Astragaloside IV alleviates cytarabine-induced intestinal mucositis by remodeling macrophage polarization through AKT signaling.

BACKGROUND: Intestinal mucositis (IM) is one of the common side effects of chemotherapy with Cytarabine (Ara-C) and contributes to the major dose-limiting factor of chemotherapy, while the effective drug for IM is little. Astragalus, one of the main active components extrated from the roots of Astragalus membranaceus (AS-IV), is a common Chinese herbal medicine used in gastrointestinal diseases. However, the effect and mechanism of AS-IV on IM is unclear. Accumulating evidence suggests that M1 macrophages play a pivotal role in IM progression. PURPOSE: The purpose of the study was to explore the protection of AS-IV and its potential molecular mechanism on intestinal mucositis injury induced by Ara-C. METHOD: The protective effect of AS-IV was investigated in LPS-induced macrophages and Ara-C-induced intestinal mucositis mouse model. H&E, immunofluorescence and western blotting were used to evaluate the damage in different doses of Ara-C. Silencing AKT targeted by siRNA was performed to explore the potential mechanisms regulating macrophage polarization effect of Ara-C, which was investigated by CCK-8, immunofluorescence and western blotting. Flow cytometry, immunofluorescence and Western blotting were used to detect macrophage surface marker proteins and inflammatory genes to explore the potential molecular mechanism of AS-IV regulating macrophage polarization. RESULTS: The Cytarabine intervention at dose of 100mg/kg significantly induced IM in mice, with the ileum the most obvious site of injury, accompanied by decreased intestinal barrier, intestinal macrophage polarization to M1 and inflammation response. The administration of AS-IV improved weight loss, food intake, ileal morphological damage, intestinal barrier destruction and inflammatory factor release in mice induced by Ara-c, and also suppressed macrophage polarization to M1, regulating in phenotypic changes in macrophages. In vitro, the expression of M1 macrophage surface marker protein was markedly decreased in LPS-induced macrophages after silencing AKT. Similarly, the western blotting of intestinal tissues and molecular docking indicated that the key mechanisms of AS-IV were remodel AKT signaling, and finally regulating M1 macrophages and decrease inflammation response. CONCLUSION: Our study highlights that AS-IV exerts protective effect in Ara-C-induced IM through inhibit polarization to M1 macrophages based on AKT, and AS-IV may serve as a novel AKT inhibitor to counteract the intestinal adverse effects of chemotherapeutic agents.

Systematic analysis of the role and significance of target genes of active ingredients of traditional Chinese medicine injections in the progression and immune microenvironment of hepatocellular carcinoma.

Background: Traditional Chinese medicine in China is an important adjuvant therapy for the treatment of hepatocellular carcinoma (HCC) and traditional Chinese medicines injections have a wide range of clinical applications. The purpose of this study was to identify the active ingredients and related genes of traditional Chinese medicine injections that can treat hepatocellular carcinoma. Methods: Effective small molecule components were extracted from 14 types of traditional Chinese medicines from 8 injections and the main gene targets were identified. The 968 patients with HCC were classified based on the target gene set, and the characteristics of patients with different subtypes were analyzed. Patients with two subtypes of HCC were compared with normal tissues and cirrhosis to identify important gene targets related to traditional Chinese medicines in HCC progression. Results: In this study, 138 important genes associated with traditional Chinese medicines were identified and two HCC subtypes were identified. By analyzing the differences between the two subtypes, 25 related genes were associated with HCC subtypes. Through clinical and pharmacological analysis, this study identified quercetin as an important traditional Chinese medicines small molecule and secreted phosphoprotein 1 (SPP1) as an important oncogene in HCC. Conclusion: Traditional Chinese medicines injection is an important adjuvant treatment modality for HCC. SPP1 is an important oncogene in HCC.

Ambient Spray Coating of Organic-Inorganic Composite Thin Films for Perovskite Solar Cell Encapsulation.

Perovskite solar cells (PSCs) are developing rapidly in recent years, showing remarkable power conversion efficiency (PCE) of 25 %, which is comparable to crystalline silicon solar cells. However, since perovskite and other functional layers are very sensitive to the environment with high humidity, illumination, and heat, PSCs meet great challenges in device stability, which significantly limit their industrialization and commercialization. Encapsulation has become an effective strategy to enhance the stability of PSCs, and various encapsulation techniques have been developed, such as atomic layer deposition and glass-glass technology. Most of the current encapsulating methods are either time-consuming and sophisticated processes, or exhibit rigid configuration, which is unsuitable for flexible and curved devices. Here, an ambient spray coating method was developed to fabricate organic-inorganic composite film for direct encapsulation of PSCs. By systematical optimization of the film composition, thickness, and microstructures, a superhydrophobic encapsulating thin film with high compactness and homogeneity was achieved. As a result, the hybrid encapsulating film with polystyrene (PS)-4033/PS-4033-SiO2 significantly improved the stability of PSCs in humid environment (60-70 % relative humidity, 35 °C) by showing about 10 times longer lifetime than that of the unencapsulated devices, which was mainly attributed to complementary effects from the high compactness of PS and high hydrophobicity of SiO2 . This work suggests that direct deposition of organic-inorganic composite on devices as encapsulating films is an efficient strategy to enhance the device stability, and this method shows great promises of application in flexible and large-area devices.

Hyperoside protects cardiomyocytes against hypoxia­induced injury via upregulation of microRNA­138.

Following hypoxia, cardiomyocytes are susceptible to damage, against which microRNA (miR)­138 may act protectively. Hyperoside (Hyp) is a Chinese herbal medicine with multiple biological functions that serve an important role in cardiovascular disease. The aim of the present study was to investigate the role of Hyp in hypoxic cardiomyocytes and its effect on miR­138. A hypoxia model was established in both H9C2 cells and C57BL/6 mice, which were stimulated by Hyp. The expression levels of miR­138 were increased in the hypoxic myocardium in the presence of Hyp at concentrations of >50 µmol/l in vivo and >50 mg/kg in vitro. Using Cell Counting Kit­8 and 5­ethynyl­2'­deoxyuridine assays, it was observed that Hyp improved hypoxia­induced impairment of cell proliferation. Cell apoptosis was evaluated by flow cytometry and a TUNEL assay. The number of apoptotic cells in the Hyp group was lower than that in the control group. As markers of myocardial injury, the levels of lactate dehydrogenase, creatine kinase­myocardial band isoenzyme and malondialdehyde were decreased in the Hyp group compared with the control group, whereas the levels of superoxide dismutase were increased. A marked decrease in the levels of cleaved caspase­3 and cleaved poly(ADP) ribose polymerase and a marked increase in expression levels of Bcl­2 were observed in the presence of Hyp. However, miR­138 inhibition by antagomir attenuated the protective effects of Hyp. Furthermore, Hyp treatment was associated with marked downregulation of mixed lineage kinase 3 and lipocalin­2, but not pyruvate dehydrogenase kinase 1, in hypoxic H9C2 cells. These findings demonstrated that Hyp may be beneficial for myocardial cell survival and may alleviate hypoxic injury via upregulation of miR­138, thereby representing a promising potential strategy for clinical cardioprotection.

The linkage between the perception of neighbourhood and physical activity in Guangzhou, China: using street view imagery with deep learning techniques.

BACKGROUND: Neighbourhood environment characteristics have been found to be associated with residents' willingness to conduct physical activity (PA). Traditional methods to assess perceived neighbourhood environment characteristics are often subjective, costly, and time-consuming, and can be applied only on a small scale. Recent developments in deep learning algorithms and the recent availability of street view images enable researchers to assess multiple aspects of neighbourhood environment perceptions more efficiently on a large scale. This study aims to examine the relationship between each of six neighbourhood environment perceptual indicators-namely, wealthy, safe, lively, depressing, boring and beautiful-and residents' time spent on PA in Guangzhou, China. METHODS: A human-machine adversarial scoring system was developed to predict perceptions of neighbourhood environments based on Tencent Street View imagery and deep learning techniques. Image segmentation was conducted using a fully convolutional neural network (FCN-8s) and annotated ADE20k data. A human-machine adversarial scoring system was constructed based on a random forest model and image ratings by 30 volunteers. Multilevel linear regressions were used to examine the association between each of the six indicators and time spent on PA among 808 residents living in 35 neighbourhoods. RESULTS: Total PA time was positively associated with the scores for "safe" [Coef. = 1.495, SE = 0.558], "lively" [1.635, 0.789] and "beautiful" [1.009, 0.404]. It was negatively associated with the scores for "depressing" [- 1.232, 0.588] and "boring" [- 1.227, 0.603]. No significant linkage was found between total PA time and the "wealthy" score. PA was further categorised into three intensity levels. More neighbourhood perceptual indicators were associated with higher intensity PA. The scores for "safe" and "depressing" were significantly related to all three intensity levels of PA. CONCLUSIONS: People living in perceived safe, lively and beautiful neighbourhoods were more likely to engage in PA, and people living in perceived boring and depressing neighbourhoods were less likely to engage in PA. Additionally, the relationship between neighbourhood perception and PA varies across different PA intensity levels. A combination of Tencent Street View imagery and deep learning techniques provides an accurate tool to automatically assess neighbourhood environment exposure for Chinese large cities.

Al2 O3 Underlayer Prepared by Atomic Layer Deposition for Efficient Perovskite Solar Cells.

Perovskite solar cells, as an emergent technology for solar energy conversion, have attracted much attention in the solar cell community by demonstrating impressive enhancement in power conversion efficiencies. However, the high temperature and manually processed TiO2 underlayer prepared by spray pyrolysis significantly limit the large-scale application and device reproducibility of perovskite solar cells. In this study, lowtemperature atomic layer deposition (ALD) is used to prepare a compact Al2 O3 underlayer for perovskite solar cells. The thickness of the Al2 O3 layer can be controlled well by adjusting the deposition cycles during the ALD process. An optimal Al2 O3 layer effectively blocks electron recombination at the perovskite/fluorine-doped tin oxide interface and sufficiently transports electrons through tunneling. Perovskite solar cells fabricated with an Al2 O3 layer demonstrated a highest efficiency of 16.2 % for the sample with 50 ALD cycles (ca. 5 nm), which is a significant improvement over underlayer-free PSCs, which have a maximum efficiency of 11.0 %. Detailed characterization confirms that the thickness of the Al2 O3 underlayer significantly influences the charge transfer resistance and electron recombination processes in the devices. Furthermore, this work shows the feasibility of using a high band-gap semiconductor such as Al2 O3 as the underlayer in perovskite solar cells and opens up pathways to use ALD Al2 O3 underlayers for flexible solar cells.

Oxytocin is implicated in social memory deficits induced by early sensory deprivation in mice.

Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long-term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling.

Reversal of muscle atrophy by Zhimu and Huangbai herb pair via activation of IGF-1/Akt and autophagy signal in cancer cachexia.

PURPOSE: Muscle atrophy is the prominent clinical feature of cancer-induced cachexia. Zhimu and Huangbai herb pair (ZBHP) has been used since ancient China times and have been phytochemically investigated for constituents that might cause anti-cancer, diabetes, and their complication. In this study, the effects and mechanisms of ZBHP on reversal of muscle atrophy were explored. METHODS: C57BL/6 mice implanted with colon-26 adenocarcinoma were chosen to develop cancer cachexia for evaluating the effects of ZBHP on reversal of muscle atrophy. The body weight, survival time, inflammatory cytokines, and pathological changes of muscle were monitored. In addition, IGF-1/Akt and autophagy pathway members were analyzed to interpret the mechanism of drug response. RESULTS: The function and morphology of skeletal muscle in cachexia model were significantly disturbed, and the survival time was shortened. Consistently, inflammatory cytokines and muscle atrophy-related atrogin-1, MuRF1, and FOXO3 were significantly increased, and IGF-1/Akt and autophagy signal pathways were depressed. Treatment with ZBHP significantly alleviated tumor-free body weight reduction and cachexia-induced changes in cytokines and prolonged survival. ZBHP treatment not only inhibited the muscle atrophy-related genes but also activated the IGF-1/Akt and autophagy signal pathways to facilitate the protein synthesis. CONCLUSIONS: The results revealed that ZBHP treatment could inhibit the muscle atrophy induced by cancer cachexia and prolong the survival time, and ZBHP may be of value as a pharmacological alternative in treatment of cancer cachexia.

Protective effect of Suxiao jiuxin pill, a traditional Chinese medicine, against acute myocardial ischemia in dogs.

BACKGROUND: The purpose of this study was to investigate the effect of Suxiao Jiuxin Pill (SX), a traditional Chinese medicine, on acute myocardial ischemia induced by coronary occlusion in anesthetized dogs. METHODS: Acute myocardial ischemia model was established by ligating the left anterior descending artery to reduce flow by 90 %. Adult mongrel dogs were randomly divided into six groups: model, SX high dose, SX middle dose, SX low dose, Isosorbide dinitrate (ISD) and Sham groups. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate (HR), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular dP/dt, coronary blood flow (CBF), myocardial blood flow (MBF), coronary vascular resistance (CVR), and epicardial electrocardiogram (EECG). After administration with SX, changes in hemodynamics were recorded. Serum enzymes and blood gas analysis were also detected. RESULTS: SX has a dose-dependent effect on the reduction of infarct size. Besides, SX exerted a notable inhibition on the elevation of serum creatine kinase MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA), and elevation in the superoxide dismutase (SOD) activity. SX also showed a capacity to recover myocardial function by significantly reducing MAP, CVR, LVSP, left ventricular systolic pressure (LVEDP), systolic blood pressure (SBP), diastolic blood pressure (SDP), and increasing CBF and myocardial blood flow (MBF). In addition, SX high dose group markedly reduced total mV of ST segment elevation (Σ-ST), total number of sites with this degree of ST segment elevation (N-ST) and oxygen extraction ratio (O2 Extr). CONCLUSION: SX can improve hemodynamic and myocardial oxygen metabolism, reduce the degree and scope of myocardial ischemia, and hence exert notable anti-anginal ischaemic effect.

Reversal of muscle atrophy by Zhimu-Huangbai herb-pair via Akt/mTOR/FoxO3 signal pathway in streptozotocin-induced diabetic mice.

Skeletal muscle atrophy is one of the serious complications of diabetes. Zhimu-Huangbai herb-pair (ZB) is widely used in Chinese traditional medicine formulas for treating Xiaoke (known as diabetes) and its complications. However, the effect of ZB on reversal of muscle atrophy and the underlying mechanisms remain unknown. In this research, we investigated the effect and possible mechanisms of ZB on skeletal muscle atrophy in diabetic mice. Animal model of diabetic muscle atrophy was developed by high fat diet (HFD) feeding plus streptozotocin (STZ) injection. After oral adminstration of ZB for 6 weeks, the effects of ZB on reversal of muscle atrophy and the underlying mechanisms were evaluated by biochemical, histological and western blot methods. The skeletal muscle weight, strength, and cross-sectional area of diabetic mice were significantly increased by ZB treatment. Biochemical results showed that ZB treatment reduced the serum glucose level, and elevated the serum insulin-like growth factor 1 (IGF-1) and insulin levels significantly compared with untreated diabetic group. The western blot results showed that ZB activated the mTOR signal pathway, shown as increased phosphorylations (p-) of Akt, mTOR, Raptor, S6K1 and reduced Foxo3 expression compared with the model group. ZB could reverse muscle atrophy in diabetic mice. This may be through activation of mTOR signaling pathway that promotes protein synthesis, and inactivation foxo3 protein that inhibits protein degradation. These findings suggested that ZB may be considered as a potential candidate drug in treatment of diabetic muscle atrophy.

Suxiaojiuxin pill enhances atherosclerotic plaque stability by modulating the MMPs/TIMPs balance in ApoE-deficient mice.

: Suxiaojiuxin pill (SX) is a famous Chinese formulated product, which has been used to treat coronary heart disease and angina pectoris in China. This study was carried out to investigate the effect and possible mechanism of SX on the stability of atherosclerotic plaque in ApoE-deficient mice. ApoE-/- mice of 6-8 weeks old were fed with high-fat diet for developing artherosclerosis. After oral administration of SX for 8 weeks, histopathology of aortic plaque was performed by Sudan III and hematoxylin-eosin staining, and muscle protein was detected by Western blotting (WB). The mRNA and proteins associated with aortic plaque stability were detected by reverse transcription-polymerase chain reaction and WB, respectively. SX treatment could not only reduce serum triglyceride level and plaque area but also increase fibrous cap thickness and collagen content compared with the model group. WB results showed that SX could increase α-smooth muscle actin, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 protein expression, whereas decrease matrix metalloproteinase 2 (MMP-2) and MMP-9 protein expression. Moreover, SX could upregulate the expression of α-smooth muscle actin mRNA and downregulate the expression of vascular endothelial growth factor mRNA. These results showed that SX could enhance atherosclerotic plaque stability in ApoE-deficient mice. The mechanism may be associated with modulating the MMPs/TIMPs balance.

Direct stimulation of adult neural stem/progenitor cells in vitro and neurogenesis in vivo by salvianolic acid B.

BACKGROUND: Small molecules have been shown to modulate the neurogenesis processes. In search for new therapeutic drugs, the herbs used in traditional medicines for neurogenesis are promising candidates. METHODOLOGY AND PRINCIPAL FINDINGS: We selected a total of 45 natural compounds from Traditional Chinese herbal medicines which are extensively used in China to treat stroke clinically, and tested their proliferation-inducing activities on neural stem/progenitor cells (NSPCs). The screening results showed that salvianolic acid B (Sal B) displayed marked effects on the induction of proliferation of NSPCs. We further demonstrated that Sal B promoted NSPCs proliferation in dose- and time-dependent manners. To explore the molecular mechanism, PI3K/Akt, MEK/ERK and Notch signaling pathways were investigated. Cell proliferation assay demonstrated that Ly294002 (PI3K/Akt inhibitor), but neither U0126 (ERK inhibitor) nor DAPT (Notch inhibitor) inhibited the Sal B-induced proliferation of cells. Western Blotting results showed that stimulation of NSPCs with Sal B enhanced the phosphorylation of Akt, and Ly294002 abolished this effect, confirming the role of Akt in Sal B mediated proliferation of NSPCs. Rats exposed to transient cerebral ischemia were treated for 4 weeks with Sal B from the 7th day after stroke. BrdU incorporation assay results showed that exposure Sal B could maintain the proliferation of NSPCs after cerebral ischemia. Morris water maze test showed that delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. SIGNIFICANCE: Sal B could maintain the NSPCs self-renew and promote proliferation, which was mediated by PI3K/Akt signal pathway. And delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. These findings suggested that Sal B may act as a potential drug in treatment of brain injury or neurodegenerative diseases.

Synthesis and antihyperlipidemic activity of acetylated derivative of ulvan from Ulva pertusa.

In this study, acetylated ulvan (AU) was prepared with acetic anhydride in N,N-dimethylacetamide, and the antihyperlipidemic activity of natural ulvan and its acetylated ulvan derivative (AU) in mice was determined. Obvious differences in antihyperlipidemic activity between natural ulvan and its derivative were observed, moreover, AU showed stronger antihyperlipidemic activity on triglyceride (TG) and low density lipoprotein cholesterol (LDL-C).

[Anti-tumor effect of ethanol extracts from Thymus quinquecostatus Celak on human leukemia cell line].

OBJECTIVE: To screen the anti-tumor fraction of ethanol extracts from Thymus quinquecostatus Celak and investigate its anti-tumor effect on human leukemia cell line. METHODS: Ethyl acetate, n-butanol and acetone fractions were separated from the ethanol extracts of wild Thymus quinquecostatus Celak. Growth inhibiting effects of these extracts on human leukemia cell lines K562 and HL-60 were determined by live cell counting and cell growth curve analysis. The possible anti-tumor mechanism was studied by morphological analysis with norcantharidin as a positive control. RESULTS: Ethyl acetate fraction could significantly inhibit the proliferations of K562 and HL-60 cells, and the inhibiting effect depended on the concentration of ethyl acetate fraction. Ethyl acetate fraction could induce apoptosis of K562 and HL-60 cells. The n-butanol and acetone fractions had no significant inhibiting effect on K562 and HL-60 cells. CONCLUSION: Ethyl acetate fraction is the major anti-tumor fraction in ethanol extracts from Thymus quinquecostatus Celak.

[Original studies on anti-tumor and immunological effect of extracts from Thymus quinquecostatus Celak in mice].

OBJECTIVE: To study the anti-tumor and immunological effect of extracts from Thymus quinquecostatus Celak on mice transplanted S180 tumor cells. METHODS: Different doses of volatile oil and alcohol extracted substances from Thymus quinquecostatus Celak were given to mice bearing S180 tumor for 9 days. Tumor inhibition rates and coefficients of spleen and thymus were determined. RESULTS: Tumor inhibition rates of the groups with alcohol extracts (40 g crude drug.kg(-1).d(-1) and 20 g crude drug.kg(-1).d(-1)) were 51.5% (P<0.01) and 36.4% (P<0.05) respectively, and those of the groups with volatile oil (40 g crude drug.kg(-1).d(-1) and 20 g crude drug.kg(-1).d(-1))were both 39.4% (P<0.05). CONCLUSION: The extracts from Thymus quinquecostatus Celak have anti-tumor activities. The coefficient of spleen in group with alcohol extracts (40 g crude drug.kg(-1).d(-1))was close to normal value, and its coefficient of thymus was between that of the negative control group and the group with cyclophosphamide (0.02 g.kg(-1).d(-1)). The anti-tumor activity of the alcohol extracts was significantly higher than that of the control group and the tumor inhibition rate was depending on drug concentration. Depending on index of immunity,the extracts from Thymus quinquecostatus Celak may have some influences on immunity.