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Objective: To explore the correlation between genotypes of Orientia (O.) tsutsugamushi and clinical characteristics of scrub typhus patients. Methods: Clinical data of patients with scrub typhus admitted to different types of medical institutions in Guangzhou from September 2012 to December 2016 were collected using medical records. Demographic data, clinical manifestations, as well as hematological and biochemical indicators of patients infected with different genotypes were analyzed and compared. Results: A total of 192 patients were included in this study, including 121 patients with Karp genotype of O. tsutsugamushi infection (63.0%), 36 patients with Gilliam genotype (19.0%), 23 patients with Kato genotype (12.0%), and 12 patients with TA763 genotype (6.0%) infection. The median value of albumin in patients with Karp genotype infection was significantly lower than that of Gilliam-infected patients (P=0.032). Patients with Karp genotype infection had a significantly longer hospital stay (9 days) than those with Gilliam genotype (7 days) (P=0.009) and Kato genotype infection (6 days) (P=0.005). Karp-infected patients also represented for the largest number of patients with complicated organ involvement (88/133, 66.2%). Furthermore, Karp-infected patients had higher risk of developing multiple organ dysfunction syndrome (18.2%) and requiring intensive care unit treatment (15.9%). Besides, patients with Gilliam genotype (8 days) and TA763 genotype infection (7.5 days) had shorter fever duration than those with Karp genotype (9 days) and Kato genotype (9 days) infection, respectively. Conclusions: Genotypes of Orientia tsutsugamushi were associated with varying clinical manifestations, organ involvement, and treatment outcomes, suggesting that genotypes ranged in virulence.

Apolipoprotein A-I(ApoA-I) is a member of blood apolipoproteins, it is the main component of High density lipoprotein(HDL). ApoA-I undergoes a series of complex processes from its generation to its composition as spherical HDL. It not only has a cholesterol reversal transport function, but also has a function in modulating the inflammatory response. ApoA-I exerts its anti-inflammatory effects mainly by regulating the functions of immune cells, such as monocytes/macrophages, dendritic cells, neutrophils, and T lymphocytes. It also modulates the function of vascular endothelial cells and adipocytes. Additionally, ApoA-I directly exerts anti-inflammatory effects against pathogenic microorganisms or their products. Intensive research on ApoA-I will hopefully lead to better diagnosis and treatment of inflammatory diseases.

Objective(s): Inadequate cytotrophoblast migration and invasion are speculated to result in preeclampsia, which is a pro-inflammatory condition. Sodium dichloroacetate (DCA) exerts anti-inflammatory actions. Thus,we sought to investigate the effect of DCA on the migration function of the lipopolysaccharide (LPS)-stimulated human-trophoblast-derived cell line (HTR-8/SVneo).Materials and Methods: HTR-8/SVneo cells were treated with LPS to suppress cell migration. Cell migration was examined by both scratch wound healing assay and transwell migration assay. Western blotting was used to analyze the expression levels of toll-like receptor-4 (TLR4), nuclear factor-κB (NF-κB), TNF-α, IL-1β, and IL-6 in the cells.Results: DCA reversed LPS-induced inhibition of migration in HTR-8/SVneo cells. Furthermore, DCA significantly suppressed LPS-induced activation of TLR4, phosphorylation of NF-κB (p65), translocation of p65 into the nucleus, and the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Treatment with inhibitors of TLR4 signal transduction (CLI095 or MD2-TLR-4-IN-1) reduced LPS-induced overexpression of pro-inflammatory cytokines, and a synergistic effect was found between TLR4 inhibitors and DCA in HTR-8/SVneo cells. Conclusion: DCA improved trophoblast cell migration function by suppressing LPS-induced inflammation, at least in part, via the TLR4/NF-κB signaling pathway. This result indicates that DCA might be a potential therapeutic candidate for human pregnancy-related complications associated with trophoblast disorder.

Abstract Background Present evidence suggests that the Doppler ultrasonographic indices, such as carotid artery blood flow (CABF) and velocity time integral (VTI), had the ability to predict fluid responsiveness in non-obstetric patients. The purpose of this study was to assess their capacity to predict fluid responsiveness in spontaneous breathing parturients undergoing caesarean section and to determine the effect of detecting and management of hypovolemia (fluid responsiveness) on the incidence of hypotension after anaesthesia. Methods A total of 72 full term singleton parturients undergoing elective caesarean section were enrolled in this study. CABF, VTI, and hemodynamic parameters were recorded before and after fluid challenge and assessed by carotid artery ultrasonography. Fluid responsiveness was defined as an increase in stroke volume index (SVI) of 15% or more after the fluid challenge. Results Thirty-one (43%) patients were fluid responders. The area under the ROC curve to predict fluid responsiveness for CABF and VTI were 0.803 (95% CI, 0.701–0.905) and 0.821 (95% CI, 0.720–0.922). The optimal cut-off values of CABF and VTI for fluid responsiveness was 175.9 ml/min (sensitivity of 74.0%; specificity of 78.0%) and 8.7 cm/s (sensitivity of 67.0%; specificity of 90.0%). The grey zone for CABF and VTI were 114.2-175.9 ml/min and 6.8–8.7 cm/s. The incidence of hypotension after the combined spinal-epidural anaesthesia (CSEA) was significantly higher in the Responders group 25.8% (8/31) than in the Non-Responders group 17.1(7/41) (P

BackgroundTacrolimus (Tac) is commonly used for postoperative immunosuppressive therapy in transplant patients. However, problems, for example, low bioavailability and unstable plasma concentration, persist for a long time, Studies have reported that the deoxyschizandrin could effectively improve these problems, but the pharmacokinetic parameters (PKs) of Tac combined with deoxyschizandrin are still unknown.MethodIn this study, an UHPLC-MS/MS method has been established for simultaneous quantitation of Tac and deoxyschizandrin. The PKs of Tac influenced by different doses of deoxyschizandrin after single and multiple administrations were analyzed, and the different impact of deoxyschizandrin and Wuzhi capsule on PKs of Tac were compared.ResultThe modified UHPLC-MS/MS method could rapid quantification of Tac and deoxyschizandrin within 2 min using bifendatatum as the internal standard (IS). All items were successfully validated. The Cmax of deoxyschizandrin increased from 148.27 ± 23.20 to 229.13 ± 54.77 ng/mL in rats after multiple administrations for 12 days. After co-administration of 150 mg/mL deoxyschizandrin, Tac had an earlier Tmax and greater Cmax and AUC0–t, and the Cmax and AUC0–t of Tac increased from 14.26 ± 4.73 to 54.48 ± 14.37 ng/mL and from 95.10 ± 32.61 to 315.23 ± 92.22 h/ng/mL, respectively; this relationship was positively proportional to the dosage of deoxyschizandrin. In addition, compared with Wuzhi capsule, the same dose of deoxyschizandrin has a better effective on Tac along with more stable overall PKs.ConclusionAn UHPLC-MS/MS method was established and validated for simultaneous detection of deoxyschizandrin and Tac. Deoxyschizandrin could improve the in vivo exposure level and stability of Tac, besides, this effect is better than Wuzhi capsule in same dose.

Background: Scutellaria baicalensis, the dry root of scutellaria baicalensis georgi, is a traditional Chinese medicine with long. In clinic, scutellaria baicalensis is commonly used in prescription for the treatment of depression. Additionally, numerous pre-clinical studies have shown that Scutellaria baicalensis and its active constituents are effective for depression. In this study, we aims to systematically review the roles of scutellaria baicalensis in depression and summarize the possible mechanism.Methods: A systematic review and meta-analysis were conducted to analyze the existing studies on the effects of scutellaria baicalensis on depression in animal models. Briefly, we searched electronic databases including Pubmed and Embase for preclinical trial studies from inception to September 2023. The items in each study were evaluated by two independent reviewers, and meta-analyses were performed on scutellaria baicalensis-induced behavioral changes in the study. Finally, random effects model is used to collect data.Results: A total of 49 studies were identified, and 13 studies were included in the final analysis. They all reported the different antidepressant effects of scutellaria baicalensis and the underlying biological mechanisms. Among the included 13 studies, the results of eight articles SPT[SMD = −2.80, 95%CI(-4.03, -1.57), p < 0.01], the results of the nine articles OFT[SMD = −2.38, 95%CI(-3.53, -1.23), p < 0.01], and the results of two articles NSFT[SMD = −2.98, 95%CI(-3.94, -2.02), p < 0.01] were significantly different from the control group. The risk of bias was moderate in all studies, however, there was a significant heterogeneity among studies.Conclusion: These results preliminarily suggest that scutellaria baicalensis can alleviate depressive behaviors and modulate underlying mechanisms, which is expected to be a promising antidepressant.

The combined prescriptions of nirmatrelvir/ritonavir and other drugs are limited due to potential drug-drug interactions, so therapeutic drug monitoring (TDM) becomes particularly important. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for determination of the nirmatrelvir/ritonavir in plasma of patients with COVID-19, providing technical and theoretical support for the TDM. Plasma samples were processed by protein precipitation using acetonitrile, and analytes were separated on an Agilent Poroshell 120 SB-C18 (2.1 × 75 mm, 2.7 μm) column at 35°C. Acetonitrile and 0.1% formic acid in water (52 : 48) were utilized as the mobile phases at a flow rate of 0.3 mL/min. In the multiple reaction monitoring (MRM) mode, nirmatrelvir and ritonavir were monitored using precursor/product ions: m/z 500.2/110.1 and 721.3/296.1, respectively, with selinexor as the internal standard. The linear range of both analytes was 2.0 ng/mL to 5000 ng/mL with good inter- and intraday precision and accuracy, and the recovery was 92.0%–107% for nirmatrelvir and 85.7%–106% for ritonavir. Finally, this method was successfully applied to monitor the exposure levels of nirmatrelvir/ritonavir in plasma samples from hemodialysis patients.

Chemotherapy-related cognitive deficits (CRCI) as one of the common adverse drug reactions during chemotherapy that manifest as memory, attention, and executive function impairments. However, there are still no effective pharmacological therapies for the treatment of CRCI. Natural compounds have always inspired drug development and numerous natural products have shown potential therapeutic effects on CRCI. Nevertheless, improving the brain targeting of natural compounds in the treatment of CRCI is still a problem to be overcome at present and in the future. Accumulated evidence shows that nose-to-brain drug delivery may be an excellent carrier for natural compounds. Therefore, we reviewed natural products with potential anti-CRCI, focusing on the signaling pathway of these drugs’ anti-CRCI effects, as well as the possibility and prospect of treating CRCI with natural compounds based on nose-to-brain drug delivery in the future. In conclusion, this review provides new insights to further explore natural products in the treatment of CRCI.

It has been estimated that in 2010, over two million patients with end-stage kidney disease may have faced premature death due to a lack of access to affordable renal replacement therapy, mostly dialysis. To address this shortfall in dialytic kidney replacement therapy, we propose a novel, cost-effective, and low-complexity hemodialysis method called allo-hemodialysis (alloHD). With alloHD, instead of conventional hemodialysis, the blood of a patient with kidney failure flows through the dialyzer’s dialysate compartment counter-currently to the blood of a healthy subject (referred to as a “buddy”) flowing through the blood compartment. Along the concentration and hydrostatic pressure gradients, uremic solutes and excess fluid are transferred from the patient to the buddy and subsequently excreted by the healthy kidneys of the buddy. We developed a mathematical model of alloHD to systematically explore dialysis adequacy in terms of weekly standard urea Kt/V. We showed that in the case of an anuric child (20 kg), four 4 h alloHD sessions are sufficient to attain a weekly standard Kt/V of >2.0. In the case of an anuric adult patient (70 kg), six 4 h alloHD sessions are necessary. As a next step, we designed and built an alloHD machine prototype that comprises off-the-shelf components. We then used this prototype to perform ex vivo experiments to investigate the transport of solutes, including urea, creatinine, and protein-bound uremic retention products, and to quantitate the accuracy and precision of the machine’s ultrafiltration control. These experiments showed that alloHD performed as expected, encouraging future in vivo studies in animals with and without kidney failure.

O2 mixed with CO2 gas has been successfully applied in converter smelting; however, up to now, there have been few studies regarding the jet characteristics of the mixed injection of the swirl oxygen lance nozzle and the influence of different ambient temperature conditions on jet characteristics compared with common nozzles. In this study, Fluent software was used to simulate the jet characteristics of a four-hole common nozzle and a four-hole swirl nozzle under four different ambient temperature conditions to inject 95% O2 + 5% CO2 and analyze the influence of different ambient temperatures on nozzle-jet characteristics. The results show that with an increase in the ambient temperature, the jet-axis velocity and nozzle centerline speed increase. Under the same distance condition, the distance between the maximum radial velocity point of the jet and the centerline of the nozzle becomes larger, with a velocity greater than that of the swirl nozzle. However, the influence of the ambient temperature on the offset of the jet centerline is small. With an increase in the ambient temperature and distance, the jet-axis temperature increases and the temperature of the nozzle centerline decreases. The research results can provide a theoretical reference for the optimal design of a CO2 + O2 swirl oxygen lance nozzle.

Abstract Background Chaihu-Guizhi-Ganjiang Decoction (CGGD) is a traditional Chinese medicine (TCM) prescription used to treat viral influenza. There is evidence that CGGD can be used to treat irritable bowel syndrome (IBS) but the potential mechanism of action and metabolites produced upon CGGD treatment remains elusive. Methods Patients with IBS were treated with pinaverium bromide (Dicetel™) and then CGGD after a washout period of 1 week. Both treatments lasted for 30 days. The efficacy and changes of metabolites in plasma after the two treatments were compared. Plasma samples were acquired before and after each treatment, and untargeted metabolics analysis was performed. Results Efficacy was measured according to the Rome IV criteria and TCM theory. Our results indicated that CGGD showed significantly better efficacy than Dicetel in the treatment of IBS utilizing each criterion. CGGD exerted greater effects on plasma metabolism than Dicetel. Dicetel treatment led to increased tryptophan metabolism (increased levels of 5-Hydroxyindoleacetaldehyde) and increased protein metabolism (increased levels of L-arginine). CGGD treatment significantly (p

Abstract Background Tanreqing capsules (TRQCs) and Tanreqing injections (TRQIs) are widely used in the treatment of respiratory diseases. In this study, a simple, rapid, and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for simultaneous quantification of the main components of Tanreqing, which include chlorogenic acid, ursodeoxycholic acid, chenodeoxycholic acid, and baicalin, in beagle dog plasma to compare their pharmacokinetic parameters. Methods Plasma samples were pretreated with protein precipitation. Chromatographic separation was performed on Waters Acquity UPLC HSS T3 (2.1 mm × 100 mm, 1.8 μm) column using a gradient elution with (A) 0.1% (v/v) formic acid aqueous solution and (B) acetonitrile. Six healthy beagles were divided into two groups, and a crossover, comparative pharmacokinetic study of TRQC (0.09 g/kg) and TRQI (0.5 mL/kg) after a single-dose administration or daily doses over 7 days was carried out. One group was administrated a single dose of TRQC and followed continuously for 7 days, whereas the other group was treated with TRQI in the same way. Results The calibration curves were linear over the ranges of 2.00–1000.00 ng/mL for baicalin, 10.00–5000.00 ng/mL for ursodeoxycholic acid, 1.00–500.00 ng/mLfor chenodeoxycholic acid and chlorogenic acid, respectively. The relative standard deviation of both intra-day and inter-day accuracy is less than 11.23%. The average extraction recovery of all compounds was greater than 82.21%. The major pharmacokinetic parameters of the four compounds were not significantly different between the two formulations (P > 0.05). Conclusions The measured levels of the four major components of TRQCs and TRQIs were comparable in these dogs, providing a reference for the clinical application of TRQCs instead of TRQIs.

Abstract Background Drug-induced mitochondrial toxicity is thought to be a common mechanism of drug hepatotoxicity. Xian-Ling-Gu-Bao (XLGB) oral preparation is a commonly used drug for osteoporosis in China. Classical safety evaluation studies have shown that the entire preparation and six Chinese herbal medicines have high safety, but the incidence of drug-induced liver damage due to XLGB remains high, the mechanism and toxic substances causing liver injury are still unclear. The purpose of this study is to identify compounds with potential mitochondrial liabilities in XLGB, and to clarify their underlying mechanisms and related pathways. Methods The mitochondrial function analysis was performed using an extracellular flux assay, which simultaneously monitored both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Through network pharmacology and in vitro experimental verification, the potential protein targets, signaling pathways and molecular mechanism of mitochondrial toxicity have been studied. Results We observed a significant decrease in mitochondrial respiration of Psoraleae Fructus and its five compounds in fundamental bioenergetics parameters such as basal respiration, ATP-linked production and maximal respiration, indicating mitochondrial dysfunction. The network pharmacology results showed that the influence of XLGB on mitochondrial dysfunction was closely related to PI3K-Akt signaling pathway, mTOR signaling pathway and Apoptosis. Western blot showed that the levels of mTOR, p-mTOR (Ser2448), Raptor, PI3K (p110α), Beclin 1, ATG5 and Caspase-9 were up-regulated after treatment with psoralidin, psoralen and bavachin, and the expression of Bcl-2 was down-regulated after bavachinin treatment. Conclusions The hepatotoxicity of XLGB is associated with mitochondrial dysfunction. Five compounds in Psoraleae Fructus showed mitochondrial damage, they are psoralidin, isobavachalcone, bavachinin, bavachin and psoralen, especially psoralidin showed significant reduction in reserve capacity and respiratory control ratios. The molecular mechanism is related to the activation of PI3K/mTOR signaling pathway to inhibit autophagy and induce mitochondrial apoptosis.

Abstract Background Recent evidence suggests that ultrasound measurements of carotid and brachial artery corrected flow time (FTc) and respirophasic variation in blood flow peak velocity (ΔVpeak) are valuable for predicting fluid responsiveness in mechanical ventilated patients. We performed the study to reveal the performance of ultrasonic measurements of radial artery FTc and ΔVpeak for predicting fluid responsiveness in mechanical ventilated patients undergoing gynecological surgery. Methods A total of eighty mechanical ventilated patients were enrolled. Radial artery FTc and ΔVpeak, and non-invasive pulse pressure variation (PPV) were measured before and after fluid challenge. Fluid responsiveness was defined as an increase in stroke volume index (SVI) of 15% or more after the fluid challenge. Multivariate logistic regression analyses and receiver operating characteristic (ROC) curve were used to screen multivariate predictors of fluid responsiveness and identify the predictive abilitie of non-invasive PPV, ΔVpeak and FTc on fluid responsiveness. Results Forty-four (55%) patients were fluid responders. Multivariate logistic regression analysis showed that radial artery FTc, ΔVpeak, and non-invasive PPV were the independent predictors of fluid responsiveness, with odds ratios of 1.152 [95% confidence interval (CI) 1.045 to 1.270], 0.581 (95% CI 0.403 to 0.839), and 0.361 (95% CI, 0.193 to 0.676), respectively. The area under the ROC curve of fluid responsiveness predicted by FTC was 0.802 (95% CI, 0.706–0.898), and ΔVpeak was 0.812 (95% CI, 0.091–0.286), which were comparable with non-invasive PPV (0.846, 95%CI, 0.070–0.238). The optimal cut-off values of FTc for fluid responsiveness was 336.6 ms (sensitivity of 75.3%; specificity of 75.9%), ΔVpeak was 14.2% (sensitivity of 88.2%; specificity of 67.9%). The grey zone for FTc was 313.5–336.6 ms and included 40 (50%) of the patients, ΔVpeak was 12.2–16.5% and included 37(46%) of the patients. Conclusions Ultrasound measurement of radial artery FTc and ΔVpeak are the feasible and reliable methods for predicting fluid responsiveness in mechanically ventilated patients. Trial registration The trial was registered at the Chinese Clinical Trial Registry (ChiCTR)(www.chictr.org), registration number ChiCTR2000040941.

Abstract In patients with kidney failure treated by hemodialysis, intradialytic arterial oxygen saturation (SaO2) time series present intermittent high-frequency high-amplitude oximetry patterns (IHHOP), which correlate with observed sleep-associated breathing disturbances. A new method for identifying such intermittent patterns is proposed. The method is based on the analysis of recurrence in the time series through the quantification of an optimal recurrence threshold ( $${{\varvec{\epsilon}}}_{\mathbf{o}\mathbf{p}\mathbf{t}}$$ ϵ o p t ). New time series for the value of $${{\varvec{\epsilon}}}_{\mathbf{o}\mathbf{p}\mathbf{t}}$$ ϵ o p t were constructed using a rolling window scheme, which allowed for real-time identification of the occurrence of IHHOPs. The results for the optimal recurrence threshold were confronted with standard metrics used in studies of obstructive sleep apnea, namely the oxygen desaturation index (ODI) and oxygen desaturation density (ODD). A high correlation between $${{\varvec{\epsilon}}}_{\mathbf{o}\mathbf{p}\mathbf{t}}$$ ϵ o p t and the ODD was observed. Using the value of the ODI as a surrogate to the apnea–hypopnea index (AHI), it was shown that the value of $${{\varvec{\epsilon}}}_{\mathbf{o}\mathbf{p}\mathbf{t}}$$ ϵ o p t distinguishes occurrences of sleep apnea with great accuracy. When subjected to binary classifiers, this newly proposed metric has great power for predicting the occurrences of sleep apnea-related events, as can be seen by the larger than 0.90 AUC observed in the ROC curve. Therefore, the optimal threshold $${{\varvec{\epsilon}}}_{\mathbf{o}\mathbf{p}\mathbf{t}}$$ ϵ o p t from recurrence analysis can be used as a metric to quantify the occurrence of abnormal behaviors in the arterial oxygen saturation time series.

Oil and gas pipelines are often exposed to the natural hazards, and the action of these natural hazards on the oil and gas pipelines may result in a series of technological hazards such as fire and explosion, which are referred to as the Natural Hazards Triggering Technological Accidents (Natech events), so that the pipelines system shows a higher vulnerability level. Herein, the relationship among risk, resilience and vulnerability was clarified by summarizing and analyzing the definition of vulnerability in different research fields. Besides, the advantages, disadvantages and applicability of various vulnerability assessment methods were reviewed, and the connotation of vulnerability in Natech events was expounded by analyzing the law of successive evolution of vulnerability. In addition, the vulnerability assessment process and crucial elements of oil and gas pipelines in Natech events were discussed from six aspects, including hazard identification, region division, etc. Finally, prospect was made in combination with the current research status for vulnerability assessment under Natech events. The research results can provide theoretical reference for quantitative vulnerability assessment of oil and gas pipelines in Natech events.

Sulodexide is a heparinoid compound with wide-ranging pharmacological activities. However, the effect of sulodexide on liver fibrogenesis has not been reported. In this study, we aim to evaluate the therapeutic potential of sulodexide in mouse model of liver fibrosis and explore the underlying antifibrotic mechanisms. We found that sulodexide treatment significantly attenuated thioacetamide (TAA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver fibrosis in mice. Transcriptome analysis revealed that sulodexide treatment downregulated fibrosis-related genes and liver sinusoidal endothelial cells (LSECs) capillarization-associated genes in fibrotic livers. Immunohistochemistry confirmed that the increased expression of LSEC capillarization-related genes (CD34, CD31 and Laminin) in liver fibrotic tissues was reduced by sulodexide treatment. Scanning electron microscopy showed that LSECs fenestrations were preserved upon sulodexide treatment. Quantitative real-time PCR and immunofluorescence demonstrated that the expression of mesenchymal markers was downregulated by sulodexide administration, suggesting sulodexide inhibited endothelial-mesenchymal transition of LSECs during liver fibrosis. Furthermore, sulodexide administration protected primary LSECs from endothelial dysfunction in vitro. In conclusion, sulodexide attenuated liver fibrosis in mice by restoration of differentiated LSECs, indicating that sulodexide treatment may present as a potential therapy for patients with liver fibrosis.

Indiscriminate drug administration may lead to drug therapy results with varying effects on patients, and the proposal of personalized medication can help patients to receive effective drug therapy. Conventional ways of personalized medication, such as pharmacogenomics and therapeutic drug monitoring (TDM), can only be implemented from a single perspective. The development of pharmacometabolomics provides a research method for the realization of precise drug administration, which integrates the environmental and genetic factors, and applies metabolomics technology to study how to predict different drug therapeutic responses of organisms based on baseline metabolic levels. The published research on pharmacometabolomics has achieved satisfactory results in predicting the pharmacokinetics, pharmacodynamics, and the discovery of biomarkers of drugs. Among them, the pharmacokinetics related to pharmacometabolomics are used to explore individual variability in drug metabolism from the level of metabolism of the drugs in vivo and the level of endogenous metabolite changes. By searching for relevant literature with the keyword “pharmacometabolomics” on the two major literature retrieval websites, PubMed and Web of Science, from 2006 to 2023, we reviewed articles in the field of pharmacometabolomics that incorporated pharmacokinetics into their research. This review explains the therapeutic effects of drugs on the body from the perspective of endogenous metabolites and pharmacokinetic principles, and reports the latest advances in pharmacometabolomics related to pharmacokinetics to provide research ideas and methods for advancing the implementation of personalized medication.

The onset of prostate cancer (PCa) is often hidden, and recurrence and metastasis are more likely to occur due to chemotherapy resistance. Herein, we identified downregulated long noncoding RNA (lncRNA) growth arrest-specific 5 (GAS5) in PCa that was associated with metastasis and paclitaxel resistance. GAS5 acted as a tumor suppressor in suppressing the proliferation and metastasis of paclitaxel-resistant PCa cells. GAS5 overexpression in vivo inhibited the tumor growth of xenografts and elevated PCa sensitivity to paclitaxel. Combination of GAS5 and paclitaxel treatment showed great potential in PCa treatment. Moreover, mechanistic analysis revealed a novel regulatory network of GAS5/miR-18a-5p/serine/threonine kinase 4 (STK4) that inhibits epithelial-to-mesenchymal transition (EMT) and enhances tumor stem cell-like-mediated sensitivity to paclitaxel in PCa. These findings provide a novel direction for the development of a potential adjunct to cancer chemotherapy that aims to improve the sensitivity of chemotherapy drugs in PCa.

Abstract Background Compared with other abiotic stresses, drought stress causes serious crop yield reductions. Poly-γ-glutamic acid (γ-PGA), as an environmentally friendly biomacromolecule, plays an important role in plant growth and regulation. Results In this project, the effect of exogenous application of γ-PGA on drought tolerance of maize (Zea mays. L) and its mechanism were studied. Drought dramatically inhibited the growth and development of maize, but the exogenous application of γ-PGA significantly increased the dry weight of maize, the contents of ABA, soluble sugar, proline, and chlorophyll, and the photosynthetic rate under severe drought stress. RNA-seq data showed that γ-PGA may enhance drought resistance in maize by affecting the expression of ABA biosynthesis, signal transduction, and photosynthesis-related genes and other stress-responsive genes, which was also confirmed by RT–PCR and promoter motif analysis. In addition, diversity and structure analysis of the rhizosphere soil bacterial community demonstrated that γ-PGA enriched plant growth promoting bacteria such as Actinobacteria, Chloroflexi, Firmicutes, Alphaproteobacteria and Deltaproteobacteria. Moreover, γ-PGA significantly improved root development, urease activity and the ABA contents of maize rhizospheric soil under drought stress. This study emphasized the possibility of using γ-PGA to improve crop drought resistance and the soil environment under drought conditions and revealed its preliminary mechanism. Conclusions Exogenous application of poly-γ-glutamic acid could significantly enhance the drought resistance of maize by improving photosynthesis, and root development and affecting the rhizosphere microbial community.

Background: Ultrasonic measurements of the respiratory variability in the diameter of internal jugular vein (IJV-CI) and subclavian vein (SCV-CI) have recently been reported to be useful in predicting fluid responses in non-obstetric patients with spontaneous respiration. This study evaluated whether IJV-CI and SCV-CI could reliably predict fluid responsiveness in parturients undergoing elective cesarean delivery. Objective: This study was conducted to determine whether two indicators measured by ultrasound are good predictors of fluid responsiveness of parturients with spontaneous respiration in elective cesarean delivery. Design: A prospective cohort study. Setting: A single-center tertiary specialty hospital in China. Patients: A total of 86 patients scheduled for elective cesarean section were included and 6 were excluded for various reasons. Interventions: Based on the results of the fluid challenge, the included parturients were divided into two groups, with those who responded to fluid challenge defined as the positive group and those who did not respond defined as the negative group. Main outcome measures: The primary endpoint was to determine the predictive value of IJV-CI and SCV-CI for fluid responsiveness (≥15% increases in SVI after fluid challenge) in spontaneous respiration patients. Results: Forty-three (53.8%) parturients were fluid responders. IJV-CI and SCV-CI proved to be the independent predictors for fluid responsiveness by multivariate logistic regression. The area under the ROC curve for IJV-CI and SCV-CI were 0.881 (95% CI, 0.808–0.953, p < 0.0005) and 0.757 (95% CI, 0.648–0.865, p < 0.0008), respectively. Their optimal cut-off values for IJV-CI and SCV-CI were 20.7% (sensitivity of 60%; specificity of 79%) and 32.0% (sensitivity of 34%; specificity of 96%), respectively. The grey zone for IJV-CI and SCV-CI for fluid responsiveness were 20.4–32.4% and 30.4–44.6% and included 25% and 23% of the patients, respectively. Conclusion: Ultrasonic-derived IJV-CI is better than SCV-CI in predicting fluid responsiveness in spontaneously breathing parturients. Both IJV-CI and SCV-CI are the accurate and readily accessible indices of fluid responsiveness in parturients undergoing elective cesarean delivery. Trial registration: chictr.org.cn (ChiCTR1900028450).

Abstract Background Spontaneous functional recovery occurs during the acute phase after stroke onset, but this intrinsic recovery remains limited. Therefore, exploring the mechanism underlying spontaneous recovery and identifying potential strategies to promote functional rehabilitation after stroke are very important. The CD200/CD200R signaling pathway plays an important role in neurological recovery by modulating synaptic plasticity during multiple brain disorders. However, the effect and mechanism of action of the CD200/CD200R pathway in spontaneous functional recovery after stroke are unclear. Methods In this study, we used a transient middle cerebral artery occlusion (MCAO) model in rats to investigate the function of CD200/CD200R signaling in spontaneous functional recovery after stroke. We performed a battery of behavioral tests (Longa test, adhesive removal test, limb-use asymmetry test, and the modified grip-traction test) to evaluate sensorimotor function after intracerebroventricular (i.c.v.) injection with CD200 fusion protein (CD200Fc) or CD200R blocking antibody (CD200R Ab) post-stroke. Density and morphology of dendritic spines were analyzed by Golgi staining. Microglia activation was evaluated by immunofluorescence staining. Western blot was used to detect the levels of protein and the levels of mRNA were measured by qPCR. Results Our study demonstrated that sensorimotor function, synaptic proteins, and structures were gradually recovered and CD200R was transiently upregulated in ipsilateral cortex after stroke. Synapse-related proteins and dendritic spines were preserved, accompanied by sensorimotor functional recovery, after stereotaxic CD200Fc injection post-stroke. In addition, CD200Fc restrained microglia activation and pro-inflammatory factor release (such as Il-1, Tnf-α, and Il-6) after MCAO. On the contrary, CD200R Ab aggravated sensory function recovery in adhesive removal test and further promoted microglia activation and pro-inflammatory factor release (such as Il-1) after MCAO. The immune-modulatory effect of CD200/CD200R signaling might be exerted partly by its inhibition of the MAPK pathway. Conclusions This study provides evidence that the CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity via inhibition of microglia activation and inflammatory factor release.

This cross-sectional study aimed to assess the knowledge, practice and attitude towards HPV vaccination among college students in Beijing, China. Furthermore, the factors influencing vaccination were analyzed. The data were collected via self-administered anonymous questionnaires completed by 884 college students who were recruited from a random sample at Peking University in China between September and December 2018. In total, 72.6% of the participants had previously heard of but had insufficient knowledge about HPV and the vaccine. The level of knowledge was significantly associated with the participants’ age, major, and family members’ or friends’ vaccination status. In total, 68.8% of the students viewed college education as the primary source from which they hoped to receive information about the vaccine. Only 9.5% of the females had received the vaccine. Relationships with doctors, sexual experience and a high level of knowledge were positive predictors of vaccine uptake. Limited knowledge about the HPV vaccine was the primary and most common reason for refusing vaccination and not recommending the vaccine to others. Knowledge of the HPV vaccine among college students at Peking University was low to moderate, and the vaccine uptake was low. Policies and measures, such as college health education, are needed to increase college students knowledge of HPV and the vaccine, which may help improve the vaccination rate.

Shengxian Decotion (SXT), a well-known Traditional Chinese Medicine (TCM) formula composed of Astragali Radix, Bupleuri Radix, Cimicifugae Rhizoma, Anemarrhenae Rhizoma and Platycodonis Radix, is clinically considered as an effective formula against cardiovascular diseases. However, the exact effective substance of SXT in treating chronic heart failure (CHF) still remains unclear. In the current study, we investigated the benefit of SXT in doxorubicin (DOX)-induced CHF rats and established a UHPLC-MS/MS method to simultaneously determine 18 key compounds in a subsequent comparative pharmacokinetic study in normal and CHF rats. Histopathological studies, transmission electron microscopy, and echocardiography were applied to assess the therapeutic effect of SXT on DOX-induced CHF rats, which indicated that SXT significantly ameliorated DOX-induced CHF, similar to enalapril. In addition, we successfully established a UHPLC-MS/MS method to determine the pharmacokinetics of the components in rat plasma, which was validated with good linearity, inter-day and intra-day precisions and accuracies, matrix effects, extraction recovery, and stability values. Our results showed that only astragaloside IV showed increased plasma exposure in the CHF rats, while saikosaponin A, quercetin, timosaponin B-II, ferulic acid, isoferulic acid and formononetin decreased compared to their pharmacokinetic characteristics in the normal and CHF rats. This study demonstrates that SXT enjoys obvious therapeutic effect on DOX-induced CHF rats, and the altered metabolism of some compounds in SXT is affected by the pathological state of CHF rats. Our findings provide a better understanding of the in vivo exposure to complex compounds of SXT, supporting effective substance screening and further investigation of the therapeutic mechanism.

It is of great clinical significance to develop potential novel strategies to prevent cardio-cerebrovascular complications in patients with hyperlipidemia. Vascular Endothelial integrity and function play a key role in the prevention of cardio-cerebrovascular diseases. Endothelial progenitor cells (EPCs) can home to sites of ischemic injury and promote endothelial regeneration and neovascularization. Hypercholesterolemia impairs the function of EPC. The present study attempted to identify the effect of piperlongumine on EPCs’ angiogenic potential and cerebral ischemic injury in high-fat diet-fed (HFD-fed) mice. Here, we showed that treatment with low-does piperlongumine (0.25 mg/kg/day) for 8 weeks significantly improved EPCs function and reduced the cerebral ischemic injury (both infarct volumes and neurobehavioral outcomes) in HFD-fed mice. In addition, low-dose piperlongumine administration increased intracellular NO level and reduced intracellular O2- level in EPCs of HFD-fed mice. Moreover, incubation with piperlongumine (1.0 μM, 24 h) reduced thrombospondin-1/2 (TSP-1/2, a potent angiogenesis inhibitor) expression levels in EPCs from HFD-fed mice, increased the therapeutic effect of EPC from HFD-fed mice on cerebral ischemic injury reduction and angiogenesis promotion in HFD-fed mice, and the donor derived EPCs homed to the recipient ischemic brain. In conclusion, low-dose piperlongumine can enhance EPCs’ angiogenic potential and protect against cerebral ischemic injury in HFD-fed mice. It is implied that treatment with low-dose piperlongumine might be a potential option to prevent ischemic diseases (including stroke) in patients with hyperlipidemia, and priming with piperlongumine might be a feasible way to improve the efficacy of EPC-based therapy for ischemic diseases.

With the increasingly obvious restriction of the ecological environment on economic development, environmental regulations are widely used to achieve “green production,” that is, to improve green total factor productivity (GTFP). First, through the econometric model, it can be concluded that command-based environmental regulations could improve GTFP, while market-based environmental regulations have no significant impact on GTFP. Unlike traditional econometric models, machine learning has no specific data requirements and research assumptions. We use Lasso regression to verify the above results by obtaining the optimal tuning parameter. Furthermore, considering that the leap of China’s economy is inseparable from foreign direct investment (FDI), we use FDI as a threshold variable. The threshold model results showe that when the intensity of FDI in China ranges between 1.2492 and 1.588, both types of environmental regulations can significantly promote GTFP. These conclusions passed the robustness test. Given the differences in economy and resource endowment among different regions in China, a regional heterogeneity test is conducted. The results show that the current environmental regulations in eastern and central China have no significant impact on GTFP. However, when the intensity of FDI in central China is greater than 3.6868, environmental regulations have a significant promoting effect on GTFP. In western China, when FDI intensity ranges between 1.3950 and 1.5880, market-based environmental regulations can significantly promote GTFP. Further, the path test of the mediation effect model reveals that command-based environmental regulations reduce GTFP by reducing FDI. The above conclusions provide empirical data for the intensity of FDI in different regions of China to improve GTFP.

Hand-foot syndrome (HFS) is a common capecitabine-based chemotherapy-related adverse event (CRAE) in patients with colorectal cancer (CRC). It is of great significance to comprehensively identify susceptible factors for HFS, and further to elucidate the biomolecular mechanism of HFS susceptibility. We performed an untargeted multi-omics analysis integrating DNA methylation, transcriptome, and metabolome data of 63 Chinese CRC patients who had complete CRAE records during capecitabine-based chemotherapy. We found that the metabolome changes for each of matched plasma, urine, and normal colorectal tissue (CRT) in relation to HFS were characterized by chronic tissue damage, which was indicated by reduced nucleotide salvage, elevated spermine level, and increased production of endogenous cytotoxic metabolites. HFS-related transcriptome changes of CRT showed an overall suppressed inflammation profile but increased M2 macrophage polarization. HFS-related DNA methylation of CRT presented gene-specific hypermethylation on genes mainly for collagen formation. The hypermethylation was accumulated in the opensea and shore regions, which elicited a positive effect on gene expression. Additionally, we developed and validated models combining relevant biomarkers showing reasonably good discrimination performance with the area under the receiver operating characteristic curve values from 0.833 to 0.955. Our results demonstrated that the multi-omics variations associated with a profibrotic phenotype were closely related to HFS susceptibility. HFS-related biomolecular variations in CRT contributed more to the relevant biomolecular mechanism of HFS than in plasma and urine. Spermine-related DNA hypermethylation and elevated expression of genes for collagen formation were closely associated with HFS susceptibility. These findings provided new insights into the susceptible factors for chemotherapy-induced HFS, which can promote the implementation of individualized treatment against HFS.

Abstract In this work a coupled (LDG-CFEM) method for singularly perturbed Volterra integro-differential equations with a smooth kernel is implemented. The existence and uniqueness of the coupled solution is given, provided that the source function and the kernel function are sufficiently smooth. Furthermore, the coupled solution achieves the optimal convergence rate p+1 $p+1$ in the L2 $L^{2}$ norm and a superconvergence rate 2p at nodes for the numerical solution UˆN $\hat{U}_{N}$ with the one-sided flux inside the boundary layer region under layer-adapted meshes uniformly with respect to the singular perturbation parameter ϵ.

ObjectiveCurrent treatment options for patients with stage 5 chronic kidney disease before dialysis (predialysis CKD-5) are determined by individual circumstances, economic factors, and the doctor’s advice. This study aimed to explore the plasma metabolic traits of patients with predialysis CKD-5 compared with maintenance hemodialysis (HD) and peritoneal dialysis (PD) patients, to learn more about the impact of the dialysis process on the blood environment.MethodsOur study enrolled 31 predialysis CKD-5 patients, 31 HD patients, and 30 PD patients. Metabolite profiling was performed using a targeted metabolomics platform by applying an ultra-high-performance liquid chromatography-tandem mass spectrometry method, and the subsequent comparisons among all three groups were made to explore metabolic alterations.ResultsCysteine metabolism was significantly altered between predialysis CKD-5 patients and both groups of dialysis patients. A disturbance in purine metabolism was the most extensively changed pathway identified between the HD and PD groups. A total of 20 discriminating metabolites with large fluctuations in plasma concentrations were screened from the group comparisons, including 2-keto-D-gluconic acid, kynurenic acid, s-adenosylhomocysteine, L-glutamine, adenosine, and nicotinamide.ConclusionOur study provided a comprehensive metabolomics evaluation among predialysis CKD-5, HD, and PD patients, which described the disturbance of metabolic pathways, discriminating metabolites and their possible biological significances. The identification of specific metabolites related to dialysis therapy might provide insights for the management of advanced CKD stages and inform shared decision-making.

Scrub typhus is a zoonotic disease caused by Orientia tsutsugamushi (O. tsutsugamushi). Orientia tsutsugamushi has various genotypes and more new strains with difference in sequences increasingly appeared. Whether the accurateness of one special nested PCR method which amplifies segment instead of entire open reading frame (ORF) sequence meets the current work of identifying new strains and classifying genotypes remains to be confirmed. And the origins and evolution of this organism have not been thoroughly elucidated. Accordingly, in this study, segments and the entire ORF of the 56-kDa type-specific antigen (TSA56) gene of O. tsutsugamushi were collected, including 209 clinically isolated strains in Guangzhou, China from 2012 to 2016 and 139 reference strains worldwide. By performing phylogenetic analysis, we proved that the accurateness of the particular PCR method which almost met detection need. This re-grouping result showed that segments perfectly represented and identified strains of Karp, Boryong, Gilliam, TA763, Kawasaki and part of Kato genotype, and this accuracy is not restricted by region and time. Sequence diversification of Shimokoshi and some Kato strains made their genotyping need to consider entire ORF sequences, but their weak recognition might not be due to recombination. The frequent genetic recombination and high point mutations contributed to genetic diversification of the TSA56 gene. Major overlapping regions of most recombination events occurred between strains of the same genotype, especially Karp and Kato genotype. And cross-genotype overlapping events occurred between Karp and Boryong/Gilliam/TA763/Kato, Kato and Kawasaki/Gilliam/TA686, Boryong and TA686, and Gilliam and Kawasaki. But Segment has quite low recombination frequency and stable mutation trend from 1943 to 2016. So segment is a relatively conserved part of the TSA56 ORF as for its stable trend of genetic diversity, and it may anchor and represent the entire TSA56 ORF gene. And genetic diversity is rejected as one potential reason for the increased incidence of scrub typhus. But an occasional recombination event created an unrecognized genotype which might be due to the breakage of VD II and AD II. Additionally, strains in Guangzhou were homologous and Karp genotype was detected as a dominant.

Abstract Background Alzheimer’s disease is characterized by progressive accumulation of β-amyloid (Aβ)-containing amyloid plaques, and microglia play a critical role in internalization and degradation of Aβ. Our previous research confirmed that Nogo-66 binding to Nogo receptors (NgR) expressed on microglia inhibits cell adhesion and migration in vitro. Methods The adhesion and migration of microglia isolated from WT and APP/PS1 mice from different ages were measured by adhesion assays and transwells. After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in APP/PS1 transgenic mice, microglial recruitment toward Aβ deposits and CD36 expression were determined. Results In this paper, we found that aging led to a reduction of microglia adhesion and migration to fAβ1–42 in WT and APP/PS1 mice. The adhesion and migration of microglia to fAβ1–42 were downregulated by the Nogo, which was mediated by NgR, and the increased inhibitory effects of the Nogo could be observed in aged mice. Moreover, Rho GTPases contributed to the effects of the Nogo on adhesion and migration of microglia to fAβ1–42 by regulating cytoskeleton arrangement. Furthermore, blocking the Nogo/NgR pathway enhanced recruitment of microglia toward Aβ deposits and expression of CD36 in APP/PS1 mice. Conclusion Taken together, Nogo/NgR pathway could take part in Aβ pathology in AD by modulating microglial adhesion and migration to Aβ and the Nogo/NgR pathway might be an important target for treating AD.

Background/Aims: Chronic cold exposure may increase energy expenditure and contribute to counteracting obesity, an important risk factor for cerebrocardiovascular diseases. This study sought to evaluate whether preventive cold acclimation before ischemia onset might be a promising option for preventing cerebral ischemic injury. Methods: After a 14-day cold acclimation period, young and aged mice were subjected to permanent cerebral ischemia, and histological analyses and behavioral tests were performed. Mouse endothelial progenitor cells (EPCs) were isolated, their function and number were determined, and the effects of EPC transplantation on cerebral ischemic injury were investigated. Results: Preventive cold acclimation before ischemia onset increased EPC function, promoted ischemic brain angiogenesis, protected against cerebral ischemic injury, and improved long-term stroke outcomes in young mice. In addition, transplanted EPCs from cold-exposed mice had a greater ability to reduce cerebral ischemic injury and promote local angiogenesis compared to those from control mice, and EPCs from donor animals could integrate into the recipient ischemic murine brain. Furthermore, transplanted EPCs might exert paracrine effects on cerebral ischemic injury, which could be improved by preventive cold acclimation. Moreover, preventive cold acclimation could also enhance EPC function, promote local angiogenesis, and protect against cerebral ischemic injury in aged mice. Conclusions: Preventive cold acclimation before ischemia onset improved long-term stroke outcomes in mice at least in part via promoting the reparative function of EPC. Our findings imply that a variable indoor environment with frequent cold exposure might benefit individuals at high risk for stroke.

Subtherapeutic antibiotics have been widely used in agriculture since the 1950s, which can be accumulated in human body through various approaches and may have long-term consequences. However, there is limited information about the link between chronic subtherapeutic antibiotic exposure and the outcome of ischemic brain injury. Here we showed that long-term treatment with subtherapeutic chlortetracycline, penicillin or vancomycin, which were widely used in agriculture approved by US Food and Drug Administration (FDA), could impair EPC functions, reduce ischemic brain angiogenesis and aggravate cerebral ischemic injury and long-term stroke outcomes in mice. In addition, transplantated EPCs from chronic antibiotic-treated mice showed a lower therapeutic effect on cerebral ischemic injury reduction and local angiogenesis promotion compared to those from control mice, and EPCs from the donor animals could integrate into the recipient ischemic brain in mice. Furthermore, transplanted EPCs might exert paracrine effects on cerebral ischemic injury reduction in mice, which could be impaired by chronic antibiotic exposure. In conclusion, chronic subtherapeutic antibiotic exposure aggravated cerebral ischemic injury in mice, which might be partly attributed to the impairment of both EPC-mediated angiogenesis and EPCs' paracrine effects. These findings reveal a previously unrecognized impact of chronic subtherapeutic antibiotic exposure on ischemic injury.

Removal of protein-bound uremic toxins (PBUTs) during conventional dialysis is insufficient. PBUTs are associated with comorbidities and mortality in dialysis patients. Albumin is the primary carrier for PBUTs and only a small free fraction of PBUTs are dialyzable. In the past, we proposed a novel method where a binding competitor is infused upstream of a dialyzer into an extracorporeal circuit. The competitor competes with PBUTs for their binding sites on albumin and increases the free PBUT fraction. Essentially, binding competitor-augmented hemodialysis is a reactive membrane separation technique and is a paradigm shift from conventional dialysis therapies. The proposed method has been tested in silico, ex vivo, and in vivo, and has proven to be very effective in all scenarios. In an ex vivo study and a proof-of-concept clinical study with 18 patients, ibuprofen was used as a binding competitor; however, chronic ibuprofen infusion may affect residual kidney function. Binding competition with free fatty acids significantly improved PBUT removal in pre-clinical rat models. Based on in silico analysis, tryptophan can also be used as a binding competitor; importantly, fatty acids or tryptophan may have salutary effects in HD patients. More chemoinformatics research, pre-clinical, and clinical studies are required to identify ideal binding competitors before routine clinical use.

Background/Aims: By inducing severe endothelial impairment, hypertension and diabetes are two leading causes of morbidity and mortality. Hypertensive patients with concomitant diabetes must take both antihypertensive and hypoglycaemic medications, for which there is a lack of experimental and clinical guidelines. This study aimed to examine the interaction between these two types of medication on the endothelial cell function. Methods: The effect of antihypertensive (nifedipine and irbesartan) and anti-diabetic (metformin and glibenclamide/glimepiride) drugs on human umbilical vein cells (HUVECs) function was examined using a modified Boyden chamber assay. The intracellular NO and O2- levels of HUVECs were detected through flow cytometry. Results: Our findings showed that nifedipine/sulphonylurea monotherapy significantly attenuated high glucose-induced (33 mM) HUVECs migration incapacity, while combination therapy of nifedipine and glibenclamide/glimepiride showed no protective effect. Both nifedipine/metformin monotherapy and combined therapy significantly mitigated the migration incapacity induced by high glucose in HUVECs. Combined with either metformin or sulphonylureas, irbesartan therapy was able to attenuate the high glucose-induced migration incapacity of HUVECs. Nifedipine monotherapy decreased the O2- levels and increased the NO levels in in vitro-cultured HUVECs treated with high glucose. However, the combination therapy of nifedipine and glibenclamide increased the O2- levels and decreased the NO levels compared to the nifedipine monotherapeutic group. Conclusion: The nifedipine and glibenclamide/glimepiride combination exerted a mutual antagonistic effect on the protection from high glucose-induced impairment in endothelial cells, which might be partially attributed to the increased O2- level and decreased NO level. These results imply that calcium channel blockers + sulphonylurea combination therapy warrants further attention in patients suffering from both hypertension and diabetes.

Our previous study demonstrated that tentacle extract (TE) from the jellyfish Cyanea capillata (C. capillata) could cause a weak relaxation response mediated by nitric oxide (NO) using isolated aorta rings. However, the intracellular mechanisms of TE-induced vasodilation remain unclear. Thus, this study was conducted to examine the role of TE on Akt/eNOS/NO and Ca2+ signaling pathways in human umbilical vein endothelial cells (HUVECs). Our results showed that TE induced dose- and time-dependent increases of eNOS activity and NO production. And TE also induced Akt and eNOS phosphorylation in HUVECs. However, treatment with specific PI3-kinase inhibitor (Wortmannin) significantly inhibited the increases in NO production and Akt/eNOS phosphorylation. In addition, TE also stimulated an increase in the intracellular Ca2+ concentration ([Ca2+]i), which was significantly attenuated by either IP3 receptor blocker (Heparin) or PKC inhibitor (PKC 412). In contrast, extracellular Ca2+-free, L-type calcium channel blocker (Nifedipine), or PKA inhibitor (H89) had no influence on the [Ca2+]i elevation. Since calcium ions also play a critical role in stimulating eNOS activity, we next explored the role of Ca2+ in TE-induced Akt/eNOS activation. In consistent with the attenuation of [Ca2+]i elevation, we found that Akt/eNOS phosphorylation was also dramatically decreased by Heparin or PKC 412, but not affected by Nifedipine or H89. However, the phosphorylation level could also be decreased by the removal of extracellular calcium. Taken together, our findings indicated that TE-induced eNOS phosphorylation and activation were mainly through PI3K/Akt-dependent, PKC/IP3R-sensitive and Ca2+-dependent pathways.

OBJECTIVES:We aimed to evaluate the relationships between climate variability, animal reservoirs and scrub typhus incidence in Southern China. METHODS:We obtained data on scrub typhus cases in Guangzhou every month from 2006 to 2014 from the Chinese communicable disease network. Time-series Poisson regression models and distributed lag nonlinear models (DLNM) were used to evaluate the relationship between risk factors and scrub typhus. RESULTS:Wavelet analysis found the incidence of scrub typhus cycled with a period of approximately 8-12 months and long-term trends with a period of approximately 24-36 months. The DLNM model shows that relative humidity, rainfall, DTR, MEI and rodent density were associated with the incidence of scrub typhus. CONCLUSIONS:Our findings suggest that the incidence scrub typhus has two main temporal cycles. Determining the reason for this trend and how it can be used for disease control and prevention requires additional research. The transmission of scrub typhus is highly dependent on climate factors and rodent density, both of which should be considered in prevention and control strategies for scrub typhus.

Pulsed waterjets are widely used in exploitation of fossil fuels for their high efficiency. With the aim to further clarify the impact performance of Helmholtz self-excited oscillation waterjets (HSEOW), numerical and experimental studies were conducted. The morphological characteristics of the erosion surfaces between conical and HSEOW nozzles were compared and the cavitation evolution was obtained. Results show that the cavitation damage caused by the HSEOW nozzle on the specimen was mainly caused by the jet cavitation cloud under submerged conditions. The cavitation effect produced by the HSEOW nozzle had a much greater destructive effect than that of a conical nozzle. The mass loss caused by HSEOW nozzles increased first with the increase of standoff distance, then decreased rapidly after reaching the maximum value. Moreover, the density of holes and the damage intensity weakened with the increase of radial distance. A dimensionless cavity length of 2 and a dimensionless cavity diameter of 8 was the optimal structure that led to maximum mass loss. These results provide a further understanding of cavitation mechanism which leads to the impact performance of pulsed water jets and optimal working parameters in the field of energy exploitation.

The peptides derived from envelope proteins have been shown to inhibit the protein-protein interactions in the virus membrane fusion process and thus have a great potential to be developed into effective antiviral therapies. There are three types of envelope proteins each exhibiting distinct structure folds. Although the exact fusion mechanism remains elusive, it was suggested that the three classes of viral fusion proteins share a similar mechanism of membrane fusion. The common mechanism of action makes it possible to correlate the properties of self-derived peptide inhibitors with their activities. Here we developed a support vector machine model using sequence-based statistical scores of self-derived peptide inhibitors as input features to correlate with their activities. The model displayed 92% prediction accuracy with the Matthew's correlation coefficient of 0.84, obviously superior to those using physicochemical properties and amino acid decomposition as input. The predictive support vector machine model for self- derived peptides of envelope proteins would be useful in development of antiviral peptide inhibitors targeting the virus fusion process.