Therapeutic effects and molecular mechanisms of natural products in thrombosis.

Thrombotic disorders, such as myocardial infarction and stroke, are the leading cause of death in the global population and have become a health problem worldwide. Drug therapy is one of the main antithrombotic strategies, but antithrombotic drugs are not completely safe, especially the risk of bleeding at therapeutic doses. Recently, natural products have received widespread interest due to their significant efficacy and high safety, and an increasing number of studies have demonstrated their antithrombotic activity. In this review, articles from databases, such as Web of Science, PubMed, and China National Knowledge Infrastructure, were filtered and the relevant information was extracted according to predefined criteria. As a result, more than 100 natural products with significant antithrombotic activity were identified, including flavonoids, phenylpropanoids, quinones, terpenoids, steroids, and alkaloids. These compounds exert antithrombotic effects by inhibiting platelet activation, suppressing the coagulation cascade, and promoting fibrinolysis. In addition, several natural products also inhibit thrombosis by regulating miRNA expression, anti-inflammatory, and other pathways. This review systematically summarizes the natural products with antithrombotic activity, including their therapeutic effects, mechanisms, and clinical applications, aiming to provide a reference for the development of new antithrombotic drugs.

Abnormalities in spontaneous brain activity and functional connectivity are associated with cognitive impairments in children with type 1 diabetes mellitus.

BACKGROUND: It remains unclear whether alterations in brain function occur in the early stage of pediatric type 1 diabetes mellitus(T1DM). We aimed to examine changes in spontaneous brain activity and functional connectivity (FC) in children with T1DM using resting-state functional magnetic resonance imaging (rs-fMRI), and to pinpoint potential links between neural changes and cognitive performance. METHODS: In this study, 22 T1DM children and 21 age-, sex-matched healthy controls underwent rs-fMRI. The amplitude of low frequency fluctuations (ALFF) and seed-based FC analysis were performed to examine changes in intrinsic brain activity and functional networks in T1DM children. Partial correlation analyses were utilized to explore the correlations between ALFF values and clinical parameters. RESULTS: The ALFF values were significantly lower in the lingual gyrus (LG) and higher in the left medial superior frontal gyrus (MSFG) in T1DM children compared to controls. Subsequent FC analysis indicated that the LG had decreased FC with bilateral inferior occipital gyrus, and the left MSFG had decreased FC with right precentral gyrus, right inferior parietal gyrus and right postcentral gyrus in children with T1DM. The ALFF values of LG were positively correlated with full-scale intelligence quotient and age at disease onset in T1DM children, while the ALFF values of left MSFG were positively correlated with working memory scores. CONCLUSION: Our findings revealed abnormal spontaneous activity and FC in brain regions related to visual, memory, default mode network, and sensorimotor network in the early stage of T1DM children, which may aid in further understanding the mechanisms underlying T1DM-associated cognitive dysfunction.

Dual Drug-Loaded Nanoliposomes Encapsulating Curcumin and 5-Fluorouracil with Advanced Medicinal Applications: Self-Monitoring and Antitumor Therapy.

Due to the presence of physiological barriers, it is difficult to achieve the desired therapeutic efficacy of drugs; thus, it is necessary to develop an efficient drug delivery system that enables advanced functions such as self-monitoring. Curcumin (CUR) is a naturally functional polyphenol whose effectiveness is limited by poor solubility and low bioavailability, and its natural fluorescent properties are often overlooked. Therefore, we aimed to improve the antitumor activity and drug uptake monitoring by simultaneously delivering CUR and 5-Fluorouracil (5-FU) in the form of liposomes. In this study, dual drug-loaded liposomes (FC-DP-Lip) encapsulating CUR and 5-FU were prepared by the thin-film hydration method; their physicochemical properties were characterized; and their biosafety, drug uptake distribution in vivo, and tumor cell toxicity were evaluated. The results showed that the nanoliposome FC-DP-Lip showed good morphology, stability, and drug encapsulation efficiency. It showed good biocompatibility, with no side effects on zebrafish embryonic development. In vivo uptake in zebrafish showed that FC-DP-Lip has a long circulation time and presents gastrointestinal accumulation. In addition, FC-DP-Lip was cytotoxic against a variety of cancer cells. This work showed that FC-DP-Lip nanoliposomes can enhance the toxicity of 5-FU to cancer cells, demonstrating safety and efficiency, and enabling real-time self-monitoring functions.

Nano-Liposomes Double Loaded with Curcumin and Tetrandrine: Preparation, Characterization, Hepatotoxicity and Anti-Tumor Effects.

(1) Background: Curcumin (CUR) and tetrandrine (TET) are natural compounds with various bioactivities, but have problems with low solubility, stability, and absorption rate, resulting in low bioavailability, and limited applications in food, medicine, and other fields. It is very important to improve the solubility while maintaining the high activity of drugs. Liposomes are micro-vesicles synthesized from cholesterol and lecithin. With high biocompatibility and biodegradability, liposomes can significantly improve drug solubility, efficacy, and bioavailability. (2) Methods: In this work, CUR and TET were encapsulated with nano-liposomes and g DSPE-MPEG 2000 (DP)was added as a stabilizer to achieve better physicochemical properties, biosafety, and anti-tumor effects. (3) Results: The nano-liposome (CT-DP-Lip) showed stable particle size (under 100 nm) under different conditions, high solubility, drug encapsulation efficiency (EE), loading capacity (LC), release rate in vitro, and stability. In addition, in vivo studies demonstrated CT-DP-Lip had no significant toxicity on zebrafish. Tumor cytotoxicity test showed that CT-DP-Lip had a strong inhibitory effect on a variety of cancer cells. (4) Conclusions: This work showed that nano-liposomes can significantly improve the physical and chemical properties of CUR and TET and make them safer and more efficient.

Evaporation Kinetics of Sessile Water Droplets on a Smooth Stainless Steel Surface at Elevated Temperatures and Pressures.

The evaporation of water droplets on a solid surface at elevated temperatures under a pressurized condition has not yet been well understood, although this phenomenon is of both theoretical and practical significance. In this work, water droplet evaporation on smooth stainless steel surfaces in nitrogen gas atmosphere at elevated pressures and temperatures (up to 2 MPa and 202.4 °C, respectively) was investigated experimentally. It was observed that the increase in pressure diminishes the proportion of the constant contact radius stage over the entire evaporation time, whereas an opposite trend was found when raising the temperature, due to the change in the surface pinning ability with pressure (and temperature). The results also suggested that the evaporation mode transition is mainly affected by temperature rather than pressure. In addition, the evaporation rate was calculated under various degrees of subcooling, revealing that the evaporation rate increases almost linearly with pressure when keeping the degree of subcooling constant. However, when fixing the test temperature, a nonlinear decrease of the evaporation rate with pressure was observed. A power law growth of the evaporation rate with temperature was also found at a constant pressure. Last, it was uncovered by a theoretical analysis that the saturated vapor concentration is the dominant factor dictating the evaporation rate.

Vitamin B6 inhibits macrophage activation to prevent lipopolysaccharide-induced acute pneumonia in mice.

Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP-activated protein kinase (AMPK) produces anti-inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin-1 beta (IL-1ß), IL-6 and tumour necrosis factor alpha (TNF-α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP-activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose-dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL-1ß, IL-6 and TNF-α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS-induced macrophage activation if AMPK was in deficient through siRNA-mediated approaches. Further, the anti-inflammatory effects produced by VitB6 or AICAR in LPS-treated macrophages were abolished in DOK3 gene knockout (DOK3-/- ) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS-induced both systemic inflammation and acute pneumonia in wild-type mice, but not in DOK3-/- mice. VitB6 prevents LPS-induced acute pulmonary inflammation in mice via the inhibition of macrophage activation.

Understanding the Temperature Dependence of Contact Angles of Water on a Smooth Hydrophobic Surface under Pressurized Conditions: An Experimental Study.

It is of both practical and scientific significance to understand the temperature dependence of contact angles of water on various surfaces. However, the variation trend of water wettability on a smooth hydrophobic surface with increasing temperature remains unclear. In this work, in situ characterization of the contact angle of water on Teflon (polytetrafluoroethylene) surfaces and the interfacial tension of water over a temperature spectrum from ∼25 to 160 °C under pressurized conditions (2, 3, and 5 MPa) in a nitrogen atmosphere was conducted by employing the sessile drop and pendant drop methods, respectively. A nearly invariant trend of the contact angle was observed over the entire temperature and pressure range. As expected, however, it was shown that the water-N2 interfacial tension almost linearly declines with increasing temperature and that pressure has a negative effect on the interfacial tension. Based on the theory of surface thermodynamics, the effects of temperature on the contact angles were analyzed in combination with the gas adsorption effect. Estimations on the solid-gas interfacial tension, surface entropy, and the heat of immersion were made to gain more insights into the temperature dependence of the water contact angle on a smooth hydrophobic surface.

Altered Brain Glymphatic Function at Diffusion-Tensor MRI in Pre-cirrhotic Metabolic Dysfunction-Associated Fatty Liver Disease.

RATIONALE AND OBJECTIVES: To evaluate glymphatic function changes and their relationships with clinical features in patients with metabolic dysfunction-associated fatty liver disease (MAFLD), thereby facilitating early intervention before this disease progresses to cirrhosis. MATERIALS AND METHODS: A cross-sectional cohort of 46 pre-cirrhotic MAFLD patients and 30 age-, sex-, and education-matched controls was enrolled, with diffusion-tensor imaging (DTI) data, laboratory and neurocognitive scores collected. The DTI analysis along the perivascular space (DTI-ALPS) index was computed for qualifying glymphatic function. Generalized linear model and partial correlation analyses were applied to evaluate relationships between the ALPS index and clinical variables. RESULTS: MAFLD group exhibited a decreased ALPS index and increased diffusivity along the y-axis in the projection fiber compared to the controls. The altered ALPS index was associated with clock drawing test (CDT) score (3.931 [0.914, 6.947], P = 0.011) and was correlated with diastolic pressure level (r = -0.315, P = 0.033) in MAFLD group. The relationships of ALPS index with CDT score (6.263 [2.069, 10.458], P = 0.003) and diastolic pressure level (r = -0.518, P = 0.014) remained in the MAFLD with metabolic syndrome (MetS) group. Furthermore, the ALPS index was even associated with Auditory Verbal Learning Test-Immediate recall score (-23.853 [-45.417, -2.289], P = 0.030) in MAFLD with MetS group. CONCLUSION: MAFLD patients may have a glymphatic dysfunction prior to cirrhosis, and this alteration may be related to cognition and diastolic pressure. Glymphatic dysfunction has a more severe impact on cognition when MAFLD patient is accompanied by MetS.

A simple and accurate method to quantify real-time contraction of vascular smooth muscle cell in vitro.

Vascular smooth muscle cells (VSMCs) constitute the medial layer of the blood vessel wall. Their contractile state regulates blood flow in physiological and pathological conditions. Current methods for assessing the contractility of VSMCs are not amenable to the high-throughput screening of pharmaceutical compounds. This study aimed to develop a method to address this shortcoming in the field. Real-time contraction was visualized in living VSMCs using the exogenous expression of green fluorescent protein (GFP). Image-Pro Plus software (IPPS) was used to measure various morphological cell indices. In phenylephrine-treated VSMCs, GFP fluorescence imaging was more accurate than brightfield imaging or phalloidin staining in representing VSMC morphology, as measured using IPPS. Among the multiple indices of VSMC shape, area and mean-diameter were more sensitive than length in reflecting the morphological changes in VSMC. We developed a new index, compound length, by combining the mean-diameter and length to differentiate contracted and uncontracted VSMCs. Based on the compound length, we further generated a contraction index to define a single-VSMC contractile status as single-VSMC contraction-index (SVCI). Finally, compound length and SVCI were validated to effectively assess cell contraction in VSMCs challenged with U46619 and KCl. In conclusion, GFP-based indices of compound length and SVCI can accurately quantify the real-time contraction of VSMCs. In future, the new method will be applied to high-throughput drug screening or basic cardiovascular research.

Understanding the effects of pressure on the contact angle of water on a silicon surface in nitrogen gas environment: Contrasts between low- and high-temperature regimes.

HYPOTHESIS: Pressure dependence of contact angle is expected to be influenced by temperature. Nevertheless, the correlation of water contact angle with pressure is rarely investigated at high temperatures (over 100 ℃). EXPERIMENTS: In this work, measurements of the contact angle and interfacial tension of water in N2 atmosphere were conducted at various pressures and temperatures (up to 17 MPa and 300 ℃). The experimental observations were elucidated based on the theory of surface thermodynamics. FINDINGS: It was shown that the water-N2 interfacial tension linearly decreases with increasing the pressure, and that the pressure coefficient declines as temperature rises. The pressure dependence of the water contact angle was found to be different for the low- and high-temperature regimes: the water contact angle increases below 100 ℃, whereas an inverse variation occurs over 100 ℃. According to the theoretical analysis, the pressure dependence of both the water interfacial tension and contact angle is attributed to N2 adsorption on the surfaces of water and silicon. The variations in the water contact angle with pressure, including both the sign and magnitude, are actually the consequence of the changes of water-N2 and Si-N2 interfacial tensions manipulated by pressure and temperature.

Unraveling the synergistic effects of solid surface material and temperature on the contact angle of water under an elevated pressure: An experimental study.

HYPOTHESIS: In terms of the Young's equation, the temperature dependence of liquid-solid contact angle is affected by the surface material, so the wetting behavior could be tuned by both changing the temperature and surface material. However, the synergistic effects of surface material and temperature on the water contact angle remain unclear, especially at elevated temperatures. EXPERIMENTS: In this study, a systematic characterization of water contact angle against various smooth metallic and nonmetallic surfaces was conducted for temperatures up to 300 ℃ in a high-pressure chamber at 15 MPa. The measured results were finally compared with the predictions made by the sharp-kink approximation model. FINDINGS: Not surprisingly, it was observed the temperature-dependent water contact angle is sensitive to the type of solid surface. The temperature coefficients and critical temperature points on the contact-angle-temperature curves can be manipulated by altering the surface material. However, the influence of surface material is weakened by raising temperature, thus leading to the nearly consistent temperature-dependent water contact angle over 120℃. Additionally, the necessity of investigating the internal flows within the water drops was highlighted to unravel the positive temperature correlation of the water contact angle at high temperatures, in view of the presence of non-spherical-cap-shaped drops.

Temperature dependence of the contact angle of water: A review of research progress, theoretical understanding, and implications for boiling heat transfer.

Contact angle, a quantitative measure of macroscopic surface wettability, plays an important role in understanding liquid-vapor heterogeneous phase change phenomena, e.g., boiling heat transfer. The contact angles of water at elevated temperatures are of particular interest for understanding of wettability-regulated boiling heat transfer in steam-based power generation. From a more theoretical perspective, the temperature dependence of contact angle of water is also essential to estimation of several key surface thermodynamic properties, such as the solid surface tension, the surface entropy, and the heats of immersion and adsorption. Here, a comprehensive review of historical efforts in measuring the contact angles of water over a wide temperature range on a variety of solids, not limited to metallic surfaces, is presented. As suggested by the literature data, the temperature dependence of contact angle of water may be classified into three regimes: (a) low temperatures below the saturation point (i.e., 100 °C at atmospheric pressure), (b) medium temperatures up to ~170 °C, and (c) high temperatures up to 300 °C at pressurized conditions. A slightly-decreasing or nearly-invariant trend of the contact angles of water on both non-metallic and metallic surfaces was reported for the low-temperature regime. In contrast, a steeper linear decline in water contact angle was demonstrated at temperatures above 100 °C. The few experimental data available on several metallic surfaces showed that the contact angle of water either again becomes nearly temperature-independent or further decreases with temperature above 210 °C. A theoretical understanding of the temperature dependence is given based on surface thermodynamic analysis, although the exact molecular mechanisms underlying these experimental observations remain unclear. Consequently, the theoretical model for predicting the variation of the contact angle of water with temperature is not well-developed. As the critical point of water (374 °C and 22.1 MPa) is approached, the surface tension, and hence the contact angle, should become vanishingly small. However, this theoretical expectation has not yet been verified due to the lack of experimental data at such high temperatures/pressures. Finally, future research directions are identified, including a systematic exploration of the contact angle at near-critical temperatures, the effects of surface oxidation, corrosion, and deposition on contact angle during operation of boilers and reactors, and the particular effect of irradiation on contact angle in nuclear reactor applications.

Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1.

BACKGROUNDS: A major side effect of statin, a widely used drug to treat hyperlipidemia, is skeletal myopathy through cell apoptosis. The aim of this study is to investigate the roles of microRNA in statin-induced injury. METHODS: Apolipoprotein E knockout (ApoE-/-) mice were administered with simvastatin (20 mg/kg/day) for 8 weeks. Exercise capacity was evaluated by hanging grid test, forelimb grip strength, and running tolerance test. RESULTS: In cultured skeletal muscle cells, statin increased the levels of miR-1a but decreased the levels of mitogen-activated protein kinase kinase kinase 1 (MAP3K1) in a time or dose dependent manner. Both computational target-scan analysis and luciferase gene reporter assay indicated that MAP3K1 is the target gene of miR-1a. Statin induced cell apoptosis of skeletal muscle cells, but abolished by downregulating of miR-1a or upregulation of MAP3K1. Further, the effects of miR-1a inhibition on statin-induced cell apoptosis were ablated by MAP3K1 siRNA. In ApoE-/- mice, statin induced cell apoptosis of skeletal muscle cells and decreased exercise capacity in mice infected with vector, but not in mice with lentivirus-mediated miR-1a gene silence. CONCLUSION: Statin causes skeletal injury through induction of miR-1a excessive expression to decrease MAP3K1 gene expression.

Temperature dependence of contact angles of water on a stainless steel surface at elevated temperatures and pressures: In situ characterization and thermodynamic analysis.

Phase change heat transfer (e.g., boiling of water) on surfaces can be enhanced by tuning the surface wettability, which is often quantified by the contact angle and is expected to be influenced by temperature and pressure. However, the temperature (and pressure) dependence of contact angles of water on metallic surfaces remain unclear. In this study, an in situ characterization of the contact angles of water on 304 stainless steel surfaces at temperatures from room temperature to 250 °C and at pressures up to 15 MPa was performed using the sessile drop method. It was shown that three distinct regimes can be identified on the contact angle-temperature curves. A slightly-decreasing trend of the contact angles with temperature was observed below 120 °C, followed by a steeper linear decrease at higher temperatures. A further rise of the decreasing rate with temperature was observed above 210 °C. In contrast to temperature, the pressure was shown to have little effects on the contact angles. Based on the theory of surface thermodynamics, the effects of temperature (and pressure) on the contact angles were analyzed in terms of the interfacial tensions. An empirical correlation was developed to predict the contact angles as a function of temperature.

Applications, phytochemistry, pharmacological effects, pharmacokinetics, toxicity of Scutellaria baicalensis Georgi. and its probably potential therapeutic effects on COVID-19: a review.

Scutellaria baicalensis Georgi. (SB) is a common heat-clearing medicine in traditional Chinese medicine (TCM). It has been used for thousands of years in China and its neighboring countries. Clinically, it is mostly used to treat diseases such as cold and cough. SB has different harvesting periods and processed products for different clinical symptoms. Botanical researches proved that SB included in the Chinese Pharmacopoeia (1st, 2020) was consistent with the medicinal SB described in ancient books. Modern phytochemical analysis had found that SB contains hundreds of active ingredients, of which flavonoids are its major components. These chemical components are the material basis for SB to exert pharmacological effects. Pharmacological studies had shown that SB has a wide range of pharmacological activities such as antiinflammatory, antibacterial, antiviral, anticancer, liver protection, etc. The active ingredients of SB were mostly distributed in liver and kidney, and couldn't be absorbed into brain via oral absorption. SB's toxicity was mostly manifested in liver fibrosis and allergic reactions, mainly caused by baicalin. The non-medicinal application prospects of SB were broad, such as antibacterial plastics, UV-resistant silk, animal feed, etc. In response to the Coronavirus Disease In 2019 (COVID-19), based on the network pharmacology research, SB's active ingredients may have potential therapeutic effects, such as baicalin and baicalein. Therefore, the exact therapeutic effects are still need to be determined in clinical trials. SB has been reviewed in the past 2 years, but the content of these articles were not comprehensive and accurate. In view of the above, we made a comprehensive overview of the research progress of SB, and expect to provide ideas for the follow-up study of SB.

Impact of Perioperative Levosimendan Administration on Risk of Bleeding After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Levosimendan, a calcium sensitizer and potassium channel opener, has been demonstrated to improve myocardial function without increasing oxygen consumption and to show protective effects in other organs. Recently, a prospective, randomized controlled trial (RCT) revealed an association between levosimendan use and a possible increased risk of bleeding postoperatively. Levosimendan's anti-platelet effects have been shown in in vitro studies. Current studies do not provide sufficient data to support a relation between perioperative levosimendan administration and increased bleeding risk. PURPOSE: Our goal was to investigate the relation between perioperative levosimendan administration and increased bleeding risk using a meta-analysis study design. METHODS: The PubMed, Ovid, EMBASE and Cochrane Library databases were searched for relevant RCTs before July 1, 2019. The outcome parameters included reoperation secondary to increased bleeding in the postoperative period, the amount of postoperative recorded blood loss, and the need for transfusion of packed red blood cells (RBCs) and other blood products. RESULTS: A total of 1160 patients in nine RCTs (576 in the levosimendan group and 584 in the control group) were included according to our inclusion criteria. Analysis showed that perioperative levosimendan administration neither increased the rate of reoperation secondary to bleeding nor increased the amount of postoperative chest tube drainage when compared with the control group. In terms of blood product transfusion, levosimendan did not influence the requirement for RBC transfusion, platelet transfusion nor fresh frozen plasma (FFP) transfusion. Levosimendan also did not shorten or prolong the aortic cross-clamp time or the cardiopulmonary bypass time. CONCLUSION: The analyzed parameters, including reoperations due to bleeding, postoperative chest drainage and the requirement for blood products, revealed that levosimendan did not increase postoperative bleeding risk. More studies with a larger sample size are needed to address a more reliable conclusion due to study limitations.