Design, synthesis and biological evaluation of a novel colchicine-magnolol hybrid for inhibiting the growth of Lewis lung carcinoma in Vitro and in Vivo

Colchicine is a bioactive alkaloid originally from Colchicum autumnale and possesses excellent antiproliferative activity. However, colchicine-associated severe toxicity, gastrointestinal side effects in particular, limits its further therapeutic use. In the current study, we thus designed and synthesized a novel hybrid (CMH) by splicing colchicine and magnolol, a multifunctional polyphenol showing favorable gastrointestinal protection. The antitumor activity of CMH in Lewis lung carcinoma (LLC) was then evaluated in vitro and in vivo. Biologically, CMH inhibited the growth of LLC cells with an IC50 of 0.26 μM, 100 times more potently than cisplatin (26.05 μM) did. Meanwhile, the cytotoxicity of CMH was 10-fold lower than that of colchicine in normal human lung cells (BEAS-2B). In C57BL/6 mice xenograft model, CMH (0.5 mg/kg) worked as efficacious as colchicine (0.5 mg/kg) to inhibit tumor growth and 2 times more potently than cisplatin (1 mg/kg). In terms of mortality, 7 out of 10 mice died in colchicine group (0.75 mg/kg), while no death was observed in groups receiving CMH or cisplatin at 0.75 mg/kg. Mechanistic studies using Western blot revealed that CMH dose-dependently suppressed the protein expression of phosphorylated ERK. Molecular docking analysis further indicated that CMH was well fitted in the colchicine binding site of tubulin and formed several hydrogen bonds with tubulin protein. These results enable our novel hybrid CMH as a potential antineoplastic agent with lower toxicity, and provide perquisites for further investigation to confirm the therapeutic potentiality of this novel hybrid

Down-regulation of TM4SF is associated with the metastatic potential of gastric carcinoma TM4SF members in gastric carcinoma

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to clarify the clinical significance of TM4SF members CD9, CD63 and CD82 in human gastric carcinoma.</p> <p>Methods</p> <p>By employing RT-PCR and immunohistochemistry, we studied the expression of CD9, CD63 and CD82 in 49 paired tissue specimens of normal gastric mucosa and carcinoma. All tissues were obtained from patients who underwent curative surgery.</p> <p>Results</p> <p>All normal gastric epithelium and gastric ulcer tissues strongly expressed transcripts and proteins of CD9, CD63 and CD82 as compared with corresponding controls. We found a significant correlation between CD63 mRNA level and different pM statuses (P = 0.036). Carcinomas in M0 stage revealed a stronger expression of CD63 than carcinomas in M1 stage. Expression of CD9 protein was found significantly stronger in pN0, pM0 than in advanced pN stages (P = 0.03), pM1 (P = 0.013), respectively. We found the relationship between CD63 expression, gender (p = 0.09) and nodal status (p = 0.028), respectively. Additionally, advanced and metastasized tumor tissues revealed significantly down-regulated CD82 protein expression (p = 0.033 and p = 0, respectively), which correlated with the tumor pTNM stage (p = 0.001).</p> <p>Conclusion</p> <p>The reduction of CD9, CD63 and CD82 expression are indicators for the metastatic potential of gastric carcinoma cells. Unlike their expression in other tumor types, the constitutive expression of CD63 may indicate that this factor does play a direct role in human gastric carcinogenesis.</p

Shale lithofacies types and reservoir characteristics from Ordovician Wufeng Formation to the first sub-member of the first member of Silurian Longmaxi Formation, northeast Zhaotong area

Shale lithofacies has an important influence on shale reservoirs. It controls the hydrocarbon generation capacity, storage performance and fracturing performance of shale to a certain extent. In order to study the shale lithofacies characteristics, reservoir characteristics and evaluation of Wufeng-Longmaxi formations in the northeast Zhaotong area, a detailed research was carried out based on core, thin section, X-ray diffraction and various geochemical test data. Calcareous/siliceous mixed shale lithofacies, mixed shale lithofacies, clayey/siliceous mixed shale lithofacies, mixed siliceous shale lithofacies, clay-rich siliceous shale lithofacies are developed in the study area. There is a difference in the vertical distribution of lithofacies between the south and the north of the study area. The lithofacies from Wufeng Formation to the first sub-member of the first member of Longmaxi Formation (Long1-1 submember) presents the characteristics of transition from clayey shale lithofacies associa- tion to siliceous shale lithofacies association and then to mixed shale lithofacies association in the southern area, while the northern area shows a transition trend from mixed shale lithofacies association to siliceous shale lithofacies association and then to mixed shale lithofacies association. Horizontally, the lithofacies distribution is highly heterogeneous and has poor continuity. The reservoir characteristics of different lithofacies are different. Siliceous shale has good reservoir properties, with the characteristics of "high TOC content, high gas content and high brittle mineral content". The TOC content and gas content of clayey shale are high, but the content of brittle minerals is very low. The properties of mixed shale reservoirs are complex, and generally, the mixed shale reservoirs with high siliceous content have better properties. Based on TOC content, gas content and brittle mineral content, the shale lithofacies evaluation standard is established by combining analytic hierarchy process and entropy method, and the dominant lithofacies are determined. Mixed siliceous shale lithofacies, calcium-rich siliceous shale litho- facies, calcareous/siliceous mixed shale lithofaciesis are class Ⅰ dominant lithofacies; clay-rich siliceous shale lithofacies, mixed shale lithofacies and clayey/siliceous mixed shale lithofacies are class Ⅱ dominant lithofacies; mixed clayey shale lithofacies and silicon-rich clayey shale lithofacies are non-dominant lithofacies

Fabrication of Micro-Scale Gratings by Nanosecond Laser and Its Applications for Deformation Measurements

This paper experimentally investigated the fabrication and optimization of micro-scale gratings formed by nanosecond laser etching. The mechanism of nanosecond laser processing and the geometric phase analysis (GPA) are discussed, and the factors influencing the fabrication process including laser energy, laser fluence, and ablation threshold of material, are experimentally studied. In order to eliminate the dependence of the processing parameters on the samples, depositing Al film on a sample before laser processing is proposed for the fabrication of high-quality gratings. The energy of the laser pulse is optimized for clear line etching on Al film considering the distance between adjacent lines of parallel gratings. The optimal energy of the laser pulse is 9.8 μJ, and the optimum fluence is 9.5 J/mm2 with the waist radius of the laser beam 25.7 μm. With the optimal parameters, experimental results indicate that the highest frequency of parallel gratings is about 30 lines/mm, with a line width of 29 μm, and the distance between two adjacent laser pulses being of 10 μm. By performing tensile tests, micro-scale gratings fabricated on specimens are experimentally verified. The verification tests prove that the proposed fabrication method for the micro-scale gratings in GPA measurements is reliable and applicable, and the micro-scale gratings can be fabricated in many areas of interest, such as the crack tip, for deformation measurements. Furthermore, the adhesion between the Al film and the tested sample is strong enough so that the pattern sticks well to the sample

Enhanced mechanical, thermal and biocompatible nature of dual component electrospun nanocomposite for bone tissue engineering

Traditionally, in the Asian continent, oils are a widely accepted choice for alleviating bone-related disorders. The design of scaffolds resembling the extracellular matrix (ECM) is of great significance in bone tissue engineering. In this study, a multicompo-nent polyurethane (PU), canola oil (CO) and neem oil (NO) scaffold was developed using the electrospinning technique. The fabricated nanofibers were subjected to various physicochemical and biological testing to validate its suitability for bone tissue engineering. Morphological analysis of the multicomponent scaffold showed a reduc-Tion in fiber diameter (PU/CO 853 141.27 nm and PU/CO/NO 633 137.54 nm) compared to PU (890 116.911 nm). The existence of CO and NO in PU matrix was confirmed by an infrared spectrum (IR) with the formation of hydrogen bond. PU/CO displayed a mean contact angle of 108.7 0.58 while the PU/CO/NO exhibited hydrophilic nature with an angle of 62.33 2.52. The developed multicomponent also exhibited higher thermal stability and increased mechanical strength compared to the pristine PU. Atomic force microscopy (AFM) analysis depicted lower surface roughness for the nanocomposites (PU/CO 389 nm and PU/CO/NO 323 nm) than the pristine PU (576 nm). Blood compatibility investigation displayed the anticoagulant nature of the composites. Cytocompatibility studies revealed the non-Toxic nature of the developed composites with human fibroblast cells (HDF) cells. The newly developed porous PU nanocomposite scaffold comprising CO and NO may serve as a potential candidate for bone tissue engineering

Sediment Waves on the Western Slope of the Chukchi Rise (Arctic Ocean) and Their Implications for the Paleoenvironment

Based on multibeam bathymetric data and high-resolution shallow sub-bottom profiles acquired during China’s 10th Arctic Scientific Expedition Cruise in 2019, a sediment wave field was found on the western slope of the Chukchi Rise, in the Arctic Ocean. This sediment wave field developed on the lower slope with water depths of between 1200 m and 1800 m and stretched 15 km in the downslope direction. It comprised several parallel sediment waves, with wavelengths ranging from 700 m to 3400 m and wave heights from 12 m to 70 m. In the vertical direction, well-stratified deposits, tens of meters thick, were affected by sediment waves, which exhibit asymmetric waveforms and upslope migration trends. The morphological and seismostratigraphic characteristics of the sediment waves suggested their genesis as a result of the interaction between the bottom current and seafloor morphology, which was also supported by hydrographical data adjacent to the sediment wave field. It was infered that this bottom current was related to the Arctic Circumpolar Boundary Current, which many researchers suggest flows through the study area

Empirical Method for Evaluating Resilient Modulus of Saturated Silty Clay under Cyclic Loading

Resilient modulus of soil is crucial for the design of a structure on a foundation subjected to a cyclic loading (e.g., traffic load or machine vibration load). This paper conducted a series of dynamic triaxial tests of saturated silty clay, considering the influence of the factors of cyclic stress ratio (CSR), static deviatoric stress ratio (SDR), and overconsolidation ratio (OCR) on the resilient modulus and dynamic damping ratio of the soil. A cyclic loading with a form of half sine wave was used to model the traffic loading. The results showed that the soil was prone to failure under a higher SDR, even though the applied CSR was less than the critical CSR. The saturated silty clay performed a strain softening behavior and its dynamic properties deteriorated significantly when higher CSR and SDR and lower OCR were involved. Based on the test results, an empirical method with a form of exponential function was proposed to evaluate the resilient modulus of the soil, considering the combined effects of CSR and SDR and OCR. The proposed method was verified through a comparison with the test results in this study and from literatures, and some recommendations for its application were offered

Downregulation of miR-485-3p promotes proliferation, migration and invasion in prostate cancer through activation of TGF-β signaling

Background. Prostate cancer (PC) is the second leading cause of cancer-related death among men worldwide. Downregulation of miR-485-3p has been revealed to participate in the tumorigenesis and progression of many types of cancer. However, the clinical and biological role of miR-485-3p in PC remains largely unknown. Methods. The expression of miR-485-3p was analyzed in the published databases and detected in our clinical samples and cell lines by RT-qPCR assay. CCK8, transwell invasion and migration, and colony formation assays were performed to investigate the biological function of miR-485-3p. Bioinformatical analysis, RIP, western blotting and luciferase reporter assays were carried out to explore the downstream mechanism of miR-485-3p. Results. The level of miR-485-3p was downregulated in PC tissues, particularly in primary PC tissues with metastasis relative to normal prostate tissues. miR-485-3p downregulation was positively correlated with poor disease-free and overall survival in patients with PC. Functionally, miR-485-3p overexpression dramatically suppressed the proliferation, migration and invasion ability of PC cells in vitro. Mechanistically, miR-485-3p overexpression suppressed the activity of TGF-β signaling by targeting TGFBR2 to play tumor-suppressive roles in PC progression. Conclusion. Our study reports the miR-485- 3p/TGFBR2/ TGF-β signaling axis in tumor development of PC, suggesting miR-485-3p may be a potential target to develop therapeutic strategies against PC

A NEW SAURICHTHYS (ACTINOPTERYGII) FROM THE SPATHIAN (EARLY TRIASSIC) OF CHAOHU (ANHUI PROVINCE, CHINA)

A new species of Saurichthys, S. majiashanensis , is described. It comes from a series of marine vertebrate-bearing beds of the upper member of the Nanlinghu Formation outcropping in the large quarry at the top of Majiashan (Majia Hill) near Chaohu (Hefei City, Anhui Province, China). Its age is Middle Spathian (Olenekian, Early Triassic). This new species deeply differs from the several pre-Spathian species of Saurichthys mainly for having only two longitudinal scale rows together with a reduced grid-like structure for the neural elements in the vertebral column. Further derived characters are in the endoskeleton of the dorsal and anal fin, where radials articulate only to anterior lepidotrichia, the posterior ones being supported by the first scale from the caudal pedicle mid-dorsal and mid-ventral rows, deeply imbedded in the body. In addition, the haemal spines of the caudal region are much enlarged and reversed, with their distal parts pointing forwards. Though the skull is lacking, postcranial characters are enough to justify the erection of a new species. This new Saurichthys species, together with other few actinopterygians, can be considered as the oldest assemblage of the Triassic Middle Fish Fauna, which bloomed probably in the early Anisian and widespread especially all over the Tethys for the Middle Triassic and at least the Carnian in the Late Triassic. This new fish assemblage, together with some of the oldest marine reptiles, is considered as the beginning of the actual Triassic recovery among marine vertebrates

Sediment Waves on the Western Slope of the Chukchi Rise (Arctic Ocean) and Their Implications for the Paleoenvironment

Based on multibeam bathymetric data and high-resolution shallow sub-bottom profiles acquired during China&rsquo;s 10th Arctic Scientific Expedition Cruise in 2019, a sediment wave field was found on the western slope of the Chukchi Rise, in the Arctic Ocean. This sediment wave field developed on the lower slope with water depths of between 1200 m and 1800 m and stretched 15 km in the downslope direction. It comprised several parallel sediment waves, with wavelengths ranging from 700 m to 3400 m and wave heights from 12 m to 70 m. In the vertical direction, well-stratified deposits, tens of meters thick, were affected by sediment waves, which exhibit asymmetric waveforms and upslope migration trends. The morphological and seismostratigraphic characteristics of the sediment waves suggested their genesis as a result of the interaction between the bottom current and seafloor morphology, which was also supported by hydrographical data adjacent to the sediment wave field. It was infered that this bottom current was related to the Arctic Circumpolar Boundary Current, which many researchers suggest flows through the study area