The Combination of Gastrodin and Gallic Acid Synergistically Attenuates AngII-Induced Apoptosis and Inflammation via Regulation of Sphingolipid Metabolism.

Background: Hypertension (HTN) is closely related to endothelial damage. While tianma (TM) and gouqizi (GQZ) have the potential to be effective in the treatment of HTN in traditional Chinese medicine, their main active ingredients and whether its exert synergistic effects and the underlying mechanisms of synergistic effects are still unclear. Objective: This study screened the active ingredients of TM and GQZ, investigated the synergistic effects of the active ingredients and explored possible mechanisms. Methods: The potential targets and mechanisms of TM and GQZ were screened using network pharmacology, and gastrodin (GAS) and gallic acid (GA) were identified as compounds with significant antihypertensive activity. The synergistic effects of the combination of GAS and GA was assessed by measuring biomarkers of AngII-induced human umbilical vein endothelial cell (HUVECs) dysfunction model. Furthermore, the anti-apoptotic and anti-inflammatory effects were evaluated by measuring inflammatory cytokine secretion, and apoptosis-related markers. Finally, key targets of the sphingolipid signaling pathway were experimentally validated by Western blotting. Results: In network pharmacology, the herb-pair exerted a synergetic effect by regulating sphingolipid pathways. The GAS and GA exerted synergistic protective effects in AngII-induced HUVECs injury by improving Nitric Oxide Content (NO) levels, alleviating lactate Endothelin-1 (ET-1), and Thromboxane B2 (TX-B2) release, reducing the secretion of inflammatory factors like interleukin-6 (IL-6), interleukin-1ß (IL-1ß), Tumor Necrosis Factor Alpha (TNF-α)), decreasing the pro-apoptotic protein BAX, and increasing the anti-apoptotic protein BCL-2. Furthermore, the results showed that the GAS and GA combination could elevate the level of S1PR1 and inhibit the expression of ROCK2 and the phosphorylation of NF-κB, which are key targets involved in sphingolipid pathways. Conclusion: Our study revealed that the combination of GAS and GA could suppress inflammation and apoptosis, which are highly correlated with sphingolipid signaling pathways, making it a potential candidate for the treatment of HTN.

NR1H4 ameliorates Parkinson's disease via inhibiting astrocyte activation and neuroinflammation in a CEBPß/NF-κB dependent manner.

Parkinson's Disease (PD) is a degenerative disease driven by neuroinflammation. Nuclear receptor subfamily 1 group H member 4 (NR1H4), a nuclear receptor involved in metabolic and inflammatory regulation, is found to be widely expressed in central nervous system. Previous studies suggested the protective role of NR1H4 in various diseases related to inflammation, whether NR1H4 participates in PD progression remains unknown. To investigate the role of NR1H4 in neuroinflammation regulation, especially astrocyte activation during PD, siRNA and adenovirus were used to manipulate Nr1h4 expression. RNA-sequencing (RNA-seq), quantitative real-time PCR, enzyme-linked immunosorbent assay, Chromatin immunoprecipitation and western blotting were performed to further study the underlying mechanisms. We identified that NR1H4 was down-regulated during PD progression. In vitro experiments suggested that Nr1h4 knockdown led to inflammatory response, reactive oxygen species generation and astrocytes activation whereasNr1h4 overexpressionhad the opposite effects. The results of RNA-seq on astrocytes revealed that NR1H4 manipulated neuroinflammation in a CEBPß/NF-κB dependent manner. Additionally, pharmacological activation of NR1H4 via Obeticholic acid ameliorated neuroinflammation and promoted neuronal survival. Our study first proved the neuroprotective effects of NR1H4against PD via inhibiting astrocyte activation and neuroinflammation in a CEBPß/NF-κB dependent manner.

Insomnia in Parkinson's Disease: Causes, Consequences, and Therapeutic Approaches.

Sleep disorders represent prevalent non-motor symptoms in Parkinson's disease (PD), affecting over 90% of the PD population. Insomnia, characterized by difficulties in initiating and maintaining sleep, emerges as the most frequently reported sleep disorder in PD, with prevalence rates reported from 27 to 80% across studies. Insomnia not only significantly impacts the quality of life of PD patients but is also associated with cognitive impairment, motor disabilities, and emotional deterioration. This comprehensive review aims to delve into the mechanisms underlying insomnia in PD, including neurodegenerative changes, basal ganglia beta oscillations, and circadian rhythms, to gain insights into the neural pathways involved. Additionally, the review explores the risk factors and comorbidities associated with insomnia in PD, providing valuable insights into its management. Special attention is given to the challenges faced by healthcare providers in delivering care to PD patients and the impact of caregiving roles on patients' quality of life. Overall, this review provides a comprehensive understanding of insomnia in PD and highlights the importance of addressing this common sleep disorder in PD patients.

Medical education challenges in Mainland China: An analysis of the application of problem-based learning.

BACKGROUND: The medical education system in mainland China faces numerous challenges and the lack of learner-centered approaches may contribute to passive learning and reduced student engagement. While problem-based learning (PBL) is common in Western medical schools, its feasibility in China is questioned due to cultural differences. This systematic review aims to summarize the application of PBL in medical education in mainland China based on existing literature, as well as to identify the challenges and opportunities encountered in its implementation. METHODS: A systematic literature review was conducted using electronic databases, including MEDLINE, Cochrane Library, EMBASE, Web of Science, Wan fang and CNKI databases. Grey literature sources were explored using Google Scholar. The search was limited to articles that include at least one English abstract up to May 1st, 2023. The inclusion criteria were studies that reported the use of PBL in medical education in mainland China. RESULTS: A total of 21 articles were included in the final analysis. The findings indicate that PBL is a well-adopted and effective learning method in most medical education, especially for developing critical thinking, problem-solving, and teamwork skills. However, the application of PBL in mainland China is limited due to various challenges, including faculty resistance, inadequate resources and cultural barriers. To effectively address these challenges, it is essential to provide faculty training, develop appropriate assessment methods to evaluate student progress within the PBL framework and create conducive spaces and resources that support collaborative learning and critical thinking. CONCLUSION: The utilization of PBL in mainland China holds potential for enhancing medical education. However, its successful implementation requires significant efforts to address the identified challenges. It is crucial to engage stakeholders in a collaborative effort to promote the application of PBL and ultimately improve the quality of medical education in mainland China.

Investigation on the effects of an elliptical wall on the dynamic behaviors of a bubble restricted by two parallel plates.

The present paper investigates the dynamic behaviors of a bubble restricted by two parallel plates near an elliptical wall. The typical experimental phenomena of the bubble are recorded employing the high-speed photography and a theoretical Kelvin impulse model is established. The impacts of the spatial position and the curvature of the wall on the bubble collapse behaviors are quantitatively investigated through the theoretical model and verified against the experimental results. The Kelvin impulse intensity and the direction during the bubble collapse process are compared and discussed for different elliptical-shaped walls. The main conclusions include: (1) During the bubble collapse process, the phenomenon of the bubble uneven splitting is discovered. (2) At different spatial positions and wall curvatures, the bubble collapse jet angle, movement distance, and velocity are in good agreement with the theoretical Kelvin impulse predictions. (3) As the short-to-long axis ratio increases, the differences in the distributions of the Kelvin impulse intensity and the direction near the elliptical wall gradually become larger, and the range of the influence of the impulse intensity expands.

Lactiplantibacillus plantarum ATCC8014 Alleviates Postmenopausal Hypercholesterolemia in Mice by Remodeling Intestinal Microbiota to Increase Secondary Bile Acid Excretion.

Hypercholesterolemia poses a significant cardiovascular risk, particularly in postmenopausal women. The anti-hypercholesterolemic properties of Lactiplantibacillus plantarum ATCC8014 (LP) are well recognized; however, its improving symptoms on postmenopausal hypercholesterolemia and the possible mechanisms have yet to be elucidated. Here, we utilized female ApoE-deficient (ApoE-/-) mice undergoing bilateral ovariectomy, fed a high-fat diet, and administered 109 colony-forming units (CFU) of LP for 13 consecutive weeks. LP intervention reduces total cholesterol (TC) and triglyceride (TG) accumulation in the serum and liver and accelerates their fecal excretion, which is mainly accomplished by increasing the excretion of fecal secondary bile acids (BAs), thereby facilitating cholesterol conversion. Correlation analysis revealed that lithocholic acid (LCA) is an important regulator of postmenopausal lipid abnormalities. LP can reduce LCA accumulation in the liver and serum while enhancing its fecal excretion, accomplished by elevating the relative abundances of Allobaculum and Olsenella in the ileum. Our findings demonstrate that postmenopausal lipid dysfunction is accompanied by abnormalities in BA metabolism and dysbiosis of the intestinal microbiota. LP holds therapeutic potential for postmenopausal hypercholesterolemia. Its effectiveness in ameliorating lipid dysregulation is primarily achieved through reshaping the diversity and abundance of the intestinal microbiota to correct BA abnormalities.

A Nomogram for Predicting the Risk of Deep Vein Thrombosis in Patients With Acute Ischemic Stroke During the COVID-19.

Deep vein thrombosis (DVT) is an important complication of stroke. As coronavirus disease 2019 (COVID-19) enters the stage of persistent and long-term management, the clinical management of DVT in stroke patients may require adjustment. The present study evaluated whether there was an increased risk of DVT in stroke patients during the COVID-19 period. Furthermore, we analyzed the possible risk factors and developed an easy-to-use nomogram to predict DVT in stroke patients during the long-term management of COVID-19. A total of 7087 stroke patients during the COVID-19 period and 14,174 patients with age, sex, and National Institutes of Health Stroke Scale (NIHSS) scores matched before the period from four centers were included. The incidence of DVT in stroke patients during the COVID-19 period (20.5%) was significantly higher than that before this period (15.9%, P < .001). Age, body mass index, smoking, D-dimer, physical activity level, NIHSS score, and intermittent pneumatic compression were significant predictors of DVT during the COVID-19 period (P < .05). A nomogram was constructed; internal and external validations showed high accuracy, and decision curve analysis showed excellent clinical applicability. This nomogram could evaluate the risk of DVT after stroke and assist in its early prevention during the long-term management of COVID-19.

Can Natural Speech Prosody Distinguish Autism Spectrum Disorders? A Meta-Analysis.

Natural speech plays a pivotal role in communication and interactions between human beings. The prosody of natural speech, due to its high ecological validity and sensitivity, has been acoustically analyzed and more recently utilized in machine learning to identify individuals with autism spectrum disorders (ASDs). In this meta-analysis, we evaluated the findings of empirical studies on acoustic analysis and machine learning techniques to provide statistically supporting evidence for adopting natural speech prosody for ASD detection. Using a random-effects model, the results observed moderate-to-large pooled effect sizes for pitch-related parameters in distinguishing individuals with ASD from their typically developing (TD) counterparts. Specifically, the standardized mean difference (SMD) values for pitch mean, pitch range, pitch standard deviation, and pitch variability were 0.3528, 0.6744, 0.5735, and 0.5137, respectively. However, the differences between the two groups in temporal features could be unreliable, as the SMD values for duration and speech rate were only 0.0738 and -0.0547. Moderator analysis indicated task types were unlikely to influence the final results, whereas age groups showed a moderating role in pooling pitch range differences. Furthermore, promising accuracy rates on ASD identification were shown in our analysis of multivariate machine learning studies, indicating averaged sensitivity and specificity of 75.51% and 80.31%, respectively. In conclusion, these findings shed light on the efficacy of natural prosody in identifying ASD and offer insights for future investigations in this line of research.

Warm Temperature Increments Strengthen the Crosstalk between Roots and Soil in the Rhizosphere of Soybean Seedlings.

The plant rhizosphere underlies the crosstalk between plant and soil and has a crucial role in plant growth and development under various environments. We examined the effect of temperature rise on the rhizosphere environment of soybean roots to clarify the rhizosphere crosstalk between roots and soil in response to warm temperature rises in a global warming background. The in situ results of root enzyme activity revealed that soybean roots secrete ß-glucosidase, and enzyme spectrum imaging demonstrated different enzymatic activities under different temperature environments. The soil enzyme kinetics results showed that soil enzymatic activity increased with increasing temperature, and soybean rhizosphere soil enzymatic activity was higher than that of non-rhizosphere soil. Rhizosphere soil and non-rhizosphere soil showed that the dominant bacterial phylum in soybean rhizosphere soil was Acidobacteria, and the dominant bacterial genus was JG30-KF-AS9. Compared with non-rhizosphere soil, rhizosphere soil was more nutrient-rich, and root secretions provided abundant carbon sources and other nutrients for soil microorganisms in the rhizosphere. Rhizosphere microorganisms affect plant growth by influencing the decomposition of soil organic carbon. The organic carbon content of rhizosphere soil was higher than that of non-rhizosphere soil under high temperatures.

Attenuation of estrogen and its receptors in the post-menopausal stage exacerbates dyslipidemia and leads to cognitive impairment.

Cognitive dysfunction increases as menopause progresses. We previously found that estrogen receptors (ERs) contribute to dyslipidemia, but the specific relationship between ERs, dyslipidemia and cognitive dysfunction remains poorly understood. In the present study, we analyzed sequencing data from female hippocampus and normal breast aspirate samples from normal and Alzheimer's disease (AD) women, and the results suggest that abnormal ERs signaling is associated with dyslipidemia and cognitive dysfunction. We replicated a mouse model of dyslipidemia and postmenopausal status in LDLR-/- mice and treated them with ß-estradiol or simvastatin, and found that ovariectomy in LDLR-/- mice led to an exacerbation of dyslipidemia and increased hippocampal apoptosis and cognitive impairment, which were associated with reduced estradiol levels and ERα, ERß and GPER expression. In vitro, a lipid overload model of SH-SY-5Y cells was established and treated with inhibitors of ERs. ß-estradiol or simvastatin effectively attenuated dyslipidemia-induced neuronal apoptosis via upregulation of ERs, whereas ERα, ERß and GPER inhibitors together abolished the protective effect of simvastatin on lipid-induced neuronal apoptosis. We conclude that decreased estrogen and its receptor function in the postmenopausal stage promote neuronal damage and cognitive impairment by exacerbating dyslipidemia, and that estrogen supplementation or lipid lowering is an effective way to ameliorate hippocampal damage and cognitive dysfunction via upregulation of ERs.

The causal relationship between COVID-19 and seventeen common digestive diseases: a two-sample, multivariable Mendelian randomization study.

OBJECTIVES: In clinical practice, digestive symptoms such as nausea, vomiting are frequently observed in COVID-19 patients. However, the causal relationship between COVID-19 and digestive diseases remains unclear. METHODS: We extracted single nucleotide polymorphisms associated with the severity of COVID-19 from summary data of genome-wide association studies. Summary statistics of common digestive diseases were primarily obtained from the UK Biobank study and the FinnGen study. Two-sample Mendelian randomization analyses were then conducted using the inverse variance-weighted (IVW), Mendelian randomization-Egger regression (MR Egger), weighted median estimation, weighted mode, and simple mode methods. IVW served as the primary analysis method, and Multivariable Mendelian randomization analysis was employed to explore the mediating effect of body mass index (BMI) and type 2 diabetes. RESULTS: MR analysis showed that a causal association between SARS-CoV-2 infection (OR = 1.09, 95% CI 1.01-1.18, P = 0.03), severe COVID-19 (OR = 1.02, 95% CI 1.00-1.04, P = 0.02), and COVID-19 hospitalization (OR = 1.04, 95% CI 1.01-1.06, P = 0.01) with gastroesophageal reflux disease (GERD). Mediation analysis indicated that body mass index (BMI) served as the primary mediating variable in the causal relationship between SARS-CoV-2 infection and GERD, with BMI mediating 36% (95% CI 20-53%) of the effect. CONCLUSIONS: We found a causal relationship between SARS-CoV-2 infection and gastroesophageal reflux disease. Furthermore, we found that the causal relationship between SARS-CoV-2 infection and GERD is mainly mediated by BMI.

Direct Simulation Monte Carlo Simulation of the Effect of Needle Valve Structures on the Rarefied Flow of Cold Gas Thrusters.

The needle valve, serving as the flow control unit of the thruster system, is a crucial component of the entire thruster. Its performance directly impacts the flow state of the rarefied gas in the micro-nozzle structure of the cold gas micro-thruster, thereby exerting a significant influence on the high precision and stability of the propulsion system as a whole. This study examines the impact of different needle valve structures on the flow and thrust in micro-nozzles using the DSMC method. The analysis includes discussions on the spatial distribution, Kn distribution, slip velocity distribution, and pressure distribution of the micro-nozzle's flow mechanism. Notably, increased curvature of the needle valve enhances the flow velocity in the throat and expansion section. The magnitude of the curvature directly affects the flow velocity, with larger curvatures resulting in higher velocities. Comparing different spool shapes, the conical spool shape minimizes the velocity gradient in the high-speed region at the junction between the spool area and the outlet pipe, particularly with a wide opening. Increasing the curvature of the spool leads to a higher velocity in the expansion section. Consequently, an arc-shaped spool valve maximizes the nitrogen flow at the nozzle during wide openings, thereby enhancing thrust. These research findings serve as a valuable reference for the structural design of the needle valve in the micro-nozzle of the cold gas micro-thruster.

High-throughput and specific detection of microorganisms by intelligent modular fluorescent photoelectric microbe detector.

Food safety has emerged as a major global issue. Detecting foodborne pathogenic microorganisms and controlling them is vital to guard against foodborne diseases caused by microorganisms. However, the current detection methods need to meet the demand for real-time detection on the spot after a simple operation. Considering unresolved challenges, we developed an Intelligent Modular Fluorescent Photoelectric Microbe (IMFP) system containing a special detection reagent. This IMFP system can automatically monitor microbial growth in which the photoelectric detection, temperature control, fluorescent probe, and bioinformatics screen are integrated into one platform and employed to detect pathogenic microorganisms. Moreover, a specific culture medium was also developed, which matched the system platform for Coliform bacteria and Salmonella typhi. The developed IMFP system could attain a limit of detection (LOD) of about 1 CFU/mL for both bacteria, while the selectivity could reach 99%. In addition, the IMFP system was applied to detect 256 bacterial samples simultaneously. This platform reflects the high-throughput needs of fields for microbial identification and related requirements, such as the development of pathogenic microbial diagnostic reagents, antibacterial sterilization performance tests, and microbial growth kinetics. The IMFP system also confirmed the other merits, such as high sensitivity, high-throughput, and operation simplicity compared to conventional methods, and it has a high potential as a tool for application in the health and food security fields.

Activation of estrogen receptor α inhibits TLR4 signaling in macrophages and alleviates the instability of atherosclerotic plaques in the postmenopausal stage.

Acute cardiovascular events increase significantly in postmenopausal women. The relationship between estrogen receptor (ER) and plaque stability in the postmenopausal stage remains to be elucidated. We aimed to explore whether ERα activation improves plaque instability in the postmenopausal stage. Here, we report that postmenopausal women showed increased macrophage activation and plaque instability with increased MCP-1, MMP9, TLR4, MYD88 and NF-κB p65 and decreased ERα and TIMP1 expression in the vascular endothelium. Moreover, ovariectomy in LDLR-/- mice resulted in a significant increase in plaque area and necrotic core area, as well as a significant decrease in collagen content and an increase in macrophage accumulation in the artery. Ovariectomy also reduced serum estrogen levels and ERα expression and upregulated TLR4 and MMP9 expression in arteries in LDLR-/- mice. Estrogen or phytoestrogen therapy upregulated the expression level of ERα in ovariectomized mice and increased plaque stability by inhibiting macrophage accumulation and TLR4 signaling. In vitro, LPS incubation of RAW264.7 cells resulted in a significant decrease in ERα and TIMP1 expression and an increase in TLR4 activation, and estrogen or phytoestrogen treatment increased ERα and TIMP1 expression and inhibited TLR4 activation and MMP9 expression in LPS-treated RAW264.7 cells. Compared to control siRNA transfected RAW264.7 cells, TLR4 siRNA promoted TIMP1 expression in RAW264.7 cells with LPS incubation, but did not affect ERα expression in RAW264.7 cells with or without LPS treatment. The ERα inhibitor MPP abolished the regulatory effect of estrogen or phytoestrogen on LPS-induced RAW264.7 cells. In conclusion, the present study demonstrates that decreased ERα expression promotes macrophage infiltration and plaque instability in the postmenopausal stage, and activation of ERα in the postmenopausal stage alleviates atherosclerotic plaque instability by inhibiting TLR4 signaling and macrophage-related inflammation.

Effects of the Wall Temperature on Rarefied Gas Flows and Heat Transfer in a Micro-Nozzle.

When the satellite is in orbit, the thruster will experience drastic temperature changes (100-1000 K) under solar radiation, which will affect the rarefied gas flow state in the micro-nozzle structure of the cold gas micro-thruster. In this study, the effect of different wall temperatures on the rarefied flow and heat transfer in the micro-nozzle is investigated based on the DSMC method. The micro-nozzle structure in this paper has a micro-channel with a large length-to-diameter ratio of 10 and a micro-scale needle valve displacement (maximum needle valve displacement up to 4 µm). This leads to more pronounced multiscale flow characteristics in the micro-nozzle, which is more influenced by the change in wall temperature. At wall temperatures ranging from 100 K to 1000 K, the spatial distribution of local Kn distribution, slip velocity distribution, temperature, and wall heat flux distribution in the micro-nozzle were calculated. The slip flow region is located in the flow channel and transforms into transition flow as the slip velocity reaches approximately 50 m/s. The spatial distribution of the flow pattern is dominated by the wall temperature at small needle valve opening ratios. The higher the wall temperature, the smaller the temperature drop ratio in the low-temperature region inside the micro-nozzle. The results of the study provide a reference for the design of temperature control of micro-nozzles in cold gas micro-thrusters.

Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability.

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6-26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0-∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection.

Study on the interaction between different pathogens of Hand, foot and mouth disease in five regions of China.

Objectives: This study aims to explore the interaction of different pathogens in Hand, foot and mouth disease (HFMD) by using a mathematical epidemiological model and the reported data in five regions of China. Methods: A cross-regional dataset of reported HFMD cases was built from four provinces (Fujian Province, Jiangsu province, Hunan Province, and Jilin Province) and one municipality (Chongqing Municipality) in China. The subtypes of the pathogens of HFMD, including Coxsackievirus A16 (CV-A16), enteroviruses A71 (EV-A71), and other enteroviruses (Others), were included in the data. A mathematical model was developed to fit the data. The effective reproduction number (R eff ) was calculated to quantify the transmissibility of the pathogens. Results: In total, 3,336,482 HFMD cases were collected in the five regions. In Fujian Province, the R eff between CV-A16 and EV-A71&CV-A16, and between CV-A16 and CV-A16&Others showed statistically significant differences (P < 0.05). In Jiangsu Province, there was a significant difference in R eff (P < 0.05) between the CV-A16 and Total. In Hunan Province, the R eff between CV-A16 and EV-A71&CV-A16, between CV-A16 and Total were significant (P < 0.05). In Chongqing Municipality, we found significant differences of the R eff (P < 0.05) between CV-A16 and CV-A16&Others, and between Others and CV-A16&Others. In Jilin Province, significant differences of the R eff (P < 0.05) were found between EV-A71 and Total, and between Others and Total. Conclusion: The major pathogens of HFMD have changed annually, and the incidence of HFMD caused by others and CV-A16 has surpassed that of EV-A71 in recent years. Cross-regional differences were observed in the interactions between the pathogens.

Graphene Oxide and Fluorescent-Aptamer-Based Novel Aptasensors for Detection of Metastatic Colorectal Cancer Cells.

Early diagnosis of metastatic colorectal cancer (mCRC) is extremely critical to improve treatment and extend survival. W3 is an aptamer that can specifically bind to mCRC cells with high affinity. Graphene oxide (GO) is a two-dimensional graphitic carbon nanomaterial, which has widely used in constructing biosensors. In this study, we have developed a no-wash fluorescent aptasensor for one-step and sensitive detection of mCRC LoVo cells. It is based on fluorescence resonance energy transfer (FRET) between GO and the W3 aptamer labeled with 5-carboxyfluorescein (FAM). GO can quench the green fluorescence of the FAM-labeled W3 (FAM-W3). In the presence of the target cells, FAM-W3 preferentially binds the target cells and detaches from the surface of GO, leading to the fluorescence of FAM recovery. It was demonstrated that the fluorescence recovery increases linearly in a wide range of 0~107 cells/mL (R2 = 0.99). The GO-based FAM-labeled W3 aptasensor (denoted as FAM-W3-GO) not only specifically recognizes mCRC cell lines (LoVo and HCT116), but also sensitively differentiates the target cells from mixed cells, even in the presence of only 5% of the target cells. Furthermore, FAM-W3-GO was applied to detect LoVo cells in human whole blood, which showed good reproducibility with an RSD range of 1.49% to 1.80%. Therefore, FAM-W3-GO may have great potential for early diagnosis of mCRC. This strategy of GO-based fluorescent aptasensor provides a simple, one-step, and highly sensitive approach for the detection of mCRC cells.

Alisol B 23-acetate adjusts bile acid metabolisim via hepatic FXR-BSEP signaling activation to alleviate atherosclerosis.

BACKGROUND: Postmenopausal women have a high incidence of atherosclerosis. Phytosterols have been shown to have cholesterol-lowering properties. Alisa B 23-acetate (AB23A) is a biologically active plant sterol isolated from Chinese herbal medicine Alisma. However, the atherosclerosis effect of AB23A after menopause and its possible mechanism have not been reported yet. PURPOSE: To explore whether AB23A can prevent atherosclerosis by regulating farnesoid X receptor and subsequently increasing fecal bile acid and cholesterol excretion to reduce plasma cholesterol levels. METHODS: Aortic samples from premenopausal and postmenopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female LDLR-/- mice and free fatty acid (FFA)-treated L02 cells were used to analyze the effect of AB23A supplementation therapy. RESULTS: AB23A increased fecal cholesterol and bile acids (BAs) excretion dependent on activation of hepatic farnesoid X receptor (FXR) in ovariectomized mice. AB23A inhibited hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) via inducing small heterodimer partner (SHP) expression. On the other hand, AB23A increased the level of hepatic chenodeoxycholic acid (CDCA), and activated the hepatic BSEP signaling. The activation of hepatic FXR-BSEP signaling by AB23A in ovariectomized mice was accompanied by the reduction of liver cholesterol, hepatic lipolysis, and bile acids efflux, and reduced the damage of atherosclerosis. In vitro, AB23A fixed abnormal lipid metabolism in L02 cells and increased the expression of FXR, BSEP and SHP. Moreover, the inhibition and silencing of FXR canceled the regulation of BSEP by AB23A in L02 cells. CONCLUSION: Our results shed light into the mechanisms behind the cholesterol-lowering of AB23A, and increasing FXR-BSEP signaling by AB23A may be a potential postmenopausal atherosclerosis therapy.

Novel Sphingosine Kinase 1 Inhibitor Suppresses Growth of Solid Tumor and Inhibits the Lung Metastasis of Triple-Negative Breast Cancer.

Targeting sphingosine kinase 1 (SphK1) has become a novel strategy for the treatment of inflammatory bowel disease and cancer via the SphK1/S1P signaling pathway. However, exploration of SphK1 inhibitor therapeutic applications has been hampered by the poor pharmacokinetic properties of these SphK1 inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel SphK1 inhibitors. The novel compound 28 selectively inhibits SphK1 and exhibits higher anti-proliferative activity compared to the positive compound PF-543 in various cancer cells, which is associated with the induction of G0/G1 phase arrest and apoptosis; besides, it could also inhibit the cell migration. Further, compound 28 can suppress in vivo growth of both colon tumor and triple-negative breast tumor and inhibits the lung metastasis of triple-negative breast cancer with higher potency compared with that of PF-543. Collectively, compound 28 represents a promising lead compound for the treatment of solid tumor and the metastasis.