LPA2 Alleviates Septic Acute Lung Injury via Protective Endothelial Barrier Function Through Activation of PLC-PKC-FAK.

Background: Increased endothelial permeability of pulmonary vessels is a primary pathological characteristic of septic acute lung injury (ALI). Previously, elevated lysophosphatidic acid (LPA) levels and LPA2 (an LPA receptor) expression have been found in the peripheral blood and lungs of septic mice, respectively. However, the specific role of LPA2 in septic ALI remains unclear. Methods: A lipopolysaccharide (LPS)-induced model of sepsis was established in wild-type (WT) and global LPA2 knockout (Lpar2-/-) mice. We examined mortality, lung injury, assessed endothelial permeability through Evans blue dye (EBD) assay in vivo, and transendothelial electrical resistance (TEER) of mouse lung microvascular endothelial cells (MLMECs) in vitro. Enzyme-linked immunosorbent assay (ELISA), histopathological, immunofluorescence, immunohistochemistry, and Western blot were employed to investigate the role of LPA2 in septic ALI. Results: Lpar2 deficiency increased vascular endothelial permeability, impaired lung injury, and increased mortality. Histological examination revealed aggravated inflammation, edema, hemorrhage and alveolar septal thickening in the lungs of septic Lpar2-/- mice. In vitro, loss of Lpar2 resulted in increased permeability of MLMECs. Pharmacological activation of LPA2 by the agonist DBIBB led to significantly reduced inflammation, edema and hemorrhage, as well as increased expression of the vascular endothelial tight junction (TJ) protein zonula occludens-1 (ZO-1) and claudin-5, as well as the adheren junction (AJ) protein VE-cadherin. Moreover, DBIBB treatment was found to alleviate mortality by protecting against vascular endothelial permeability. Mechanistically, we demonstrated that vascular endothelial permeability was alleviated through LPA-LPA2 signaling via the PLC-PKC-FAK pathway. Conclusion: These data provide a novel mechanism of endothelial barrier protection via PLC-PKC-FAK pathway and suggest that LPA2 may contribute to the therapeutic effects of septic ALI.

The generation of 5-N-glycolylneuraminic acid as a consequence of high levels of reactive oxygen species.

The presence of N-glycolylneuraminic acid (Neu5Gc), a non-human sialic acid in cancer patients, is currently attributed to the consumption of red meat. Excess dietary red meat has been considered a risk factor causing chronic inflammation and for the development of cancers. However, it remains unknown whether Neu5Gc can be generated via a chemical reaction rather than via a metabolic pathway in the presence of high levels of reactive oxygen species (ROS) found in the inflammatory and tumor environments. In this study, the conversion of N-acetylneuraminic acid (Neu5Ac) to Neu5Gc has been assessed in vitro under conditions mimicking the hydroxyl radical-rich humoral environment found in inflammatory and cancerous tissues. As a result, Neu5Gc has been detected via liquid chromatography-multiple reaction monitoring mass spectrometry. Furthermore, this conversion has also been found to take place in serum biomatrix containing ROS and in cancer cell cultures with induced ROS production.

Deep Learning Based Real-Time Semantic Segmentation of Cerebral Vessels and Cranial Nerves in Microvascular Decompression Scenes.

Automatic extraction of cerebral vessels and cranial nerves has important clinical value in the treatment of trigeminal neuralgia (TGN) and hemifacial spasm (HFS). However, because of the great similarity between different cerebral vessels and between different cranial nerves, it is challenging to segment cerebral vessels and cranial nerves in real time on the basis of true-color microvascular decompression (MVD) images. In this paper, we propose a lightweight, fast semantic segmentation Microvascular Decompression Network (MVDNet) for MVD scenarios which achieves a good trade-off between segmentation accuracy and speed. Specifically, we designed a Light Asymmetric Bottleneck (LAB) module in the encoder to encode context features. A Feature Fusion Module (FFM) was introduced into the decoder to effectively combine high-level semantic features and underlying spatial details. The proposed network has no pretrained model, fewer parameters, and a fast inference speed. Specifically, MVDNet achieved 76.59% mIoU on the MVD test set, has 0.72 M parameters, and has a 137 FPS speed using a single GTX 2080Ti card.

Lysophosphatidic Acid Receptor 3 Suppress Neutrophil Extracellular Traps Production and Thrombosis During Sepsis.

Sepsis consists of life-threatening organ dysfunction resulting from a dysregulated response to infection. Recent studies have found that excessive neutrophil extracellular traps (NETs) contribute to the pathogenesis of sepsis, thereby increasing morbidity and mortality. Lysophosphatidic acid (LPA) is a small glycerophospholipid molecule that exerts multiple functions by binding to its receptors. Although LPA has been functionally identified to induce NETs, whether and how LPA receptors, especially lysophosphatidic acid receptor 3 (LPA3), play a role in the development of sepsis has never been explored. A comprehensive understanding of the impact of LPA3 on sepsis is essential for the development of medical therapy. After intraperitoneal injection of lipopolysaccharide (LPS), Lpar3-/-mice showed a substantially higher mortality, more severe injury, and more fibrinogen content in the lungs than wild-type (WT) mice. The values of blood coagulation markers, plasma prothrombin time (PT) and fibrinogen (FIB), indicated that the Lpar3-/- mice underwent a severe coagulation process, which resulted in increased thrombosis. The levels of NETs in Lpar3-/- mice were higher than those in WT mice after LPS injection. The mortality rate and degree of lung damage in Lpar3-/- mice with sepsis were significantly reduced after the destruction of NETs by DNaseI treatment. Furthermore, in vitro experiments with co-cultured monocytes and neutrophils demonstrated that monocytes from Lpar3-/- mice promoted the formation of NETs, suggesting that LPA3 acting on monocytes inhibits the formation of NETs and plays a protective role in sepsis. Mechanistically, we found that the amount of CD14, an LPS co-receptor, expressed by monocytes in Lpar3-/-mice was significantly elevated after LPS administration, and the MyD88-p65-NFκB signaling axis, downstream of toll-like receptor 4 signaling, in monocytes was overactivated. Finally, after an injection of the LPA3 agonist (2S)-1-oleoyl-2-methylglycero-3-phosphothionate (OMPT), the survival rate of mice with sepsis was improved, organ damage was reduced, and the production of NETs was decreased. This suggested the possible translational value and application prospects of (2S)-OMPT in the treatment of sepsis. Our study confirms an important protective role of LPA3 in curbing the development of sepsis by suppressing NETs production and thrombosis and provides new ideas for sepsis treatment strategies.

SL-HarDNet: Skin lesion segmentation with HarDNet.

Automatic segmentation of skin lesions from dermoscopy is of great significance for the early diagnosis of skin cancer. However, due to the complexity and fuzzy boundary of skin lesions, automatic segmentation of skin lesions is a challenging task. In this paper, we present a novel skin lesion segmentation network based on HarDNet (SL-HarDNet). We adopt HarDNet as the backbone, which can learn more robust feature representation. Furthermore, we introduce three powerful modules, including: cascaded fusion module (CFM), spatial channel attention module (SCAM) and feature aggregation module (FAM). Among them, CFM combines the features of different levels and effectively aggregates the semantic and location information of skin lesions. SCAM realizes the capture of key spatial information. The cross-level features are effectively fused through FAM, and the obtained high-level semantic position information features are reintegrated with the features from CFM to improve the segmentation performance of the model. We apply the challenge dataset ISIC-2016&PH2 and ISIC-2018, and extensively evaluate and compare the state-of-the-art skin lesion segmentation methods. Experiments show that our SL-HarDNet performance is always superior to other segmentation methods and achieves the latest performance.

Analysis of Glycemic Improvement in Hemodialysis Patients Based on Time in Range, Assessed by Flash Glucose Monitoring.

INTRODUCTION: This study aimed to investigate the application value of "time in ranges (TIRs)" in dialysis patients with diabetes and summarize the experience of optimizing glycemic control by flash glucose monitoring (FGM) system. METHODS: In this monocentric 2-week pilot study, FGM was applied for 14 days in 57 type 2 diabetes mellitus medically stable patients under maintenance hemodialysis to determine their glycemic improvement. The diagnostic value of TIR versus HbA1c in detecting glucose fluctuations and levels was evaluated using receiver operating characteristic analysis. RESULTS: Average glucose exhibited stronger association with TIR (r = -0.785, p < 0.001) than HbA1c (r = 0.644, p < 0.001), and mean amplitude of glycemic excursion (MAGE) had the same conclusion (r = -0.568, p < 0.001 for TIR vs. r = 0.423, p = 0.016 for HbA1c). TIR exhibited a higher area under curve than HbA1c in detecting significant derangements in glucose fluctuation, using a 14-day average FGM-derived coefficient of variation >36% as the reference standard (difference between areas: 0.237; 95% CI 0.092-0.383, p = 0.001). We found a significant improvement in TIR (58.38 ± 19.42 vs. 46.45 ± 24.42 mmol/L, p < 0.001) and a significant decline in MAGE (median 5.64 vs.7.42 mmol/L, p < 0.001) compared to the baseline without deterioration of time spent in hypoglycemia. CONCLUSION: TIR seems to be feasible and clinically useful for AGP analysis in dialysis patients with diabetes, and FGM can be used to improve glycemic control.

Deep Neural Network-Based Semantic Segmentation of Microvascular Decompression Images.

Image semantic segmentation has been applied more and more widely in the fields of satellite remote sensing, medical treatment, intelligent transportation, and virtual reality. However, in the medical field, the study of cerebral vessel and cranial nerve segmentation based on true-color medical images is in urgent need and has good research and development prospects. We have extended the current state-of-the-art semantic-segmentation network DeepLabv3+ and used it as the basic framework. First, the feature distillation block (FDB) was introduced into the encoder structure to refine the extracted features. In addition, the atrous spatial pyramid pooling (ASPP) module was added to the decoder structure to enhance the retention of feature and boundary information. The proposed model was trained by fine tuning and optimizing the relevant parameters. Experimental results show that the encoder structure has better performance in feature refinement processing, improving target boundary segmentation precision, and retaining more feature information. Our method has a segmentation accuracy of 75.73%, which is 3% better than DeepLabv3+.

Anaerobic co-digestion of corn stover and chicken manure using continuous stirred tank reactor: The effect of biochar addition and urea pretreatment.

The performance of biochar mediated anaerobic co-digestion (co-AD) of corn stover (CS) and chicken manure (CM) using continuous stirred tank reactor (CSTR) was studied. Results showed that urea pretreated CS (UPCS) and biochar addition in anaerobic digestion (AD) system can improve co-AD. The effect of urea pretreatment is similar to that of biochar addition, and their synergistic effect was apparent under medium and high OLR conditions. When the OLR was 4.2 and 6.3 g VS/L/d, the biochar mediated UPCS/CM co-AD operated stably with the VMP of 2.160 and 1.616 L/L/d, and VMP of the biochar mediated UPCS /CM were 32.8%-89.6% and 27.8%-96.4% higher than other reactors, respectively. The results reveal that urea pretreatment and biochar addition promoted AD process through strengthening the buffer capacity system established by ammonia nitrogen and volatile fatty acids and improving the degradation of lignocellulosic biomass.

Male social rank and food competition in a primate multi-level society.

OBJECTIVES: Social animals often have dominance hierarchies, with high rank conferring preferential access to resources. In primates, competition among males is often assumed to occur predominantly over reproductive opportunities. However, competition for food may occur during food shortages, such as in temperate species during winter. Higher-ranked males may thus gain preferential access to high-profitability food, which would enable them to spend longer engaged in activities other than feeding. MATERIALS AND METHODS: We performed a field experiment with a breeding band of golden snub-nosed monkeys, a species that lives in a multi-level society in high-altitude forests in central China. We provisioned monkey's high-profitability food during winter when natural foods are limited, and then recorded the times individual adult males spent engaged in different behaviors. RESULTS: Higher-ranking males spent less time feeding overall and fed on provisioned foods at a higher rate than lower-ranking males. Higher-ranking males therefore had more time to spend on alternative behaviors. We found no significant difference according to rank in times spent moving or resting. However, high-ranking males spend significantly longer on affiliative behaviors with other members of their social sub-units, especially grooming and being groomed, behaviors known to promote social cohesion in primates. DISCUSSION: We show that preferential access to high-profitability foods likely relaxes time-budget constraints to higher-ranking males. High-ranking males thus spend more time on non-feeding activities, especially grooming, which may enhance social cohesion within their social sub-unit. We discuss the potential direct and indirect benefits to high-ranking males associated with preferential access to high-value food during winter.

Hydrogen Sulfide Promotes Cardiomyocyte Proliferation and Heart Regeneration via ROS Scavenging.

Neonatal mouse hearts can regenerate completely in 21 days after cardiac injury, providing an ideal model to exploring heart regenerative therapeutic targets. The oxidative damage by Reactive Oxygen Species (ROS) is one of the critical reasons for the cell cycle arrest of cardiomyocytes (CMs), which cause mouse hearts losing the capacity to regenerate in 7 days or shorter after birth. As an antioxidant, hydrogen sulfide (H2S) plays a protective role in a variety of diseases by scavenging ROS produced during the pathological processes. In this study, we found that blocking H2S synthesis by PAG (H2S synthase inhibitor) suspended heart regeneration and CM proliferation with ROS deposition increase after cardiac injury (myocardial infarction or apex resection) in 2-day-old mice. NaHS (a H2S donor) administration improved heart regeneration with CM proliferation and ROS elimination after myocardial infarction in 7-day-old mice. NaHS protected primary neonatal mouse CMs from H2O2-induced apoptosis and promoted CM proliferation via SOD2-dependent ROS scavenging. The oxidative DNA damage in CMs was reduced with the elimination of ROS by H2S. Our results demonstrated for the first time that H2S promotes heart regeneration and identified NaHS as a potent modulator for cardiac repair.

The expression and functional analysis of the sialyl-T antigen in prostate cancer.

Aberrant glycosylation is a featured characteristic of cancer and plays a role in cancer pathology; thus an understanding of the compositions and functions of glycans is critical for discovering diagnostic biomarkers and therapeutic targets for cancer. In this study, we used MALDI-TOF-MS analysis to determine the O-glycan profiles of prostate cancer cells metastasized to bone (PC-3), brain (DU145), lymph node (LNCaP), and vertebra (VCaP) in comparison to immortalized RWPE-1 cells derived from normal prostatic tissue. Prostate cancer (CaP) cells exhibited an elevation of simple/short O-glycans, with a reduction of complex O-glycans, increased O-glycan sialylation and decreased fucosylation. Core 1 sialylation was increased dramatically in all CaP cells, and especially in PC-3 cells. The expression of Neu5Acα2-3Galß1-3GalNAc- (sialyl-3T antigen) which is the product of α2,3-sialyltransferase-I (ST3Gal-I) was substantially increased. We therefore focused on exploring the possible function of ST3Gal-I in PC-3 cells. ST3Gal-I silencing studies showed that ST3Gal-I was associated with PC-3 cell proliferation, migration and apoptosis. Further in vivo studies demonstrated that down regulation of ST3Gal-I reduced the tumor size in xenograft mouse model, indicating that sialyl-3T can serve as a biomarker for metastatic prostate cancer prognosis, and that ST3Gal-I could be a target for therapeutic intervention in cancer treatment.

Meconopsis horridula Hook. f. & Thomson extract and its alkaloid oleracein E exert cardioprotective effects against acute myocardial ischaemic injury in mice.

Meconopsis horridula Hook. f. & Thomson (MH) is a traditional Tibetan medicine used to promote blood circulation, remove bruises, remove stasis and relieve chest pain which benefit to cardiovascular diseases. Oleracein E (OE), a major tetrahydroisoquinoline alkaloid, can be isolated from MH ethanol extract. The antioxidant and anti-apoptotic effects of OE have been reported by previous pharmacological research. The objective of this article was to investigate the cardioprotective effects of MH extract and OE in an ICR mouse of acute myocardial ischaemic injury. A left anterior descending (LAD) artery ligation mouse model of AMI was established. In vivo, cardiac function after MH and OE treatment was determined through measurement of EF, FS, LVEDd, and LVEDs by echocardiography. The levels of SOD, MDA, CK-MB and LDH in serum were also detected. A TUNEL assay was used to verify apoptosis. Changes in collagen deposition and inflammatory cell infiltration in ischemic myocardial tissue were observed by histopathological examination. In vitro, H9c2 cells were pre-treated with OE for 6 h, and then cultured in serum-free medium with H2O2 for 2 h. CCK8 assay measured cell viability, and flow cytometry determined apoptosis levels and ROS content. The mechanism was explored by western blotting. These results showed that MH and OE significantly affected acute myocardial ischaemia by improving cardiac function and that OE downregulated the expression of related proteins in the MAPK signalling pathway. These findings provide substantial evidence of MH may applicate in clinic, and indicate that such medicines have potential value for the treatment of ischaemia-induced heart disease.

N-Butyrylated hyaluronic acid ameliorates gout and hyperuricemia in animal models.

Context: Hyaluronic acid (HA) plays critical roles in the structural skeleton, joint lubrication, renal function and cell signaling. We previously showed that partially N-butyrylated, low molecular weight, hyaluronic acid (BHA) exhibited an anti-inflammatory effect in cultured human macrophage, where inflammation was induced either by a TL-4 agonist or the low molecular weight HA itself, in dose-dependent fashion. Objectives: To investigate the anti-inflammatory, antioxidative, and antihyperuricemic effects of BHA using animal models of acute gouty arthritis and hyperuricemia. Materials and methods: The anti-inflammatory effect of articular BHA (10 and 50 µg) injections was evaluated by measuring joint swelling and the serum levels of inflammatory cytokines in a model of acute gouty arthritis induced by intra-articular injection of monosodium urate crystals in Wistar rats (n = 10/group), in comparison to the control group with saline injection. Antioxidative and antihyperuricemic activities were investigated using intraperitoneal injections of oteracil potassium and yeast extract hyperuricemic Balb/C mice, which were treated with intraperitoneal injection of BHA at day 6-8 in the model. Results: In the gouty arthritis rat model, BHA at a higher dosage (50 µg) demonstrated a strong anti-inflammatory effect by reducing the degree of articular swelling and the serum levels of IL-1ß, IL-8, IFN-γ, and MCP-1 by 5.56%, 6.55%, 15.58% and 33.18%. In the hyperuricemic mouse model, lower dosage BHA (10 µg) was sufficient to provide antioxidative activities by significantly decreasing the ROS levels in both serum and liver by 14.87% and 8.04%, while improving liver SOD by 12.77%. Intraperitoneal injection of BHA suppressed uric acid production through reducing liver XO activity by 19.78% and decreased the serum uric acid level in hyperuricemic mice by 30.41%. Conclusions: This study demonstrated for the first time that BHA exhibits anti-inflammatory, antioxidative and antihyperuricemic effects in vivo, suggesting a potential therapeutic application of BHA in gouty arthritis and hyperuricemia.

Enhanced Platelet Response to Clopidogrel in Zucker Diabetic Fatty Rats due to Impaired Clopidogrel Inactivation by Carboxylesterase 1 and Increased Exposure to Active Metabolite.

Clopidogrel (Clop), a thienopyridine antiplatelet prodrug, is metabolized by cytochrome P450s (CYPs) to an active metabolite, Clop-AM, and hydrolyzed by carboxylesterase (CES)1 to the inactive Clop-acid. Patients with type 2 diabetes (T2DM) tend to have a poor response to Clop due to reduced generation of Clop-AM. Whether a similar response occurs in the Zucker diabetic fatty (ZDF) rat, a commonly used animal model of T2DM, has not been explored. In this work, we compared ZDF and control rats for hepatic CES1- and CYP-mediated Clop metabolism; pharmacokinetics of Clop, Clop-AM, and Clop-acid; and the antiplatelet efficacy of Clop. In contrast to clinical findings, Clop-treated ZDF rats displayed significantly less (50%) maximum platelet aggregation at 4 hours than control rats; the enhanced efficacy was accompanied by higher formation of Clop-AM and lower formation of Clop-acid. In vitro studies showed that hepatic levels of CES1 protein and activity and Ces1e mRNA were significantly lower in ZDF than in control rats, as were the mRNA levels of CYP2B1/2, CYP2C11, and CYP3A2, and levels of CYP2B6-, CYP2C19-, and CYP3A4-related proteins and enzymatic activities in liver microsomes of ZDF rats. Interestingly, liver microsomes of ZDF rats produced higher levels of Clop-AM than that of control rats despite their lower CYP levels, although the addition of fluoride ion, an esterase inhibitor, enhanced Clop-AM formation in control rats more than in ZDF rats. These results suggest that the reduction in CES1-based Clop inactivation indirectly enhances Clop efficacy in ZDF rats by making more Clop available for CYP-mediated Clop-AM formation.

[Advance of a representative traditional Tibetan medicine Meconopsis horridula on its phytochemical and pharmacological aspects].

Meconopsis horridula is one of alpine plants belonging to family Papaveraceae, mainly distributed in Himalaya Range area. M. horridula is a rare alpine flower, and is a kind of traditional Tibetan medicine, which has been included in more than 40 compound formulae, having efficacies of clearing away heat and alleviating pain, activating blood circulation to remove stasis, traditionally used for the treatment of fractures, injuries, and chest and back pains. Modern research shows that the whole plant of M. horridula contains alkaloids, flavonoids, and terpenes, and its pharmacological activities including antitumor, antivirus and myocardial protection etc. However, due to various factors, the current research of M.horridula still faces many challenges. This paper summaries herein a progress of MH on its ecological resources, traditional uses, and studies on chemical constituents and pharmacological effects, hopefully to provide a useful reference for the ecological protection and applications.

[A new lignan from stem bark of Syringa pinnatifolia].

One new lignan, named Z-pinnatifolin A, along with ten known analogues, were isolated from the stem bark of Syringa pinnatifolia by various chromatographic methods. Their structures were extensively determined on basis of MS and NMR spectroscopic data analyses, and comparison with those in literature. Among them, compounds 3,4, and 8-11 were isolated from this genus for the first time, and 5-7 were isolated from the specie for the first time. Compound 1 showed a moderate inhibition on NO production in BV-2 cells. The present study provides a preliminary data for clarification of bioactive ingredients of S.pinnatifolia with anti-myocardial ischemic effect.

Corydalis hendersonii Hemsl. protects against myocardial injury by attenuating inflammation and fibrosis via NF-κB and JAK2-STAT3 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Corydalis hendersonii Hemsl. (CH) with heat clearing and detoxifying effects are well described in Tibetan folk medicine. It has been used for centuries in China largely for the treatment of high altitude polycythemia, a pathophysiological condition referred to "plethora" in Tibetan medicine, hypertension, hepatitis, edema, gastritis, and other infectious diseases. AIM OF THE STUDY: To investigate the cardioprotective effects of Corydalis hendersonii extract in an ICR mouse model of myocardial ischemic injury. MATERIALS AND METHODS: Ethanol [85% (v/v)] extract of CH whole plant was prepared, and their chemical profile was analyzed with use of HPLC-DAD and IT-TOF-ESI-MS. A mouse model of AMI was established by ligation of the left ventricular dysfunction (LAD) coronary artery. Mice were randomly divided into six groups (n = 12 per group): sham group, model group, CH groups treated with three doses of CH (100, 200, and 400mg/kg, intragastric), and a positive control group (captopril, 16.67mg/kg, intragastric). Heart function was evaluated by measurement of ejection fraction (EF) and fractional shortening (FS) by echocardiography. Serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), plasma levels of angiotensin II (AngII), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the cardiac tissue homogenate, protein expressions of signal-transduction proteins, p65, IκBα, JAK2, and STAT3 in heart tissues were measured by ELISA and Western blot analyses. Inflammatory cell infiltration and changes in collagen deposition in the myocardial ischemic heart tissues were observed by histopathological examination. Platelet aggregation in vitro was also assessed. RESULTS: CH treatment showed a dose-dependent cardioprotective effect. It significantly reduced left ventricular end-diastolic diameter (LVEDd) and left ventricular end-diastolic diameter (LVEDs), improved EF and FS as compared to those in the model group; attenuated the increase levels of CK-MB and LDH in serum; reduced expressions of AngII, TNF-α, IL-6 and IL-1ß in plasma, MMP-2 and MMP-9 expressions in the cardiac tissue homogenate; and down-regulated myocardial expressions of p-p65, p-IκBα, p-JAK2, p-STAT3, MMP-2, and MMP-9 in AMI mice. Also, an obvious reduction in inflammatory cell infiltration in the myocardial infarct was found in all CH treated groups. Besides, CH also inhibited platelet aggregation induced by THR, ADP, and AA. CONCLUSION: CH extract exerted a protective effect against myocardial ischemic injury via inhibition of inflammation, myocardial fibrosis, and platelet aggregation. This study demonstrates such protection for the first time and provides a basis for development of CH-based drugs for treatment of ischemic heart disease in clinical settings.

Anti-Proliferative Effect of Triterpenoidal Glycosides from the Roots of Anemone vitifolia through a Pro-Apoptotic Way.

A cytotoxicity-guided phytochemical investigation of Anemone vitifolia roots led to the isolation of six oleanane saponins (1-6), which were reported from the species for the first time. Their structures were determined by comparing its MS and NMR data with those in literature. Compounds 1-4 showed significant inhibitory effects on the proliferation of hepatocellular carcinoma HepG2 cells with IC50 values ranging from 2.0 to 8.5 µM, compared to positive control methotrexate with IC50 value of 15.8 µM. Flow cytometry analysis revealed that compounds 1-4 exerted anti-proliferative effects through a pro-apoptotic way of hepatocellular carcinoma cells.

Lignans from the stem bark of Syringa pinnatifolia.

Four new lignans, alashinols A-D (1-4), a new hydrolysis product, alashinols E (5), and seven known analogues were isolated from the stem bark of Syringa pinnatifolia Hemsl. These new lignans were characterized using 1D and 2D NMR and MS data, and their absolute configurations were determined by experimental and calculated electronic circular dichroism and X-ray diffraction analyses. Alashinol B (2) exhibited two conformers that adopted an unusual unit cell packing. Anti-inflammatory evaluation revealed that compounds 1, 4, 6, and 8 showed moderate inhibition against NO production in lipopolysaccharide-induced macrophages RAW 264.7 cells with IC50 values range from 43.3-60.9µM, and 1 decreased the TNF-α and IL-6 level in a concentration-dependent manner at 40-160µM and exhibited considerable neuroprotective effect against the glutamate-induced injury in PC12 cell line. Analogues 3 and 9 showed protective effects against oxygen glucose deprivation/reoxygenation in H9c2 cells.

Anti-myocardial ischemia effect of Syringa pinnatifolia Hemsl. by inhibiting expression of cyclooxygenase-1 and -2 in myocardial tissues of mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The peeled stem of Syringa pinnatifolia Hemsl. (SP) is a traditional medicine in Inner Mongolia, China. The powder form of SP has been widely used for hundreds of years to relieve "He-Yi" related myocardial ischemia independently or in a traditional Chinese medicine preparation. MATERIALS AND METHODS: SP was extracted with 95% and 80% ethanol. Chemical profiling was performed using HPLC-DAD and IT-TOF-ESI-MS analyses. Myocardial ischemia was produced by ligation of the left anterior descending (LAD) coronary artery to evaluate the anti-myocardial ischemia effect of SP. Male C57BL/6 mice were randomly divided into six groups (n=10 per group): a sham group, a model group, groups pretreated with SP at three dosages (20mg/kg, 40mg/kg, and 80mg/kg, intragastrically), and a positive control group (acetylsalicylic acid, ASA, 53mg/kg, intragastrically). Echocardiography was performed to determine heart function by measuring ejection fraction and fractional shortening. The levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in serum, and 6-keto-PGF1α and TXB2 both in plasma and in protein homogenate of myocardial tissue were also measured. The levels of cyclooxygenase (COX)-1 and -2 in the heart tissue and their expressions in mouse myocardial tissue were determined using Western blot and an immunofluorescence assay, respectively. Inflammatory cell infiltration and collagen deposition changes in the myocardial ischemic tissue were observed by pathological examination. RESULTS: Intragastric pretreatment with SP produced a dose-dependent increase in cardiac function. SP at 80mg/kg significantly improved the EF (p<0.001) and FS (p<0.01) compared with the model group, as well as the levels of serum CK-MB and LDH decreased obviously (p<0.001), approaching those in the sham group. Besides, an obvious reduction in inflammatory cells infiltration and collagen deposition in the infarcted myocardial tissue was shown in each SP treatment group. In addition, SP increased 6-keto-PGF1α and decreased TXB2 levels in the plasma, whereas the opposite pattern was observed in the protein homogenate from the myocardial tissues at the infarction edge, but keeping balance the ratio of 6-keto-PGF1α and TXB2, which is better than ASA in plasma. The mechanisms is associated with the downregulated expressions of COX-1 (p<0.05) and COX-2 (p<0.001). CONCLUSIONS: Ethanol extract of SP has a protective effect against myocardial ischemia via down regulation of COX-1 and COX-2 expression and by adjusting the ischemia-induced imbalance between 6-keto-PGF1α and TXB2. This study shows substantial evidence to support the clinical application of SP and indicates that such medicine has great potential for treating ischemia-induced heart disease.