Cyclodextrins as therapeutic drugs for treating lipid metabolism disorders.

OBJECTIVE: This study sought to systematically compare the efficacy and mechanism of cyclodextrins as drug interventions in lipid metabolism diseases, potentially providing ideas for subsequent research directions and clinical applications. METHODS: We used the bibliometric method for feature mining, applied VOSviewer software for clustering analysis, and applied content analysis for objective descriptions and accurate analysis. RESULTS: (1) We collected more than 50 studies, which is the basic database of this study. (2) The academic bubble map showed that this research area was popular in the United States. (3) Cluster analysis showed that the intensively studied diseases in this field were Niemann-Pick type C (NPC), atherosclerosis (AS), and obesity. The hot-spot cyclodextrin types were HP-ß-CD. (4) Literature measurement revealed the involvement of 15 types of lipid metabolism diseases. Among them, NPC, diabetes, and obesity were studied in clinical trials. Dyslipidemia and AS have been reported relatively more frequently in animal experiments. The studies of cellular experiments provide insight into the molecular mechanisms that intervene in lipid metabolism diseases from multiple perspectives. The exploration of the molecular mechanisms by which cyclodextrins exert their pharmacological effects mainly revolves around lipid metabolism. CONCLUSION: It is worthwhile to investigate the role and mechanism of cyclodextrins in other lipid metabolism diseases. The potential efficacy evaluation of cyclodextrins as pharmaceutical drugs for oral or injectable formulations is less studied and may become a new focus in the future.

Ganglioside GM3-Functionalized Reconstituted High-Density Lipoprotein (GM3-rHDL) as a Novel Nanocarrier Enhances Antiatherosclerotic Efficacy of Statins in apoE-/- C57BL/6 Mice.

Previously, we found that exogenous ganglioside GM3 had an antiatherosclerotic efficacy and that its antiatherosclerotic efficacy could be enhanced by reconstituted high-density lipoprotein (rHDL). In this study, we hypothesized that GM3-functionalized rHDL (i.e., GM3-rHDL) as a nanocarrier can promote the efficacy of traditional antiatherosclerotic drugs (e.g., statins). To test this hypothesis, lovastatin (LT) was used as a representative of statins, and LT-loaded GM3-rHDL nanoparticle (LT-GM3-rHDL or LT@GM3-rHDL; a mean size of ~142 nm) and multiple controls (e.g., GM3-rHDL without LT, LT-loaded rHDL or LT-rHDL, and other nanoparticles) were prepared. By using two different microsphere-based methods, the presences of apolipoprotein A-I (apoA-I) and/or GM3 in nanoparticles and the apoA-I-mediated macrophage-targeting ability of apoA-I/rHDL-containing nanoparticles were verified in vitro. Moreover, LT-GM3-rHDL nanoparticle had a slowly sustained LT release in vitro and the strongest inhibitory effect on the foam cell formation of macrophages (a key event of atherogenesis). After single administration of rHDL-based nanoparticles, a higher LT concentration was detected shortly in the atherosclerotic plaques of apoE-/- mice than non-rHDL-based nanoparticles, suggesting the in vivo plaque-targeting ability of apoA-I/rHDL-containing nanoparticles. Finally, among all nanoparticles LT-GM3-rHDL induced the largest decreases in the contents of blood lipids and in the areas of atherosclerotic plaques at various aortic locations in apoE-/- mice fed a high-fat diet for 12 weeks, supporting that LT-GM3-rHDL has the best in vivo antiatherosclerotic efficacy among the tested nanoparticles. Our data imply that GM3-functionalized rHDL (i.e., GM3-rHDL) can be utilized as a novel nanocarrier to enhance the efficacy of traditional antiatherosclerotic drugs (e.g., statins).

Visual analysis and evaluation of clinical research on Traditional Chinese medicine compounds in treating insomnia of Yin deficiency syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Insomnia is a common form of sleep disorder. Traditional Chinese medicine (TCM) compounds have definite curative effects and a low incidence of adverse reactions, which is recognized to be an effective intervention means for the treatment of insomnia. AIM OF THE STUDY: Based on mining the clinical research data of treating insomnia of yin deficiency syndrome (IYDS) with TCM compounds systematically, the study is to analyze the research hotspots and development trends in this field, explore the medication rule, evaluate the quality of research, so as to provide reference and direction for clinical application and scientific research in this field. MATERIALS AND METHODS: The relevant literature was retrieved and managed by evidence-based medicine strategy and EndNote software respectively. The bibliometric method was used to mine and analyze data characteristics. The VOSviewer software was used to make visual knowledge maps, the IBM SPSS Modeler software was used for association rule analysis of herbs, and the Cochrane tool and MINORS scale were used for quality analysis of literature. RESULTS: (1) A total of 184 related studies were included according to the inclusion and exclusion criteria. (2) The research popularity showed a dynamic upward trend and the research hotspot showed a trend of migration and refinement, etc. (3) The commonly used herbs in this field were Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow, etc; the commonly used TCM prescriptions were Huanglian Ejiao Decoction, etc; the commonly used dosage forms were traditional decoction, etc; the commonly used combinations of herbs included Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow-Poria cocos（Schw.）Wolf, etc. (4) The rate of the studies containing ethical review numbers and clear inclusion standards did not reach 50%, and the risk bias of methodological was high. However, a separate analysis of data showed that the specification of study design was on the rise obviously in recent years, and Meta-analysis and sensitivity analysis could confirm the effectiveness and stability of clinical efficacy which was the key indicator in treating IYDS with TCM prescriptions. There were significant differences among administration protocols of different clinical studies of the same name TCM compounds. However, the scientific significance of each unique dosing regimen were expected to be elaborated or discussed. CONCLUSION: The clinical research number of TCM compounds treating IYDS was in a dynamic upward trend, and the outcome indicators tended to be diversified and detailed. The dosage forms mainly included decoction, supplemented by Chinese patent medicine. The design of clinical studies in this field was not standardized enough, but the key indicators were scientific and stable. We expected that later studies could pay more attention to improving the standardization of trial design, reducing the risk bias in the process of methodological design, conducting high-quality standardized multicenter, large-sample randomized controlled clinical trials to provide scientific evidence with high evidentiary strength, establishing the recognized administration protocols for the same name TCM prescriptions or clarifying the targeting of different protocols, and promoting the application and popularity of TCM compounds in treating IYDS.

Chinese herbal medicine formula combined with calcium antagonist in the treatment of hypertension: a systematic review and meta-analysis.

OBJECTIVE: Chinese herbal medicine formula and calcium antagonist are commonly used medicines for hypertension in China. This study aims to examine the efficacy and safety of for the treatment of Chinese herbal medicine formula combined calcium antagonist hypertension. METHODS: PubMed, the Cochrane library, CNKI, VIP, Sinomed, and Wanfang Database were searched up to January 31, 2021. Data analysis was performed using the Recman 5.3. The source of clinical heterogeneity used stata16.0 for sensitivity analysis. RESULTS: 17 RCTs and 1587 cases were finally included. The results shows that the traditional Chinese medicine decoction combined with calcium antagonists is better than calcium antagonists alone in the treatment of hypertension. In addition, it can effectively alleviate the adverse reactions caused by calcium antagonists. However, due to the low quality of methodology and the small-scale research, more high-quality clinical trials are still needed for verification.

Enhanced Anti-Atherosclerotic Efficacy of pH-Responsively Releasable Ganglioside GM3 Delivered by Reconstituted High-Density Lipoprotein.

Recently, the atheroprotective role of endogenous GM3 and an atherogenesis-inhibiting effect of exogenous GM3 suggested a possibility of exogenous GM3 being recruited as an anti-atherosclerotic drug. This study seeks to endow exogenous GM3 with atherosclerotic targetability via reconstituted high-density lipoprotein (rHDL), an atherosclerotic targeting drug nanocarrier. Unloaded rHDL, rHDL loaded with exogenous GM3 at a low concentration (GM3L-rHDL), and rHDL carrying GM3 at a relatively high concentration (GM3H-rHDL) were prepared and characterized. The inhibitory effect of GM3-rHDL on lipid deposition in macrophages was confirmed, and GM3-rHDL did not affect the survival of red blood cells. In vivo experiments using ApoE-/- mice fed a high fat diet further confirmed the anti-atherosclerotic efficacy of exogenous GM3 and demonstrated that GM3 packed in HDL nanoparticles (GM3-rHDL) has an enhanced anti-atherosclerotic efficacy and a reduced effective dose of GM3. Then, the macrophage- and atherosclerotic plaque-targeting abilities of GM3-rHD, most likely via the interaction of ApoA-I on GM3-rHDL with its receptors (e.g., SR-B1) on cells, were certified via a microsphere-based method and an aortic fragment-based method, respectively. Moreover, we found that solution acidification enhanced GM3 release from GM3-rHDL nanoparticles, implying the pH-responsive GM3 release when GM3-rHDL enters the acidic atherosclerotic plaques from the neutral blood. The rHDL-mediated atherosclerotic targetability and pH-responsive GM3 release of GM3-rHDL enhanced the anti-atherosclerotic efficacy of exogenous GM3. The development of the GM3-rHDL nanoparticle may help with the application of exogenous GM3 as a clinical drug. Moreover, the data imply that the GM3-rHDL nanoparticle has the potential of being recruited as a drug nanocarrier with atherosclerotic targetability and enhanced anti-atherosclerotic efficacy.

A Systematic Review and Meta-Analysis of High-Frequency Prescription of Zhigancao Decoction Combined with Conventional Western Medicine in the Treatment of Chronic Heart Failure.

BACKGROUND: Chronic heart failure is the main critical illness and cause of death in the later stages of cardiovascular disease, and it is one of the two major challenges in the field of cardiovascular research. The clinical application of traditional Chinese medicine in the prevention and treatment of chronic heart failure has been relatively common in China, and the "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine" has been published in China. Combining the literature in this field, the authors found that Zhigancao Decoction has been used in the treatment of chronic heart failure with more clinical research reports and higher frequency (this article refers to it as a high-frequency prescription for short). However, Zhigancao Decoction was not included in the recommended prescriptions in the "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine," and there was no relevant systematic review and meta-analysis. For this reason, this article has carried out two parts of work, including systematically organizing the literature in this research field and carrying out systematic review and meta-analysis. This can provide stronger evidence support for Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure and provide a new option for the improvement and update of the "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine." METHODS: This article used the bibliometric method to investigate the research articles on the treatment of chronic heart failure with integrated traditional Chinese and Western medicine and analyzed the high-frequency prescriptions which are used and reported frequently. In addition, we also used manual and computer-aided search methods, the search scope includes CNKI, WANFANG, VIP, SinoMed, Web of Science, PubMed, and Cochrane Library, and the search content is the clinical randomized control of Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure trials (RCTs). The search period is from the establishment of the database to January 29, 2021. The literature was managed and screened by EndNote software; the quality of the included literature was evaluated according to the modified Jadad scale, and the risk bias was assessed using the Cochrane tool; the results of the included studies were analyzed using the Review Manager 5.3 software; the sources of heterogeneity between the studies were analyzed using Stata16.0 software for sensitivity analysis. RESULTS: According to the bibliometric analysis, the maximum number of research reports is 553, which are arranged in descending order of 21 prescriptions, including Zhenwu Decoction, Zhigancao, and powder of five drugs containing poria. The second most frequently used prescription is Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure, but its systematic review and meta-analysis still need further research. A total of 17 clinical randomized controlled trials of Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure were included in the search, with a total of 1752 subjects. Meta-analysis results show that Zhigancao combined with conventional Western medicine is more effective than conventional Western medicine in the treatment of chronic heart failure. The advantages are the following 5 outcome indicators: total clinical effective rate, left ventricular ejection fraction, left ventricular end-diastolic diameter, B-type natriuretic peptide, and 6-minute walk test. CONCLUSIONS: There are many prescriptions combined with Western medicine to treat chronic heart failure, among which Zhigancao Decoction is the second most frequently used prescription. There are many original studies on Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure. The quality of the evaluation research shows that the overall standard is scientific, and a few experimental designs are slightly irregular. Meta-analysis shows that Zhigancao Decoction combined with conventional Western medicine has better therapeutic effects and safety than conventional Western medicine. This shows the characteristics and advantages of integrated Chinese and Western medicine in the treatment of cardiovascular diseases and is worth recommending.

Systematic Evaluation of Toxicity of Aconite Based on Bibliometric Method.

AIM: Based on the bibliometric method, the toxicity of aconite is analyzed and evaluated. METHODS: Studies on the toxicity of aconite were retrieved from CNKI, CQVIP, Chinese Biomedical Literature Service System, and PubMed, ranging from January 1985 to November 2020. All those studies were formed into the Database of Literature of Toxicity of Aconite (DLTA). Studies on the toxicity of aconite were retrieved from CNKI, CQVIP, SinoMed, and PubMed, respectively. Collecting relevant information in DLTA, we analyzed the hotspots, factors and mechanism of aconite toxicity, and attenuation methods. RESULTS: A total of 445 studies on the toxicity of aconite have been collected. "Compatibility attenuation" and "Processing attenuation" have been the hotspots of aconite toxicity in recent years. Many studies support that the main toxic reactions of aconite are heart damage, liver toxicity, nephrotoxicity, and neurotoxicity. The toxic effect of aconite is related to the effect on the central nervous system. Exciting the vagus nerve reduces the autonomy of the sinus node and damages myocardial cells. The decoction time, dosage, and administration of aconite are the main factors of the toxicity of aconite. There are few studies about the effect of the origin of aconite and the specifications of the medicinal materials on toxicity. Therefore, it is impossible to analyze its relevance. At present, the commonly used methods to reduce the toxicity of aconite mainly include three methods: drug compatibility, processing, and decoction. The most common compatibility with aconite medicines includes licorice, dried ginger, ginseng, and ephedra. Black sliced aconite, steamed slices, and fried slices are less toxic than other processed products. Aconite decoction for more than 60 minutes can basically reach the safe range, and more than 2 hours of decoction may cause the loss of active ingredients. CONCLUSIONS: The research on the mechanisms of aconite dosage-efficacy-toxicity, compatibility, processing, liver toxicity, and nephrotoxicity is still not comprehensive and in-depth. Researchers should perfect toxicity studies of aconite, remove the constraints that affect its clinical application, and promote the clinical use of aconite safely and reasonably.

AFM detects the effects of acidic condition on the size and biomechanical properties of native/oxidized low-density lipoprotein.

Solution acidification exists under some physiological conditions (e.g. lysosomes in cells) and diseases (e.g. atherosclerosis, tumors, etc.). It is poorly understood whether and how acidification influences the size and biomechanical (stiffness and stickiness) properties of native Low-density lipoprotein (LDL) and its oxidized form (oxLDL) which plays a vital role in atherogenesis and tumorigenesis. Atomic force microscopy (AFM) evaluated that gradient acidification from pH 7.4 to pH 4.4 caused an expanding-first-and-then-shrinking decrease in size and a dramatic decrease in stiffness (but no statistically significant changes in stickiness) of LDL/oxLDL particles by influencing secondary/tertiary structures and lipid release detected by infrared spectral analysis and cholesterol detection, respectively. The smaller and softer characteristics of LDL/oxLDL at acidic conditions versus at the neutral pH partially explains the atherogenic role of acidification. The data may provide important information for a better understanding of LDL/oxLDL and some diseases (e.g. atherosclerosis and tumors).

China's practice to prevent and control COVID-19 in the context of large population movement.

BACKGROUND: The emerging infectious disease, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a serious threat in China and worldwide. Challenged by this serious situation, China has taken many measures to contain its transmission. This study aims to systematically review and record these special and effective practices, in hope of benefiting for fighting against the ongoing worldwide pandemic. METHODS: The measures taken by the governments was tracked and sorted on a daily basis from the websites of governmental authorities (e.g. National Health Commission of the People's Republic of China). And the measures were reviewed and summarized by categorizations, figures and tables, showing an ever-changing process of combating with an emerging infectious disease. The population shift levels, daily local new diagnosed cases, daily mortality and daily local new cured cases were used for measuring the effect of the measures. RESULTS: The practices could be categorized into active case surveillance, rapid case diagnosis and management, strict follow-up and quarantine of persons with close contacts, and issuance of guidance to help the public understand and adhere to control measures, plus prompt and effective high-level policy decision, complete activation of the public health system, and full involvement of the society. Along with the measures, the population shift levels, daily local new diagnosed cases, and mortality were decreased, and the daily local new cured cases were increased in China. CONCLUSIONS: China's practices are effective in controlling transmission of SARS-CoV-2. Considering newly occurred situations (e.g. imported cases, work resumption), the control measures may be adjusted.

Design and synthesis of robust Z-scheme ZnS-SnS2 n-n heterojunctions for highly efficient degradation of pharmaceutical pollutants: Performance, valence/conduction band offset photocatalytic mechanisms and toxicity evaluation.

Petal-like ZnS-SnS2 heterojunctions with Z-scheme band alignment were prepared by one-pot solvothermal strategy. The optimal (1:1) ZnS-SnS2 can degrade 93.46 % of tetracycline and remove 73.9 % COD of pharmaceutical wastewater under visible-light irradiation due to the efficient production of H, O2-, h+ and OH. The toxicity evaluation by ECOSAR prediction and the growth of E. coli indicates efficient toxicity reduction of tetracycline by photocatalysis and the non-toxicity of ZnS-SnS2. The attacked sites on tetracycline by reactive species were analyzed according to Fukui index, and two degradation pathways of tetracycline were inferred via the identification of intermediate products. Tetracycline degradation efficiency and the energy consumption in different water bodies were compared, and it was found that the electrical energy per order (EE/O) was the lowest in Ganjiang River. The valence band offset (ΔEVBO) and conduction band offset (ΔECBO) of ZnS-SnS2 were 1.02 eV and 0.22 eV, respectively. The probable photocatalytic mechanism of ZnS/SnS2 heterojunctions with Z-scheme band alignment based on ΔEVBO and ΔECBO was first presented.

Exogenous GM3 ganglioside inhibits atherosclerosis via multiple steps: A potential atheroprotective drug.

Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. A significant increase in ganglioside GM3 content generally happens in atherosclerotic plaques causing a GM3-enriched microenvironment. It remains unclear whether the GM3-enriched microenvironment influences atherogenesis. This study sought to answer the question by investigating exogenous GM3 effects on multiple steps involved in atherogenesis. First, the physicochemical properties of native low-density lipoprotein (LDL) and LDL enriched with exogenous GM3 (GM3-LDL) were characterized by dynamic laser scattering, atomic force microscopy, and agarose gel electrophoresis. Then, electrophoretic mobility, conjugated diene and malondialdehyde production, and amino group blockage of GM3-LDL/LDL were measured to determine LDL oxidation degrees and cellular recognition/internalization of GM3-LDL/GM3-oxLDL were detected via confocal microscopy and flow cytometry. Subsequently, influences of exogenous GM3 addition on the monocyte-adhering ability of endothelial cells and on lipid deposition in macrophages were investigated. Finally, exogenous GM3 effect on atherogenesis was evaluated using apoE-/- mice fed a high-fat diet. We found that exogenous GM3 addition increased the size, charge, and stability of LDL particles, reduced LDL susceptibility to oxidation and its cellular recognition/internalization, impaired the monocyte-adhering ability of endothelial cells and lipid deposition in macrophages. Moreover, exogenous GM3 treatment also significantly decreased blood lipid levels and atherosclerotic lesion areas in atherosclerotic mice. The data imply that exogenous GM3 had an inhibitory effect on atherogenesis, suggesting a protective role of a GM3-enriched microenvironment in atherosclerotic plaques and implying a possibility of exogenous GM3 as an anti-atherosclerotic drug.

Effects of MßCD on Lipoxygenase-Induced LDL Oxidation.

Beta-cyclodextrin (ß-CD) has been applied as drug/food carriers or potential drugs for treating some diseases. Most recently, some evidence indicated that methyl-ß-cyclodextrin (MßCD) and 2-hydroxypropyl-ß-cyclodextrin (2-HPßCD), two major derivatives of ß-CD, may inhibit atherogenesis, implying that cyclodextrins also can be potential drugs for treating atherosclerosis. It is well known that modification (e.g. oxidation) of low-density lipoprotein (LDL) is one of the most critical steps of atherogenesis. Lipoxygenase, an enzyme able to be expressed by atherosclerosis-related vascular cells, is generally regarded as a possible in vivo agent of LDL oxidation. In this study, the effects of MßCD on LDL oxidation induced by lipoxygenase were investigated by measuring the electrophoretic mobility, conjugated diene formation, malondialdehyde (MDA) production, and amino group blockage of LDL. We found that the lipids depleted from LDL by MßCD could be oxygenated more readily by lipoxygenase whereas the lipoxygenase-induced oxidation of the remaining lipid-depleted LDL decreased. The data imply that MßCD has an inhibitory effect on lipoxygenase-induced LDL oxidation and probably helps to inhibit atherogenesis.

Methyl-ß-Cyclodextrin Impairs the Monocyte-Adhering Ability of Endothelial Cells by Down-Regulating Adhesion Molecules and Caveolae and Reorganizing the Actin Cytoskeleton.

Due to its powerful ability to deplete cholesterol from the plasma membrane of cells, methyl-ß-cyclodextrin (MßCD) has been widely used as a putative research tool in cell biology. Recently, recruiting MßCD as an effective drug (e.g., antitumor drugs) has been developed. However, it remains unclear whether MßCD, when it enters the blood circulation as a drug, influences the functions of the endothelium, e.g., the adhesion of leukocytes to the endothelium. In this study, we found that MßCD can impair the adhesion of monocytes to the monolayer of endothelial cells by lowering the cell-surface adhesive force and expression of adhesion molecules and caveolae-related molecules on/in endothelial cells, and reorganizing the actin cytoskeleton of endothelial cells. The data imply that MßCD, when recruited as a drug, potentially helps to inhibit inflammation or initiation/progression of atherosclerosis since its important early step is the adhesion of circulating leukocytes (e.g., monocytes) to the endothelium.

Effects of cyclodextrins on the structure of LDL and its susceptibility to copper-induced oxidation.

Cyclodextrins (CDs) have long been widely used as drug/food carriers and were recently developed as drugs for the treatment of diseases (e.g. Niemann-Pick C1 and cancers). It is unknown whether cyclodextrins may influence the structure of low-density lipoprotein (LDL), its susceptibility to oxidation, and atherogenesis. In this study, four widely used cyclodextrins including α-CD, γ-CD, and two derivatives of ß-CD (HPßCD and MßCD) were recruited. Interestingly, agarose gel electrophoresis (staining lipid and protein components of LDL with Sudan Black B and Coomassie brilliant blue, respectively but simultaneously) shows that cyclodextrins at relatively high concentrations caused disappearance of the LDL band and/or appearance of an additional protein-free lipid band, implying that cyclodextrins at relatively high concentrations can induce significant electrophoresis-detectable lipid depletion of LDL. Atomic force microscopy (AFM) detected that MßCD (as a representative of cyclodextrins) induced size decrease of LDL particles in a dose-dependent manner, further confirming the lipid depletion effects of cyclodextrins. Moreover, the data from agarose gel electrophoresis, conjugated diene formation, MDA production, and amino group blockage of copper-oxidized LDL show that cyclodextrins can impair LDL susceptibility to oxidation. It implies that cyclodextrins probably help to inhibit atherogenesis by lowering LDL oxidation.

Imaging and force measurement of LDL and HDL by AFM in air and liquid.

The size and biomechanical properties of lipoproteins are tightly correlated with their structures/functions. While atomic force microscopy (AFM) has been used to image lipoproteins the force measurement of these nano-sized particles is missing. We detected that the sizes of LDL and HDL in liquid are close to the commonly known values. The Young's modulus of LDL or HDL is ∼0.4 GPa which is similar to that of some viral capsids or nanovesicles but greatly larger than that of various liposomes. The adhesive force of LDL or HDL is small (∼200 pN). The comparison of AFM detection in air and liquid was also performed which is currently lacking. Our data may provide useful information for better understanding and AFM detection of lipoproteins.

Fixation-induced cell blebbing on spread cells inversely correlates with phosphatidylinositol 4,5-bisphosphate level in the plasma membrane.

While most attention has been focused on physiologically generated blebs, the molecular mechanisms for fixation-induced cell blebbing are less investigated. We show that protein-fixing (e.g. aldehydes and picric acid) but not lipid-stabilizing (e.g. OsO4 and KMnO4) fixatives induce blebbing on spread cells. We also show that aldehyde fixation may induce the loss or delocalization of phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane and that the asymmetric distribution of fixation-induced blebs on spread/migrating cells coincides with that of PIP2 on the cells prefixed by lipid-stabilizing fixatives (e.g., OsO4). Moreover, fixation induces blebbing less readily on PIP2-elevated spread cells but more readily on PIP2-lowered or lipid raft-disrupted spread cells. Our data suggest that fixation-induced lowering of PIP2 level at cytoskeleton-attaching membrane sites causes bleb formation via local breakdown of the membrane-cytoskeleton coupling.

Probiotics increase T regulatory cells and reduce severity of experimental colitis in mice.

AIM: To investigate the effect of probiotics on regulating T regulatory cells and reducing the severity of experimental colitis in mice. METHODS: Forty C57/BL mice were randomly divided into four groups. Colitis was induced in the mice using 2,4,6-trinitrobenzene sulfonic acid (TNBS). After 10-d treatment with Bifico capsules (combined bifidobacterium, lactobacillus and enterococcus), body weight, colonic weight, colonic weight index, length of colon, and histological scores were evaluated. CD4+CD25+Foxp3+T cell in mesenteric lymph nodes were measured by flow cytometry, and cytokines in colonic tissue homogenates were analyzed by a cytometric bead array. RESULTS: The colonic weight index and the colonic weight of colitis mice treated with Bifico were lower than that of TNBS-induced mice without treatment. However, colonic length and percent of body weight amplification were higher than in TNBS-induced mice without treatment. Compared with TNBS-induced mice without treatment, the level of CD4+CD25+Foxp3+T cells in mesenteric lymph nodes, the expression of interleukin (IL)-2, IL-4 and IL-10 in colonic tissues from colitis mice treated with Bifico were upregulated, and tumor necrosis factor-α and interferon-γ were downregulated. CONCLUSION: Probiotics effectively treat experimental colitis by increasing CD4+CD25+Foxp3+T cell and regulating the balance of Th1 and Th2 cytokines in the colonic mucosa.