Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti‐cancer efficacy and acquired ...drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi‐kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis‐related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c‐Kit), mitosis‐related kinase Aurora B and chronic inflammation‐related kinase CSF‐1R in a high potency manner with the IC50 at a single‐digit nanomolar range. Consequently, CS2164 displayed anti‐angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand‐dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B‐mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF‐1R phosphorylation that led to the suppression of ligand‐stimulated monocyte‐to‐macrophage differentiation and reduced CSF‐1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well‐tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi‐kinase inhibitor with potent anti‐tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer.
In this paper, we designed, discovered, and evaluated a novel orally active multi‐kinase inhibitor, CS2164, which simultaneously inhibits the angiogenesis‐related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFR‐alpha, and c‐Kit), mitosis‐related kinase Aurora B, and chronic inflammatory‐related kinase CSF‐1R in a high potency manner with the IC50 at a single digital nanomolar range. Through both in vitro cell based studies and in vivo animal xenograft models, we provide solid preclinical evidence for the potent anti‐tumor efficacy of CS2164.
Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that ...Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis.
The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression.
The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition.
The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.
Polysaccharides from the fungus
have been found to be biologically active. In this study, we carried out a preliminary characterisation and assessment of the hypoglycaemic activities of the ...polysaccharides (IOEP) from
obtained by liquid fermentation. Two polysaccharides, IOEP1 and IOEP2, were isolated from IOEP. IOEP1, with a molecular weight of 20 KDa, was mainly composed of galatose and mannose, while IOEP2, with a molecular weight of 200 KDa, was mainly composed of arabinose. Fourier-transform infrared analysis showed that both IOEP1 and IOEP2 were pyran-type polysaccharides. ¹H-NMR spectra showed that the glycosidic bonds of IOEP1 and IOEP2 were both α-type and β-type. In addition, IOEP1 and IOEP2 strongly increased the glucose consumption of HepG2 cells and insulin-resistant HepG2 cells in vitro. These findings provide a theoretical basis that IOEP1 and IOEP2 might be suitable as anti-diabetes agents in functional foods and natural drugs.
Abstract
Layered h-BN may serve as an important dielectric and thermal management material in the next-generation nanoelectronics, in which its interactions with electron beam play an important role ...in device performance and reliability. Previous studies report variations in the failure strength and mode. In this study, using molecular dynamics simulations, we study the effect of local heat injection due to the electron beam and h-BN interaction on the failure start time and failure mode. It is found that at the same heat injection rate, the failure start time decreases with the increase in the layer number. With the introduction of point defects in the heating zone, the failure always starts from the defect site, and the start time can be significantly shortened. For monolayer h-BN, failure always starts within the layer, and once failure starts, its propagation is through melting or vaporization of the h-BN atoms, and no swelling occurs. For multiple layers, once failure starts within the h-BN film, swelling occurs first. With continued heating, the large pressure induced by melting and vaporization can cause the burst of the layers above, leading to the formation of a pit. In the presence of multiple defects within the heating zone, these defects can interact, causing a further reduction in the failure start time. We also reveal the relation of beam power with layer-by-layer failure mode and swelling/pit formation mode. The present work not only reproduces many interesting experimental observations, but also reveal several interesting mechanisms responsible for the failure processes and modes. It is expected that the findings revealed here may provide useful references for the design and engineering of h-BN for device applications.
The rise of Tibet and growth of Asia resulted from successive accretion of Gondwana-derived continental fragments at the expense of Tethyan oceans, yet how and where the eastern Paleo-Tethys closed ...in SE Asia remain controversial. Here we report new and synthesized detrital zircon data from Borneo and relevant regions revealing that West and SW Borneo show consistent Precambrian age profiles resembling that of Northern Australia (Kimberley to Pine Creek), but contrasting with those of NW/NE Australia, Bird's Head, and Cathaysia/Indochina. Considering the questionable suture between West and SW Borneo, we suggest a united Borneo basement that originated from Northern Australia, with a position between Sumatra and Timor. Surprisingly, Borneo lacks NE Australia-sourced ca. 1700–1400 and 400–280 Ma zircons that prevail in Triassic-Jurassic strata of Timor, Babar, and Tanimbar offshore Northern Australia, which may be best explained by pre-Triassic rifting of the Borneo basement from Northern Australia. Combining with recent investigations, we propose a new tectonic scenario involving a Permian separation of Borneo (probably together with Sumatra) from northern Gondwana through opening of the Meso-Tethys Ocean followed by a Triassic docking with Eurasia that closed the eastern Paleo-Tethys. Thus, assembly of Sundaland (continental core of SE Asia) completed in the Late Triassic, rather than Cretaceous as previously thought, and the tail (or the southeasternmost section) of eastern Paleo-Tethys lies within the Kuching zone of Borneo. Our new reconstruction challenges current understanding of Gondwana dispersion and Asian accretion, shedding new light on Asian climate change and biogeographic diversity.
•Borneo basement (West and SW Borneo) originated from Northern Australia.•Borneo basement left Northern Australia in the Permian during the opening of the Meso-Tethys Ocean.•Borneo basement docked with Sundaland in the Triassic during the closure of eastern Paleo-Tethys Ocean.
•Licorice defect in TCM recipes leads to the hepatotoxicity in administrated mice.•GA inhibits viral hepatitis by suppressing HMGB1 release and cytokine activity.•GA treatment effect on infected mice ...is similar with HMGB1 neutralizing antibody.•HMGB1-TLR4 axis is involved in murine hepatic injury during MHV infection.
Various human disorders are cured by the use of licorice, a key ingredient of herbal remedies. Glycyrrhizic acid (GL), a triterpenoid glycoside, is the aqueous extract from licorice root. Glycyrrhetinic acid (GA) has been reported to be a major bioactive hydrolysis product of GL and has been regarded as an anti-inflammatory agent for the treatment of a variety of inflammatory diseases, including hepatitis. However, the mechanism by which GA inhibits viral hepatic inflammatory injury is not completely understood. In this study, we found that, by consecutively treating mice with a traditional herbal recipe, licorice plays an important role in the detoxification of mice. We also employed a murine hepatitis virus (MHV) infection model to illustrate that GA treatment inhibited activation of hepatic inflammatory responses by blocking high-mobility group box 1 (HMGB1) cytokine activity. Furthermore, decreased HMGB1 levels and downstream signaling triggered by injection of a neutralizing HMGB1 antibody or TLR4 gene deficiency, also significantly protected against MHV-induced severe hepatic injury. Thus, our findings characterize GA as a hepatoprotective therapy agent in hepatic infectious disease not only by suppressing HMGB1 release and blocking HMGB1 cytokine activity, but also via an underlying viral-induced HMGB1-TLR4 immunological regulation axis that occurs during the cytokine storm. The present study provides a new therapy strategy for the treatment of acute viral hepatitis in the clinical setting.
Cancer patients with diabetes have an increasing risk of Dox-induced cardiotoxicity. Despite previous studies reporting benefits of dapagliflozin on the cardiovascular system, it remains unknown ...whether dapagliflozin has a cardioprotective effect in cancer patients with diabetes. We aimed to investigate the potential of dapagliflozin for preventing doxorubicin (Dox)-induced cardiotoxicity. Using Taiwan National Health Insurance Database, the incidence of heart failure of cancer patients with or without diabetes was investigated. Streptozotocin (STZ)-induced diabetic rats were pretreated with oral dapagliflozin for 6 weeks followed by Dox for 4 weeks via intraperitoneal injection. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes cultured in high glucose were treated with dapagliflozin at 10 μM and subsequently exposed to Dox at 1 μM. Apoptosis and endoplasmic reticulum (ER) stress-related protein expression were measured. Among the studied patients, those with diabetes had a higher risk of major adverse cardiovascular events including the development of heart failure. In diabetic rats, dapagliflozin reduced cardiac fibrosis and significantly improved cardiac function. Dapagliflozin effectively inhibited Dox-induced apoptosis and reactive oxygen species in cardiomyocytes under high glucose. Mechanistically, we showed that dapagliflozin decreased the cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2. Dapagliflozin also significantly reduced ER stress-associated proteins including GRP78, PERK, eIF-2α, ATF-4, and CHOP. Our study revealed for the first time that dapagliflozin mitigated Dox-induced cardiomyocyte apoptosis in diabetes. These results indicate that dapagliflozin could be useful for preventing cardiotoxicity in diabetic cancer patients receiving Dox treatment.
Evaluating sea surface temperature (SST) products is essential before their application in marine environmental monitoring and related studies. SSTs from the in situ SST Quality Monitor (iQuam) ...system, Advanced Microwave Scanning Radiometer 2 (AMSR2) aboard the Global Change Observation Mission 1st-Water, and the Microwave Radiation Imager (MWRI) aboard the Chinese Fengyun-3D satellite are intercompared utilizing extended triple collocation (ETC) and direct comparison methods. Additionally, error characteristic variations with respect to time, latitude, SST, sea surface wind speed, columnar water vapor, and columnar cloud liquid water are analyzed comprehensively. In contrast to the prevailing focus on SST validation accuracy, the random errors and the capability to detect SST variations are also evaluated in this study. The result of ETC analysis indicates that iQuam SST from ships exhibits the highest random error, above 0.83 °C, whereas tropical mooring SST displays the lowest random error, below 0.28 °C. SST measurements from drifters, tropical moorings, Argo floats, and high-resolution drifters, which possess random errors of less than 0.35 °C, are recommended for validating remotely sensed SST. The ability of iQuam, AMSR2, and MWRI to detect SST variations diminishes significantly in ocean areas between 0°N and 20°N latitude and latitudes greater than 50°N and 50°S. AMSR2 and iQuam demonstrate similar random errors and capabilities for detecting SST variations, whereas MWRI shows a high random error and weak capability. In comparison to iQuam SST, AMSR2 exhibits a root-mean-square error (RMSE) of about 0.51 °C with a bias of −0.05 °C, while MWRI shows an RMSE of about 1.26 °C with a bias of −0.14 °C.
Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. The epithelial‐to‐mesenchymal transition (EMT) is a key contributor in the ...metastatic process. In this study, we found that miR‐655 was down‐regulated in TNBC, and its expression levels were associated with molecular‐based classification and lymph node metastasis in breast cancer. These findings led us to hypothesize that miR‐655 overexpression may inhibit EMT and its associated traits of TNBC. Ectopic expression of miR‐655 not only induced the up‐regulation of cytokeratin and decreased vimentin expression but also suppressed migration and invasion of mesenchymal‐like cancer cells accompanied by a morphological shift towards the epithelial phenotype. In addition, we found that miR‐655 was negatively correlated with Prrx1 in cell lines and clinical samples. Overexpression of miR‐655 significantly suppressed Prrx1, as demonstrated by Prrx1 3′‐untranslated region luciferase report assay. Our study demonstrated that miR‐655 inhibits the acquisition of the EMT phenotype in TNBC by down‐regulating Prrx1, thereby inhibiting cell migration and invasion during cancer progression.
MicroRNAs (miRNAs) are a group of short (approximately 22 nt) non-coding RNAs that play important regulatory roles. MiRNA precursors (pre-miRNAs) are characterized by their hairpin structures. ...However, a large amount of similar hairpins can be folded in many genomes. Almost all current methods for computational prediction of miRNAs use comparative genomic approaches to identify putative pre-miRNAs from candidate hairpins. Ab initio method for distinguishing pre-miRNAs from sequence segments with pre-miRNA-like hairpin structures is lacking. Being able to classify real vs. pseudo pre-miRNAs is important both for understanding of the nature of miRNAs and for developing ab initio prediction methods that can discovery new miRNAs without known homology.
A set of novel features of local contiguous structure-sequence information is proposed for distinguishing the hairpins of real pre-miRNAs and pseudo pre-miRNAs. Support vector machine (SVM) is applied on these features to classify real vs. pseudo pre-miRNAs, achieving about 90% accuracy on human data. Remarkably, the SVM classifier built on human data can correctly identify up to 90% of the pre-miRNAs from other species, including plants and virus, without utilizing any comparative genomics information.
The local structure-sequence features reflect discriminative and conserved characteristics of miRNAs, and the successful ab initio classification of real and pseudo pre-miRNAs opens a new approach for discovering new miRNAs.
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