A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis.

OBJECTIVE: Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood. METHODS: Experimental fungal keratitis was established in wild-type and gene knockout (TLR4-/- and GSDMD-/-) mice by infecting mouse corneas with Candida albicans. The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, Western blotting, and immunohistochemistry were conducted in this research. RESULTS: Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas. CONCLUSIONS: The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.

Highly Expressed LINC00958 Modulates the Growth and Epithelial-Mesenchymal Transition of Bladder Cancer Cells Through SAPK/JNK Signaling Pathway.

Objective: To determine the expression of LINC00958 (BLACAT2) in bladder cancer (BC), the most common malignancy in the urinary system, and to determine its exact mechanism of action, so as to provide novel references for future clinical diagnosis and treatment of BC and lay a foundation for the follow-up research on LINC00958. Materials and Methods: Human bladder transitional cell carcinoma cells (T24 and J82) and human normal urothelial cells (SV-HUC-1) were purchased to detect the expression of LINC00958 and SAPK/JNK signaling pathway-related proteins. sh-LINC00958 targeting to silence LINC00958 expression and corresponding negative blank (sh-Control) were transfected into T24 and J82. Additionally, BC cells cultured with SP600125 (SP600125 group), a specific inhibitor of SAPK/JNK signaling pathway, and those cultured with the same amount of normal saline (Blank group) were also constructed. Cell growth capacity, cell invasiveness, and expression of epithelial-mesenchymal transition (EMT)-associated proteins were determined using CCK-8 & clone formation assays, Transwell assay, and Western blot, respectively. Results: The online databases Gene Expression Profiling Interactive Analysis, European Bioinformatics Institute, and StarBase revealed elevated LINC00958 expression in BC, and a potential association between LINC00958 and patient prognosis and survival. PCR results showed that LINC00958 was increased in T24 and J82 compared with the sh-Control group (p < 0.05). The results of biological behavior test revealed that the proliferation and invasiveness capacity of the sh-LINC00958 group decreased, while that of the SP600125 group increased compared with the Blank group (both p < 0.05). In the rescue experiment, the influence of sh-LINC00958 on BC cells was completely reversed by SP600125 (p > 0.05); In addition, the expression of E-cadherin, an EMT marker protein, was lower compared with the SH-LINC0958 group, while the Vimentin expression was higher (p < 0.05). Similarly, the wound-healing assay determined reduced cell healing rate in the sh-LINC00958 group (p < 0.05), and there was no difference between the sh-LINC00958+SP600125 group and the sh-Control group (p > 0.05). Conclusion: LINC00958 shows elevated expression in BC and promotes the growth and EMT of BC cell via inhibiting the SAPK/JNK signaling pathway, which has important potential as a new clinical diagnostic marker and therapeutic target for BC.

Effects of microplastics on cadmium accumulation by rice and arbuscular mycorrhizal fungal communities in cadmium-contaminated soil.

Both microplastics (MPs) and cadmium (Cd) are common contaminants in soil-rice systems, but their combined effects remain unknown. Thereby, we explored the effects of three MPs, i.e., polyethylene terephthalate (PET), polylactic acid (PLA), and polyester (PES), on Cd accumulation in rice and the community diversity and structure of arbuscular mycorrhizal fungi (AMF) in soil spiked with or without Cd. Results showed that 2% PLA decreased shoot biomass (-28%), but PET had a weaker inhibitive effect. Overall, Cd alone did not significantly change shoot and root biomass and increased root biomass in combination with 0.2% PES. MPs generally increased soil Cd availability but decreased Cd accumulation in rice tissues. Both MPs and Cd improved the bioavailability and uptake of Fe and Mn in rice roots. MPs altered the diversity and community composition of AMF, depending on their type and dose and co-existing Cd. Overall, 2% PLA caused the most distinct changes in soil properties, plant growth and Cd accumulation, and AMF communities, but showed no synergistic interactions with Cd. In conclusion, MPs can mediate rice performance and Cd accumulation via altering soil properties, nutrient uptake, and root mycorrhizal communities, and biodegradable PLA MPs thought environment-friendly can exhibit higher phytotoxicity than conventional MPs.

LINC00958 Inhibits Autophagy of Bladder Cancer Cells via Sponge Adsorption of miR-625-5p to Promote Tumor Angiogenesis and Oxidative Stress.

Objective: This study further explored LINC00958's role in promoting tumor angiogenesis (AG) and oxidative stress (OS) development by inhibiting BC cell autophagy through sponge adsorption of miR-625-5p. Methods: BC patients and healthy controls who visited our hospital between June 2017 and February 2019 were selected as the research group (RG) and the control group (CG), respectively, with a total of 133 study subjects. Peripheral blood LINC00958 and miR-625-5p in both cohorts of participants were detected. Additionally, human bladder transitional cell carcinoma cells (T24 and J82) and human normal urothelial cells (SV-HUC-1) were purchased. Alterations in cell biological behavior were observed after transfecting miR-625-5p-mimics, miR-625-5p-inhibition, and miR-625-5p-NC sequences into these cells, respectively. Besides, ELISA was performed to quantify inflammatory factors (IFs), AG indicators, and OS indexes in cells. Subsequently, a double luciferase reporter (DLR) assay was performed to verify the targeting relationship between LINC00958 and miR-625-5p. Finally, BALB/c-nu nude mice were purchased, and T24 cells transfected with silenced LINC00958 and miR-625-5p expression sequences were used to establish subcutaneous tumors to observe tumor growth and pathological changes. Results: RG exhibited higher LINC00958 and lower miR-625-5p than CG. LINC00958 and miR-625-5p were strongly linked to myometrial invasion (MI), lymph node metastasis (LNM), distant metastasis (DM), and histology in BC patients, and the increase of LINC00958 and the decrease of miR-625-5p predicted an increased risk of prognostic death in such patients. After miR-625-5p inhibition, the capacity of BC cells to proliferate, invade, and migrate enhanced and the AG, inflammatory response, and OS injury increased, while the apoptosis rate and autophagy ability decreased. The DLR assay revealed inhibited LINC00958WT fluorescence activity by miR-625-5p-mimics, while the biological behavior of BC cells cotransfected with sh-LINC00958 and miR-625-5p-inhibition had no difference with the functions of sh-control and miR-625-5p-NC cotransfected cells. Finally, the nude mouse tumorigenesis experiment showed that the tumor mass, volume, and histopathological features of the sh-LINC00958 group were decreased compared with the sh-control group, while those of the miR-625-5p-inhibition group were increased versus miR-625-5p-NC. Conclusions: In BC, LINC00958 is highly expressed while miR-625-5p is underexpressed. LINC00958 can inhibit cell autophagy to enhance cell activity; promote OS, inflammation, and AG; and regulate tumor immunity by targeting miR-625-5p, thus participating in the development of BC.

Characterization of the immune related lncRNAs in bladder cancer to aid immunotherapy.

Bladder cancer (BLCA) is the 10th most common form of cancer worldwide. Currently, the response rate of BLCA patients to novel immunotherapy and immune checkpoint inhibitor (ICI) treatment is around 30% or less. Therefore, there is an urgent clinical demand to understand the regulation of immune function in BLCA patients. LncRNAs are known to play fundamental roles in the regulation of the immune system in the tumor microenvironment. In this report, we performed a comprehensive analysis to identify immune-related lncRNAs (IRLs) in BLCA patients using The Cancer Genome Atlas (TCGA) databases. BLCA patients were divided into five TME subtypes. Subtype HMIE was strongly related to survival and high anti-tumor activity of patients. Through a four-step analysis, we identified 34 IRLs as subtype HMIE related lncRNAs (HMIE-lncs).The correlation analysis with immune cell infiltration and target gene pathway enrichment showed that 34 HMIE-lncs were correlated with immune cell activation and tumor cell killing. Among them, 24 lncRNAs were related to good prognosis. We constructed a risk model to predict BLCA. Cross tumor validation was performed, and the results showed that the 34 HMIE-lncs identified in the BLCA patients in this study were highly expressed in the immune-favorable TME subtype (IE) in most of the other cancer types.

Effects of Additives on Coke Reactivity and Sulfur Transformation during Co-pyrolysis of Long Flame Coal and High-Sulfur Coking Coal.

A silica-aluminum-based mineral (GL) was selected for inspecting the effects of interactions of minerals in coal blends on the coke reactivity index (CRI) and sulfur transformation during co-pyrolysis of long flame coal and high-sulfur coking coal. Results indicate a good compatibility for the supply of active hydrogen, decomposition of sulfur, and regulation of reactivity. The experimental values of sulfur content in different coal blend cokes are lower than the calculated values, which can be determined as a result of the directional regulation effect of long flame coal on sulfur transformation. The addition of GL in coal blends significantly reduces the CRI of the corresponding coke, and the effect of GL on coke reactivity is also verified by a 10 kg coke oven experiment. When increasing the ratio of long flame coal, the sulfur fixation in the solid phase has a tendency to be enhanced by alkaline minerals. Also, GL plays a role in reducing the capture of sulfur free radicals by alkaline minerals, which improves the sulfur removal during pyrolysis of coal blends and then reduces the sulfur content in coke. This work provides a reference for using silica-aluminum-based minerals to reduce the capture of sulfur and catalytic effect on coke reactivity.

Analysis of Cardiac Amyloidosis Progression Using Model-Based Markers.

Deposition of amyloid in the heart can lead to cardiac dilation and impair its pumping ability. This ultimately leads to heart failure with worsening symptoms of breathlessness and fatigue due to the progressive loss of elasticity of the myocardium. Biomarkers linked to the clinical deterioration can be crucial in developing effective treatments. However, to date the progression of cardiac amyloidosis is poorly characterized. There is an urgent need to identify key predictors for disease progression and cardiac tissue function. In this proof of concept study, we estimate a group of new markers based on mathematical models of the left ventricle derived from routine clinical magnetic resonance imaging and follow-up scans from the National Amyloidosis Center at the Royal Free in London. Using mechanical modeling and statistical classification, we show that it is possible to predict disease progression. Our predictions agree with clinical assessments in a double-blind test in six out of the seven sample cases studied. Importantly, we find that multiple factors need to be used in the classification, which includes mechanical, geometrical and shape features. No single marker can yield reliable prediction given the complexity of the growth and remodeling process of diseased hearts undergoing high-dimensional shape changes. Our approach is promising in terms of clinical translation but the results presented should be interpreted with caution due to the small sample size.

Variation, sources and historical trend of black carbon in Beijing, China based on ground observation and MERRA-2 reanalysis data.

Based on the ground-measurements and MERRA-2 (Modern-Era Retrospective Analysis for Research and Applications, Version 2) reanalysis data, the temporal-spatial variation of black carbon (BC) in Beijing and the affecting factors were investigated. According to the ground-measured BC concentration in November months of 2014, 2015 and 2016, the before-heating period in November 2014 showed the lowest BC concentration as a result of the efficient emission controls for the Asia-Pacific Economic Cooperation (APEC) meeting. Except for November 2014, the BC mass concentration during the heating periods was notably lower than the before-heating periods in November 2015 and 2016. Wind speed and relative humidity appeared to be two important meteorological parameters affecting BC pollution. The MERRA-2 BC concentration was validated through comparison with the continuous ground BC measurements in 2015 and 2016, affirming its reliability in demonstrating the large scale and long term variations of the ground BC concentration. The MERRA-2 BC spatial distribution, the potential source regions determined by concentration weighted trajectory (CWT) analysis, and the regional emission inventories were combined to reveal the potential source regions and source types of BC in Beijing. Transportation emission in Beijing and residential emissions in the neighboring regions such as Hebei appeared to be important sources of BC in Beijing. According to the historical trends of MERRA-2 BC concentration and typical fossil fuel consumption (1980-2017), local coal and coke are no longer the major factor affecting the BC concentration, instead, liquid fuels such as gasoline, kerosene, and diesel may highly contribute to the BC pollution in Beijing in recent years. Regional transport of BC may have also contributed to the loading of BC in Beijing. Open biomass burning may be a non-negligible factor for the short-term variation of BC in the atmosphere.

Correction: Se2Mo10V3, a heteropoly compound containing selenium, inhibits tumor growth.

[This corrects the article DOI: 10.18632/oncotarget.18909.].

METTL3-mediated N6-methyladenosine mRNA modification enhances long-term memory consolidation.

The formation of long-term memory is critical for learning ability and social behaviors of humans and animals, yet its underlying mechanisms are largely unknown. We found that the efficacy of hippocampus-dependent memory consolidation is regulated by METTL3, an RNA N6-methyladenosine (m6A) methyltransferase, through promoting the translation of neuronal early-response genes. Such effect is exquisitely dependent on the m6A methyltransferase function of METTL3. Depleting METTL3 in mouse hippocampus reduces memory consolidation ability, yet unimpaired learning outcomes can be achieved if adequate training was given or the m6A methyltransferase function of METTL3 was restored. The abundance of METTL3 in wild-type mouse hippocampus is positively correlated with learning efficacy, and overexpression of METTL3 significantly enhances long-term memory consolidation. These findings uncover a direct role of RNA m6A modification in regulating long-term memory formation, and also indicate that memory efficacy difference among individuals could be compensated by repeated learning.

Constitutive laws with damage effect for the human great saphenous vein.

Strain energy-based constitutive laws with damage effect were proposed by using existing both uniaxial tensile test and tubular biaxial inflation test data on the human great saphenous vein (GSV) segments. These laws were applied into GSV coronary artery bypass grafts (CABG) by employing a thin-walled vessel model to evaluate their passive biomechanical performance under coronary artery physiological conditions at a fixed axial pre-stretch. At a peak systolic pressure in 100-150 mmHg, a 20-33% GSV diameter dilation was predicted with the law based on tubular biaxial inflation test data and agreed well with 25% dilation in clinical observation in comparison with as small as 2-4% dilation estimated with the law based on uniaxial tensile test data. The constitutive law generated by tubular biaxial inflation test data was mostly suitable for GSV CABG under coronary artery physiological conditions than that based on uniaxial tensile test results. With these laws, the fibre ultimate stretch was extracted from uniaxial tensile test data and the structural sub-failure/damage threshold of 1.0731 was decided for the human GSV. GSV fibres could exhibit damage effect but unlikely undergo a structure failure/break, suggesting a damage factor might exist during CABG arterialization. The damage in GSV tissue might initiate or contribute to early remodelling of CABG after implantation.

Design, synthesis, and anticancer properties of isocorydine derivatives.

Isocorydine (ICD), an aporphine alkaloid, is widely distributed in nature. Its ability to target side population (SP) cells found in human hepatocellular carcinoma (HCC) makes it and its derivative 8-amino-isocorydine (NICD) promising chemotherapeutic agents for the treatment of HCC. To improve the anticancer activity of isocorydine derivatives, twenty derivatives of NICD were designed and synthesized through chemical structure modifications of the aromatic amino group at C-8. The anti-proliferative activities of all synthesized compounds against human hepatocellular (HepG2), cervical (HeLa), and gastric (MGC-803) cancer cell lines were evaluated using an MTT assay. The results showed that all the synthetic compounds had some tumor cell growth inhibitory activity. The compound COM33 (24) was the most active with IC50 values under 10 µM (IC50 for HepG2 = 7.51 µM; IC50 for HeLa = 6.32 µM). FICD (12) and COM33 (24) were selected for further investigation of their in vitro and in vivo activities due to their relatively good antiproliferative properties. These two compounds significantly downregulated the expression of four key proteins (C-Myc, ß-Catenin, CylinD1, and Ki67) in HepG2 cells. The tumor inhibition rate of COM33 (24) in vivo was 73.8% after a dose 100 mg/kg via intraperitoneal injection and the combined inhibition rate of COM33 (24) (50 mg/kg) with sorafenib (50 mg/kg) was 66.5%. The results indicated that these isocorydine derivatives could potentially be used as targeted chemotherapy agents or could be further developed in combination with conventional chemotherapy drugs to target cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT), the main therapeutic targets in HCC.

[Research on anticancer activity of isocorydine and its derivatives].

Isocorydine and its analogs were extracted from Dicranostigma leptopodum and Stephania yunnanensis through the method of natural products chemistry. Its derivatives were prepared by chemical structure modifications from isocorydine. MTT method was used to study the inhibitory effect of those compounds on the growth of HepG2, HeLa and MGC-803 cancer cell lines in vitro. The results showed that isocorydine and its analogs all have the growth inhibition for those cancer cell lines. This paper investigated the structure-activity relationship of isocorydine and its derivatives with anticancer activity in the aspect of stereochemical structure, functional groups positions of the compounds and the electron density of aromatic rings based on the single crystal diffraction structure and the molecular docking of EGFR and isocorydine.

Se2Mo10V3, a heteropoly compound containing selenium, inhibits tumor growth.

Selenium compounds have strong anti-tumor effects and are well-tolerated. We examined the anti-tumor effects of (NH4)2H15Se2VIMo10V3O52·2H2O (Se2Mo10V3), a heteropoly compound containing selenium. Se2Mo10V3 inhibited proliferation in K562 cells with a half-maximal inhibitory concentration of 78.72±2.82 mg/L after 48 h and 24.94±0.88 mg/L after 72 h. Typical apoptotic morphologies were also observed in K562 cells treated with Se2Mo10V3, as were increased intracellular levels of Ca2+, Mg2+, H+, and reactive oxygen species, and decreased mitochondrial membrane potential. In addition, Se2Mo10V3 treatment triggered cytochrome C release and inhibited IκBα degradation and NF-κB translocation. In vivo experiments revealed that 5 or 10 mg/kg Se2Mo10V3 inhibited the growth of sarcoma 180 and hepatoma 22 xenograft tumors. These results indicate that Se2Mo10V3 inhibits tumor growth both in vitro and in vivo and induces apoptosis in K562 cells, possibly by inhibiting the NF-κB/IκBα pathway.

Synthetic Isoliquiritigenin Inhibits Human Tongue Squamous Carcinoma Cells through Its Antioxidant Mechanism.

Isoliquiritigenin (ISL), a natural antioxidant, has antitumor activity in different types of cancer cells. However the antitumor effect of ISL on human tongue squamous carcinoma cells (TSCC) is not clear. Here we aimed to investigate the effects of synthetic isoliquiritigenin (S-ISL) on TSCC and elucidate the underlying mechanisms. S-ISL was synthesized and elucidated from its nuclear magnetic resonance spectrum and examined using high performance liquid chromatography. The effects of S-ISL on TSCC cells (Tca8113) were evaluated in relation to cell proliferation, apoptosis and adhesion, migration, and invasion using sulforhodamine B assay, fluorescence microscopy technique, flow cytometry (FCM) analysis, and Boyden chamber assay. The associated regulatory mechanisms were examined using FCM and fluorescence microscopy for intracellular reactive oxygen species (ROS) generation, Gelatin zymography assay for matrix metalloproteinase (MMP) activities, and Western blot for apoptosis regulatory proteins (Bcl-2 and Bax). Our data indicated that S-ISL inhibited Tca8113 cell proliferation, adhesion, migration, and invasion while promoting the cell apoptosis. Such effects were accompanied by downregulation of Bcl-2 and upregulation of Bax, reduction of MMP-2 and MMP-9 activities, and decreased ROS production. We conclude that S-ISL is a promising agent targeting TSCC through multiple anticancer effects, regulated by its antioxidant mechanism.

4-isothiocyanate-2, 2, 6, 6-tetramethyl piperidinooxyl inhibits angiogenesis by suppressing VEGFR2 and Tie2 phosphorylation.

Reactive oxygen species (ROS) are involved in the signaling pathway and are triggered by angiogenic factors, including vascular endothelial growth factor and angiopoietins. 4-isothiocyanate-2, 2, 6, 6-tetramethyl piperidinooxyl (4-ISO-Tempo) is one of the nitroxides that exhibits antioxidant activity. However, the anti-angiogenic effect of 4-ISO-Tempo remains unknown. The aim of this study was to investigate the effect of 4-ISO-Tempo on tumor proliferation and angiogenesis as well as its underlying mechanisms. Our results revealed that 4-ISO-Tempo significantly inhibited the viability of neoplastic and endothelial cells. Furthermore, the effective concentration of 4-ISO-Tempo on human microvascular endothelial cell 1 (HMEC-1) was lower than that on human lung adenocarcinoma A549 and human colon cancer SW620 cells. This suggested that endothelial cells were more sensitive to 4-ISO-Tempo than tumor cells. Furthermore, we demonstrated that 4-ISO-Tempo also suppressed secretion of matrix metalloproteinase (MMP)-2 and MMP-9, and migration and tube formation of HMEC-1 cells. The mechanism is attributed to the decreasing ROS generation and further phosphorylation of vascular endothelial growth factor receptor 2 and Tie2. Our findings suggest that 4-ISO-Tempo should be investigated for its usefulness in anti-angiogenesis therapies.

Laparoscopic-Assisted Resection for Retroperitoneal Dumbbell-Shaped Lumbar Spinal Schwannomas: Operative Technique and Surgical Results.

BACKGROUND: Retroperitoneal dumbbell lumbar spinal schwannomas (RDLSSs) classified as the Eden type 4 are composed of small intervertebral foramen components and large paravertebral components extending into the retroperitoneal cavity. The surgical management of RDLSSs s remains a great challenge for all neurosurgeons because of the features of tumor. OBJECTIVE: To present our experience in the laparoscopic resection of RDLSSs and to evaluate endoscopy surgery by an anterior approach for the treatment of RDLSSs. METHODS: We performed a retrospective review of 3 patients with RDLSSs who underwent laparoscopic surgery by an anterior approach between June 2013 and July 2014. Patient demographics, operative reports, and pre- and postoperative images were reviewed. RESULTS: All tumors were removed completely with retroperitoneal laparoscopy by the anterior approach. There were no major morbidities related to the surgical procedure in this series, and all patients recovered from surgery. The preoperative symptoms either improved or resolved in 2 patients, whereas they remained unchanged in 1 patient. Postoperative follow-up ranged from 12 to 24 months, and none of the patients showed signs of tumor recurrence or spinal deformity. CONCLUSIONS: The operative plan should be tailored to the features of the RDLSS. Retroperitoneal laparoscopy surgery by the anterior approach can produce safe and effective resection of RDLSSs with minimal postoperative complications. This procedure may be preferred for RDLSSs mainly located in the retroperitoneum without spinal canal extension.

An Invariant-Based Damage Model for Human and Animal Skins.

Constitutive modelling of skins that account for damage effects is important to provide insight for various clinical applications, such as skin trauma and injury, artificial skin design, skin aging, disease diagnosis, surgery, as well as comparative studies of skin biomechanics between species. In this study, a new damage model for human and animal skins is proposed for the first time. The model is nonlinear, anisotropic, invariant-based, and is based on the Gasser-Ogden-Holzapfel constitutive law initially developed for arteries. Taking account of the mean collagen fibre orientation and its dispersion, the new model can describe a wide range of skins with damage. The model is first tested on the uniaxial test data of human skin and then applied to nine groups of uniaxial test data for the human, swine, rabbit, bovine and rhino skins. The material parameters can be inversely estimated based on uniaxial tests using the optimization method in MATLAB with a root mean square error ranged between 2.15% and 12.18%. A sensitivity study confirms that the fibre orientation dispersion and the mean fibre angle are among the most important factors that influence the behaviour of the damage model. In addition, these two parameters can only be reliably estimated if some histological information is provided. We also found that depending on the location of skins, the tissue damage may be brittle controlled by the fibre breaking limit (i.e., when the fibre stretch is greater than 1.13-1.32, depending on the species), or ductile (due to both the fibre and the matrix damages). The brittle damages seem to occur mostly in the back, and the ductile damages are seen from samples taken from the belly. The proposed constitutive model may be applied to various clinical applications that require knowledge of the mechanical response of human and animal skins.

Isocorydine derivatives and their anticancer activities.

In order to improve the anticancer activity of isocorydine (ICD), ten isocorydine derivatives were prepared through chemical structure modifications, and their in vitro and in vivo activities were experimentally investigated. 8-Amino-isocorydine (8) and 6a,7-dihydrogen-isocorydione (10) could inhibit the growth of human lung (A549), gastric (SGC7901) and liver (HepG2) cancer cell lines in vitro. Isocorydione (2) could inhibit the tumor growth of murine sarcoma S180-bearing mice, and 8-acetamino-isocorydine (11), a pro-drug of 8-amino-isocorydine (8), which is instable in water solution at room temperature, had a good inhibitory effect on murine hepatoma H22-induced tumors. The results suggested that the isocorydine structural modifications at C-8 could significantly improve the biological activity of this alkaloid, indicating its suitability as a lead compound in the development of an effective anticancer agent.

Natural antioxidant-isoliquiritigenin ameliorates contractile dysfunction of hypoxic cardiomyocytes via AMPK signaling pathway.

Isoliquiritigenin (ISL), a simple chalcone-type flavonoid, is derived from licorice compounds and is mainly present in foods, beverages, and tobacco. Reactive oxygen species (ROS) is a critical factor involved in modulating cardiac stress response signaling during ischemia and reperfusion. We hypothesize that ISL as a natural antioxidant may protect heart against ischemic injury via modulating cellular redox status and regulating cardioprotective signaling pathways. The fluorescent probe H2DCFDA was used to measure the level of intracellular ROS. The glucose uptake was determined by 2-deoxy-D-glucose-(3)H accumulation. The IonOptix System measured the contractile function of isolated cardiomyocytes. The results demonstrated that ISL treatment markedly ameliorated cardiomyocytes contractile dysfunction caused by hypoxia. ISL significantly stimulated cardioprotective signaling, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) signaling pathways. The ROS fluorescent probe H2DCFDA determination indicated that ISL significantly reduced cardiac ROS level during hypoxia/reoxygenation. Moreover, ISL reduced the mitochondrial potential (Δψ) of isolated mouse cardiomyocytes. Taken together, ISL as a natural antioxidant demonstrated the cardioprotection against ischemic injury that may attribute to the activation of AMPK and ERK signaling pathways and balance of cellular redox status.