfection by these two fungi in the ...literature, and Aspergillus fumigatus is the predominant Aspergillus species in the coinfection. We report here the first case of coinfection by Aspergillus terreus and P. jirovecii pneumonia and caspofungin can be an appropriate choice for salvage treatment of the coinfection. A 51‐year‐old man with a history of immune thrombocytopenia treated with prednisone over 2 months was admitted to emergency intensive care unit for acute respiratory failure and a cavity was found on chest computed tomography. Therefore, his trachea was immediately intubated. The patient was treated with a large spectrum of antibiotic regimen, consisting initially of imipenem/cilastatin, moxifloxacin and fluconazole followed by fluconazole, imipenem/cilastatin, vancomycin, trimethoprim–sulphamethoxazole (TMP‐SMZ) and azithromycin. When the polymerase chain reaction analysis of the bronchoalveolar lavage sample revealed P. jirovecii and A. terreus, all the antibiotics were stopped except TMP‐SMZ, and voriconazole was added. Two weeks later, the patient showed clinical improvement but radiological deterioration. Consequently, caspofungin was started for salvage therapy, then the patient showed gradual clinical improvement. He was discharged with oral voriconazole and TMP‐SMZ. The antifungal treatment was continued for 6 months until complete radiological absorption. In conclusion, early bronchoscopy with bronchoalveolar lavage fluid should be considered in order to diagnose and treat promptly in those treated with corticosteroids combined with immunocompromised and caspofungin could be an appropriate choice for salvage treatment of coinfection by P. jirovecii and A. terreus.
The authors report the first case of coinfection by Aspergillus terreus and Pneumocystis jirovecii pneumonia. First‐line treatment drugs voriconazole and trimethoprim–sulphamethoxazole does not show a good therapeutic effect in their case. Finally, they combine caspofungin as a salvage treatment, and the patient showed clinical improvement.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Honokiol, the main bioactive extract of
exhibits extensive therapeutic actions. Its treatment for advanced non-small cell lung cancer is undergoing clinical trials in China. However, the published ...safety evaluation studies have focused on extract mixtures of
in which the honokiol content was well below the reported clinical dose of the honokiol monomer. Therefore, safety assessment of the honokiol monomer is urgently needed. Our previous studies have already demonstrated that a high dose of the honokiol microemulsion (0.6 μg/mL) induces developmental toxicity in rats and zebrafish by inducing oxidative stress. By exploring the relationship between time and toxicity, we found that developmental toxic responses were stage-dependent. They mainly occurred within the first 24 h post fertilization (hpf) especially the first 12 hpf. In zebrafish, low doses of honokiol microemulsion (0.15, 0.21 μg/mL) significantly decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the mRNA expression of
In contrast, high dose (0.6 μg/mL) increased the levels of ROS and MDA, decreased activities and mRNA expression of superoxide dismutase (SOD) and catalase (CAT), and increased mRNA expression of
and
By acridine orange staining, we found that a high dose of honokiol microemulsion induced apoptosis mainly in zebrafish brain. In rat pheochromocytoma cells (PC12 cells), low doses of the honokiol microemulsion (1, 5, 10 µM) exerted a protective effect against H
O
-induced oxidative damage while high doses (≥20 µM) induced oxidative stress, which further confirms the dual effects of honokiol microemulsion on nerve cells. These dual roles of the honokiol microemulsion in oxidation-reduction reactions and apoptosis may be regulated by the forkhead box class O (FoxO) signaling pathway. Due to the potential of developmental toxicity, we recommend that the administration of high dose honokiol microemulsion in pregnant women should be considered with caution.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The Ras-specific guanine nucleotide exchange factors Son of Sevenless (SOS) regulates Ras activation by converting inactive GDP-bound to active GTP-bound states. The catalytic activity of Ras is ...further allosterically regulated by GTP-Ras bound to a distal site through a positive feedback loop. To address the mechanism underlying the long-range allosteric activation of the catalytic K-Ras4B by an additional allosteric GTP-Ras through SOS, we employed molecular dynamics simulation of the K-Ras4B
•SOS
complex with and without an allosteric GTP-bound K-Ras4B
. We found that the binding of an allosteric GTP-K-Ras4B
enhanced the affinity between the catalytic K-Ras4B
and SOS
, forming a more stable conformational state. The peeling away of the switch I from the nucleotide binding site facilitated the dissociation of GDP, thereby contributing to the increased nucleotide exchange rate. The community networks further showed stronger edge connection upon allosteric GTP-K-Ras4B
binding, which represented an increased interaction between catalytic K-Ras4B
and SOS
. Moreover, GTP-K-Ras4B
binding transmitted allosteric signaling pathways though the Cdc25 domain of SOS that enhanced the allosteric regulatory from the K-Ras4B
allosteric site to the catalytic site. This study may provide an in-depth mechanism for abnormal activation and allosteric regulation of K-Ras4B
.
The widespread coronavirus disease 2019 (COVID-19) outbreak impacted the mental health of infected patients admitted to Fangcang shelter hospital a large-scale, temporary structure converted from ...existing public venues to isolate patients with mild or moderate symptoms of COVID-19 infection.
This study aimed to investigate the risk factors of the infected patients from a new pharmacological perspective based on psychiatric drug consumption rather than questionnaires for the first time.
We summarised the medical information and analysed the prevalence proportion, characteristics, and the related risk factors of omicron variants infected patients in the Fangcang Shelter Hospital of the National Exhibition and Convention Center (Shanghai) from 9 April 2022 to 31 May 2022.
In this study, 6,218 individuals at 3.57% of all admitted patients in the Fangcang shelter were collected suffering from mental health problems in severe conditions including schizophrenia, depression, insomnia, and anxiety who needed psychiatric drug intervention. In the group, 97.44% experienced their first prescription of psychiatric drugs and had no diagnosed historical psychiatric diseases. Further analysis indicated that female sex, no vaccination, older age, longer hospitalization time, and more comorbidities were independent risk factors for the drug-intervened patients.
This is the first study to analyse the mental health problems of omicron variants infected patients hospitalised in Fangcang shelter hospitals. The research demonstrated the necessity of potential mental and psychological service development in Fangcang shelters during the COVID-19 pandemic and other public emergency responses.
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