Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin⁻Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis.

Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He⁻pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 µM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 µM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 µM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure⁻activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.

Design, Synthesis and Biological Evaluation of Ligustrazine-Flavonoid Derivatives as Potential Anti-Tumor Agents.

In the clinic some anti-tumor drugs have shown damage to normal blood vessels, which could lead to vascular diseases. Therefore, it is necessary to evaluate the effects of anti-tumor drugs on normal blood vessels at the beginning of the drug design process. In this study, ligustrazine (TMP) and flavonoids were selected as raw materials. Sixteen novel TMP-flavonoid derivatives were designed and synthesized. Interestingly, compounds 14 and 16 were obtained by hydrolysis of a dihydroflavone to a chalcone under alkaline conditions. The cytotoxicity of the TMP-flavonoid derivatives was evaluated on five human tumor cell lines and one classical type of normal endothelial cell lines (HUVEC-12) by an MTT assay. Part of the derivatives showed better anti-tumor activities than the corresponding raw materials. Among them, compound 14 exhibited the closest activity to the positive control against the Bel-7402 cell line (IC50 = 10.74 ± 1.12 µM; DDP IC50 = 6.73 ± 0.37 µM) and had no toxicity on HUVEC-12 (IC50 > 40 µM). Subsequently, fluorescence staining and flow cytometry analysis indicated that compound 14 could induce apoptosis of Bel-7402 cell lines. Moreover, the structure-activity relationships of these derivatives were briefly discussed.

Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS.

The neuroprotective evaluation of ligustrazine derivatives has become a research focus all over the world. A novel ligustrazine derivative, (3,5,6-Trimethylpyrazin-2-yl)methyl(E)-3-(4-((3,5,6-trimethylpyrazin-2-l)methoxy)phenyl)acrylate (T-CA), has shown protective effects against CoCl2-induced neurotoxicity in a differentiated PC12 cell model and middle cerebral artery occlusion (MCAO) model in our previous studies. However, nearly none of the parent drugs existed after rapid metabolism due to uncertain reasons. Thus, the fragmentation regularities of mass spectra, and metabolites, of T-CA in rats were examined using liquid chromatography-electrospray ionizationion trap mass spectrometry (LC/LTQ-Orbitrap MS) in this research. The main fragment ion, mass spectrum characteristics, and the structural information were elucidated. When compared with a blank sample, we identified five kinds of T-CA metabolites, including three phase I metabolites and two phase II metabolites. The results showed that the metabolic pathways of T-CA in rats via oral administration were hydrolysis (ether bond rupture, ester bond rupture), oxidation, reduction, glucose aldehyde acidification, etc. In addition, three main metabolites were synthesized and their structures were identified by superconducting high-resolution NMR and high-resolution mass spectroscopy (HR-MS). The neuroprotective activity of these metabolites was validated in a PC12 cell model. One of the metabolites (M2) showed significant activity (EC50 = 9.67 µM), which was comparable to the prototype drug T-CA (EC50 = 7.97 µM). The current study provides important information for ligustrazine derivatives, pertaining to the biological conversion process in vivo.

Origin and Formation Mechanism Investigation of Compound Precipitation from the Traditional Chinese Prescription Huang-Lian-Jie-Du-Tang by Isothermal Titration Calorimetry.

Previous studies have shown that compounds in the form of precipitate (CFP) from Huang-Lian-Jie-Du-Tang (HLJDT) were stable, and the CFP content reached 2.63% of the whole decoction and had good neuroprotective effects. However, there has been no research on their specific source. In this study, it was found that HLJDT CFP mainly came from the reaction of Scutellaria baicalensis and Coptis chinensis by studying the separated prescription components (accounting for 81.33% of HLJDT CFP). Unlike previous studies on HLJDT CFP, in this research the chemical composition of Scutellaria baicalensis-Coptis chinensis (SB-CC) CFP was identified by high performance liquid chromatography coupled with mass spectrometry (HPLC-MSn), which further proved that the main source of HLJDT CFP was Scutellaria baicalensis-Coptis chinensis CFP compared with previous HLJDT CFP studies. To explain the reaction mechanism between the decoctions of Scutellaria baicalensis and Coptis chinensis, isothermal titration calorimetry (ITC) was used to analyze their binding heat and the thermodynamic parameters (ΔH, ΔS, ΔG, n, Ka) of the reaction between baicalin and berberine, which are the main components of Scutellaria baicalensis and Coptis chinensis, respectively. The results showed that the reaction between decoctions of Scutellaria baicalensis and Coptis chinensis was exothermic and the reaction between baicalin and berberine was a spontaneous and enthalpy-driven chemical reaction, the binding ratio being 1:1. In addition, HLJDT CFP (EC50 = 14.71 ± 0.91 µg/mL) and SB-CC CFP (EC50 = 6.11 ± 0.12 µg/mL) showed similar protective activities on PC12 cells injured by cobalt chloride (CoCl2). This study provided a new angle to research on the main chemical components and therapeutic values of CFP in Traditional Chinese Medicine compounds.

An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents.

Glycyrrhetinic Acid (GA), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity.

A Horn Peptide-Thermoresponsive Hydrogel for Angiogenesis and Bone Regeneration.

The management of critical-sized bone defects presents a formidable clinical challenge, especially given the increasing incidence of bone diseases in the aging population. Consequently, there is an increased demand for minimally invasive bone repair materials that can effectively address this challenge, particularly in outpatient settings. In this study, the goal is to develop an injectable and biodegradable biomaterial that adheres to and fills bone-defect sites to support bone regeneration. The osteogenic and angiogenic activities of animal horn peptides are investigated by incorporating them into biologically active moieties, in combination with a novel thermosensitive hydrogel. The resulting thermosensitive hydrogel exhibited essential biological functionalities, allowing precise modulation of its physical and chemical properties. Notably, the hydrogel incorporating the horn peptide rapidly filled the bone defect site, promoting both angiogenesis and bone induction. Consequently, this approach significantly accelerates new bone regeneration. In summary, the findings of this study present a promising, minimally invasive solution for addressing critical-sized bone defects.

Identification of a novel oligopeptide from defatted walnut meal hydrolysate as a potential neuroprotective agent.

Free radical damage and oxidative stress are thought to play a crucial role in the development of neurodegenerative diseases. Walnut peptides, especially walnut oligopeptides, have been shown to protect nerve cells from oxidative stress and inflammatory damage, as well as improve memory function. In this study, walnut peptides were obtained from walnut meal through enzymatic hydrolysis, ultrafiltration, and gel filtration chromatography. A novel oligopeptide called AQ was successfully isolated and its chemical structure was identified as AASCDQ using ESI-MS/MS. AQ demonstrated remarkable scavenging activity against O2- free radicals (81.00%), DPPH free radicals (79.40%), and ABTS free radicals (67.09%) at a concentration of 1 mg mL-1. Furthermore, AQ exhibited strong neuroprotective effects against hydrogen peroxide-induced damage in SH-SY5Y cells, reducing cell injury and apoptosis. AQ also effectively inhibited the secretion of pro-inflammatory factors NO (IC50 = 46.03 ± 0.32 µM) and suppressed the expression of IL-6 and TNF-α in RAW264.7 cells stimulated by LPS. In vivo experiments demonstrated that AQ promoted angiogenesis in the quail chick chorioallantoic membrane assay and reduced ROS accumulation in Caenorhabditis elegans, thereby extending its lifespan. The anti-inflammatory mechanism of AQ was further confirmed by western blotting. In summary, the novel oligopeptide AQ possesses potential neuroprotective effects, including antioxidant, anti-inflammatory, angiogenic, and anti-aging properties, making it a promising candidate for the development of functional foods and pharmaceutical products.

Red blood cell-mimicking liposomes loading curcumin promote diabetic wound healing.

The excessive inflammatory response is known to be a major challenge for diabetic wound healing, while bacteria secreted toxin, α-hemolysin (Hlα), was recently reported to prolong inflammation and delay diabetic wound healing. In this study, we designed a red blood cell membrane (RBCM)-mimicking liposome containing curcumin (named RC-Lip) for the treatment of diabetic wounds. RC-Lips were successfully fabricated using the thin film dispersion method, and the fusion of RBC membrane with the liposomal membrane was confirmed via surface protein analysis. RC-Lips efficiently adsorbed Hlα, thereby reducing the damage and pro-apoptotic effects of Hlα on keratinocytes. Furthermore, they remarkably facilitated liposome uptake into macrophages with advanced curcumin release and regulation of M2 macrophage polarization. In a diabetic mouse and infected wound model, RC-Lips treatment significantly promoted wound healing and re-epithelialization while downregulating interleukin-1ß (IL-1ß) and upregulating interleukin-10 (IL-10). In summary, the results showed that the spongiform RC-Lips effectively modulate the inflammatory response after adsorbing Hlα and regulating M2 macrophage polarization, leading to a significant promotion of wound healing in diabetic mice. Hence, this study provides a prospective strategy of efficiently mediating inflammatory response for diabetic wounds.

Role of wound microbiome, strategies of microbiota delivery system and clinical management.

Delayed wound healing is one of the most global public health threats affecting nearly 100 million people each year, particularly the chronic wounds. Many confounding factors such as aging, diabetic disease, medication, peripheral neuropathy, immunocompromises or arterial and venous insufficiency hyperglycaemia are considered to inhibit wound healing. Therapeutic approaches for slow wound healing include anti-infection, debridement and the use of various wound dressings. However, the current clinical outcomes are still unsatisfied. In this review, we discuss the role of skin and wound commensal microbiota in the different healing stages, including inflammation, cell proliferation, re-epithelialization and remodelling phase, followed by multiple immune cell responses to commensal microbiota. Current clinical management in treating surgical wounds and chronic wounds was also reviewed together with potential controlled delivery systems which may be utilized in the future for the topical administration of probiotics and microbiomes. This review aims to introduce advances, novel strategies, and pioneer ideas in regulating the wound microbiome and the design of controlled delivery systems.

Identification of a three-gene prognostic signature for radioresistant esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is causing a high mortality rate due to the lack of efficient early prognosis markers and suitable therapeutic regimens. The prognostic role of genes responsible for the acquisition of radioresistance in ESCC has not been fully elucidated. AIM: To establish a prognostic model by studying gene expression patterns pertinent to radioresistance in ESCC patients. METHODS: Datasets were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The edgeR, a Bioconductor package, was used to analyze mRNA expression between different groups. We screened genes specifically responsible for radioresistance to estimate overall survival. Pearson correlation analysis was performed to confirm whether the expression of those genes correlated with each other. Genes contributing to radioresistance and overall survival were assessed by the multivariate Cox regression model through the calculation of ßi and risk score using the following formula: . RESULTS: We identified three prognostic mRNAs (cathepsin S [CTSS], cluster of differentiation 180 [CD180], and SLP adapter and CSK-interacting membrane protein [SCIMP]) indicative of radioresistance. The expression of the three identified mRNAs was related to each other (r > 0.70 and P < 0.05). As to 1-year and 3-year overall survival prediction, the area under the time-dependent receiver operating characteristic curve of the signature consisting of the three mRNAs was 0.716 and 0.841, respectively. When stratifying patients based on the risk score derived from the signature, the high-risk group exhibited a higher death risk and shorter survival time than the low-risk group (P < 0.0001). Overall survival of the low-risk patients was significantly better than that of the high-risk patients (P = 0.018). CONCLUSION: We have developed a novel three-gene prognostic signature consisting of CTSS, CD180, and SCIMO for ESCC, which may facilitate the prediction of early prognosis of this malignancy.

Bone Tissue Engineering in the Treatment of Bone Defects.

Bones play an important role in maintaining exercise and protecting organs. Bone defect, as a common orthopedic disease in clinics, can cause tremendous damage with long treatment cycles. Therefore, the treatment of bone defect remains as one of the main challenges in clinical practice. Today, with increased incidence of bone disease in the aging population, demand for bone repair material is high. At present, the method of clinical treatment for bone defects including non-invasive therapy and invasive therapy. Surgical treatment is the most effective way to treat bone defects, such as using bone grafts, Masquelet technique, Ilizarov technique etc. In recent years, the rapid development of tissue engineering technology provides a new treatment strategy for bone repair. This review paper introduces the current situation and challenges of clinical treatment of bone defect repair in detail. The advantages and disadvantages of bone tissue engineering scaffolds are comprehensively discussed from the aspect of material, preparation technology, and function of bone tissue engineering scaffolds. This paper also summarizes the 3D printing technology based on computer technology, aiming at designing personalized artificial scaffolds that can accurately fit bone defects.

Comparative Clinical Efficacy of 'Concurrent Chemoradiotherapy (CCRT) and Anlotinib' Than CCRT in Patients with Locally Advanced ESCC.

Objective: Radiotherapy or chemoradiotherapy has been preferred as the clinical therapeutic modalities to combat locally advanced esophageal squamous cell carcinoma (ESCC). The aim of this retrospective study is to ascertain combinatorial efficacy of anlotinib with concurrent radiotherapy (CCRT) rather than CCRT alone. Methods: Locally advanced ESCC patients registered between August 2018 to April 2019 in the third People's hospital of Zhengzhou, the First affiliated hospital of Zhengzhou University, Anyang Cancer Hospital, the Affiliated Hospital of Qingdao University were selected for this retrospective study; and these patients segregated into two groups subsequently who received combinatorial regimen with CCRT and anlotinib compared for treatment-related toxicity, response rates, safety, survival outcomes, than CCRT alone. Results: Progression free survival (PFS) was 0.577 (95% CI, 0.333-0.902, P = 0.014); the median overall survival time was 5 months (95% CI, 4.1-7.5) for the CCRT group, whereas 9 months (95% CI, 7.3-18.0) for the group received 'anlotinib with CCRT' (HR = 0.578, 95% CI, 0.337-0.924, P = 0.021). Overall objective response rates were considerable with a statistical difference between the two groups at 6 months (P1 = 0.027, P2 = 0.015) and 12 months (P1 = 0.012, P2 = 0.027). Overall adverse events are mitigated in combinatorial regimen than CCRT alone except the incidence of hypertension, which was higher in 'anlotinib with CCRT' group than CCRT group (P = 0.023). Total 13 patients exhibited hand-foot skin reactions in the group that received anlotinib in combination with CCRT. Anlotinib in combination with CCRT enhanced the overall survival (OS) rates, whereas incidence of treatment-related toxicity is minimized than CCRT alone. Conclusion: Combinatorial regimen of anlotinib with CCRT significantly enhanced clinical efficacy, safety and may benefit for treating the locally advanced ESCC patients.

Testing lncRNAs signature as clinical stage-related prognostic markers in gastric cancer progression using TCGA database.

LncRNA expression can be conducive to gastric cancer (GC) prognosis. The objective of this study is to ascertain five specific lncRNAs involved in tumor progression of GC and their role as prognostic markers to diagnose clinical stage-wise GC. High-throughput RNA sequencing data were obtained from The Cancer Genome Atlas (TCGA) database and performed genome-wide lncRNA expression analysis using edgeR package, Bioconductor.org, and R-statistical computing to analyze differentially expressed lncRNA analysis. Cutoff parameters were FDR < 0.05 and |Log2FC| > 2. Total 351 tumor samples with differentially expressed lncRNAs were divided into group-1 lncRNAs such as AC019117.2 and LINC00941, and group-2 lncRNAs such as LINC02410, AC012317.2, and AC141273.1 by 2:1. The Spearman correlation coefficients (p < 0.05) and correlation test function (cor.test ()) were performed for lncRNAs as per clinical stage. Cytoscape software was used to construct lncRNA-mRNA interaction networks. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway (p < 0.05) analysis were conducted using the clusterProfiler package. Kaplan-Meier survival analysis was performed to determine the overall survival of patients based on the expression of five lncRNAs in different clinical stages of GC. AC019117.2 and LINC00941 of group 1 inferred a positive correlation with clinical stages of stage I to stage IV, and their expressions were higher in tumor tissues than normal tissues. On the contrary, LINC02410, AC012317.2, and AC141273.1 of group 2 exhibited a negative correlation with clinical stage, and they exhibited more expression in normal tissues compared to tumor tissues. GO and KEGG pathway analysis reported that AC019117.2 may interact with LINC00941 via ITGA3 and trophoblast glycoprotein (TPBG) to foster tumor progression. Tumor-specific group-1 lncRNAs were conducive to the poor overall survival and exhibited a positive correlation with the clinical stages of stage I to stage IV in GC as per the lncRNA-mRNA networking analysis. These five lncRNAs could be considered as clinically useful lncRNA-based prognostic markers to predict clinical stage-wise GC progression.

The Outlook of the Development of Innovative Products from Biocompatible Natural Spider Silk in the Beauty Thread-Lifting Industry.

Embedding thread lift rhytidectomy, also known as "thread lifting" in China, with the natures of simple operation, less trauma and quick recovery, is progressively used in clinical practice as a new technology of face lifting. Herewith, a brief introduction of the previous advances of thread lifting techniques and materials in the facial beauty industry, combined with the discussion on various types of sutures, common complications, and the site of actions were provided. The main limitations of present thread lifting material include: (1) the use of non-absorbable sutures is liable to cause allergies and a series of complications; (2) the absorbable sutures are easily degradation, and people need to reshape in a relatively short period. Therefore, the high biocompatible spider silk was proposed as a novel material of thread lifting suture and related devices, the advantages and preliminary achievements on spider silk were also addressed.

High serum superoxide dismutase activity improves radiation-related quality of life in patients with esophageal squamous cell carcinoma.

OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in China. Intensity-modulated radiation therapy and volume-modulated arc therapy have become the main treatments for esophageal carcinoma; however, side effects caused by radiotherapy greatly impact the quality of life in these patients. This study aimed to explore the impact of serum superoxide dismutase (SOD) levels on the prognosis of patients with ESCC undergoing radiotherapy. METHODS: Patients aged between 18 and 80 years with lower-middle ESCC who underwent radiotherapy were eligible for this assessment. Adverse events, responses, treatment outcomes, and overall survival (OS) were assessed. Between 2012 and 2014, 195 patients were enrolled, of which 65 were assigned to the low- and high-SOD groups based on their serum SOD values. RESULTS: The baseline characteristics were similar between the two groups, except for the T staging. Adverse events in the low-SOD group were significantly higher than those in the high-SOD group (radiation esophagitis, p=0.007; radiation pneumonitis, p=0.032; leukopenia, p=0.023; thrombocytopenia, p=0.037; anemia, p=0.041). There were no significant differences in response, treatment outcomes, or OS. CONCLUSION: In conclusion, high serum SOD activity improved post-radiotherapy quality of life but did not impact the prognosis of patients with ESCC. To the best of our knowledge, this study is the first to report that serum SOD activity is associated with radiation-induced toxicity and moderately increased radiotherapeutic response in patients with ESCC undergoing radiotherapy.

lncRNA KLF3-AS1 Suppresses Cell Migration and Invasion in ESCC by Impairing miR-185-5p-Targeted KLF3 Inhibition.

Esophageal squamous cell carcinoma (ESCC) is a common cancer occurring in males and females worldwide. Accumulating evidence continues to highlight the crucial roles of long non-coding RNAs (lncRNAs) in the process of tumorigenesis. However, the regulatory mechanism of lncRNAs in ESCC remains unclear. The aim of this study is to elucidate the role of lncRNA Krüppel-like factor 3 antisense RNA 1 (KLF3-AS1) in ESCC by regulating miR-185-5p and KLF3. Initially, ESCC cell spheres with stem cell-like properties were prepared by suspension culture, and subsequently characterized by assessing colony formation ability and stem cell markers. LncRNA KLF3-AS1 was found to be poorly expressed in ESCC and could upregulate the expression of KLF3 by binding to miR-185-5p. lncRNA KLF3-AS1 upregulation was observed to inhibit miR-185-5p, thereby contributing to decreased expression of SOX2 and Oct4 (octamer-binding transcription factor 4). Furthermore, enhancement of lncRNA KLF3-AS1 resulted in reduced colony formation ability, cell invasion and migration, and tumor volume in vivo while promoting cell apoptosis in ESCC through downregulation of miR-185-5p. Collectively, this study indicated that lncRNA KLF3-AS1 inhibited ESCC cell invasion and migration by impairing miR-185-5p-mediated inhibition of KLF3, highlighting a promising novel potential target for ESCC treatment.

Periplaneta americana extract promotes intestinal mucosa repair of ulcerative colitis in rat.

PURPOSE: To investigate the mechanism of Periplaneta americana extract promoting intestinal mucosal repair of OXZ-induced colitis in rat. METHODS: All experiments used an equal number of male and female SD rats (n=48). We injected OXZ into the colon to induce UC rat model. To determine the optimal concentration of P. Americana's extract (PA-40), it was classified into low (L), medium (M), and high (H) doses. After OXZ treatment, each drug was administered by enema for 7 consecutive days. Rats were divided into the following 6 groups: (1) Saline treatment group (NC), (2) OXZ treatment UC model group (MC), (3) OXZ + budesonide group (BUN), (4) OXZ + PA-40 L group, (5) OXZ + PA-40 M group, (6) OXZ + PA-40 H group. Disease activity index (DAI) scores, colon length, histopathological score, serum cytokine level (IL-4, IL-10, iNOS, tNOS), and amount of MPO, EGF, IL-13 in colonic mucosa were measured. RESULTS: PA treatment had a significant healing effect on the OXZ-colitis model and significantly reduced the lesioned area, especially in the PA-40H groups. PA treatment did not alter the expression of IL-10 and MPO level, but increased EGF (epidermal growth factor) and decrease IL-13 in the colonic tissue. PA inhibited the rise of NOSs (nitric oxide synthase) and decreased the serum IL-4 level. CONCLUSIONS: The data suggest that Periplaneta americana extract may be a potential compound for the treatment of colonic lesions. The mechanism may be related to inhibiting the secretion of IL-13 and promoting the formation of EGF.

Vanadium occupation and its leachability differences in trioctahedral and dioctahedral mica.

Vanadium in black shale is found mainly in aluminosilicate minerals such as mica. Vanadium occupation in mica directly determines the vanadium leaching rate from black shale. The essential difference of leachability is demonstrated on the basis of quantum chemical simulation methods and experimental verification. The results show that the optimal location of vanadium in black shale is most likely in the octahedron of mica whether it is dioctahedral or trioctahedral mica. The simulations of the dissolution process of octahedral layers and the leaching experiments proved that the octahedron in trioctahedral mica was attacked by H+ and F- at lower related potential energy than in dioctahedral mica during the structural collapse process. It reflects a key feature of differentiation on the leachability of different mica-type black shale, which can provide guidance for selection of low-consumption leaching technology in actual production on account of structural differences.

CircRNA_100367 regulated the radiation sensitivity of esophageal squamous cell carcinomas through miR-217/Wnt3 pathway.

BACKGROUND: Circular RNAs (circRNAs) play important roles in regulating the radioresistance of esophageal squamous cell carcinoma (ESCC). This study aimed to determine the role of hsa_circRNA_100367 in regulating radioresistance of ESCC. RESULTS: Higher expression and potency of endothelial to mesenchymal transformation (EMT) was found in radioresistant ESCC cells (KYSE-150R) than in ESCC cells (KYSE-150). Silencing circRNA_100367 inhibited the proliferation and migration of KYSE-150R cells, and decreased the expression of ß-catenin (an important molecule in Wnt pathway) in KYSE-150R cells. Additionally, circRNA_100367 bound to miR-217, and miR-217 targeted Wnt3. Low Wnt3 expression was associated with the short survival time in patients with ESCC and Wnt3 knockdown inhibited the proliferation and migration of KYSE-150R cells. CircRNA_100367 enhanced the radioresistance of KYSE-150R cells through miR-217/Wnt3 pathway. In vivo, circRNA_100367 silence reduced the growth of KYSE-150R cells under radiation. CONCLUSION: Our results revealed that circRNA_100367 attenuated radioresistance of ESCC through miR-217/Wnt3 pathway. METHODS: CircRNAs related with the radioresistance of ESCC were analyzed by hierarchical cluster analysis. The relationship between circRNA_100367 and miR-217, Wnt3 was detected by RNA immunoprecipitation (RIP), RNA pull-down and luciferase reporte assays. The proliferation and migration ESCC cells were detected by MTT, Transwell and colony formation assays.

Synthesis and biological evaluation of podophyllotoxin derivatives as selective antitumor agents.

To improve podophyllotoxin's cytotoxicity and selective effect, twenty-two podophyllotoxin derivatives had been designed and synthesized. The cytotoxicity of these compounds was evaluated on A549, MCF-7, HepG2 and L-02 cell lines. As a result, most of the compounds were more potent than the positive drugs Etoposide (VP-16) and Doxorubicin which were widely used in clinical for antitumor. There were no magnitude differences about these de-protected (without Boc group) podophyllotoxin amino acid derivatives' cytotoxicity between three tumor cell lines and normal hepatic L-02 cells. Interestingly, some protected (with Boc group) amino acid derivatives and some ligustrazine derivatives showed high selectivity, especially the compound 2 (sarcosine derivative with Boc group). It exhibited highly selectivity both on the cancer cells and the normal cells. The IC50 of compound 2 was 9.5 ±â€¯0.03 nM, 132.6 ±â€¯24.1 nM, 96.4 ±â€¯1.3 nM and 160.2 ±â€¯4.7 nM against A549, MCF-7, HepG2 and L-02 cells, respectively. The SI (IC50L-02/IC50A549) value of compound 2, Doxorubicin and Etoposide was 16.9, 0.2 and 0.5, respectively. Meanwhile, SI (IC50MCF-7/IC50A549) value and SI (IC50HepG2/IC50A549) value of compound 2 were 14.0 and 10.1, respectively. In summary, compound 2 showed high selectivity especially on A549 cells. Further research on cell apoptosis indicated that compound 2 could induce apoptosis of A549 cells through nuclei fragmentation and had lower toxicity to normal hepatic L-02 cells. The detection of apoptosis and cell cycle analysis indicated that compound 2 induced A549 cells apoptosis and prevented A549 cells transition from S to G2 phase while there were no obvious changes on L-02 cells. Moreover, the structure-activity relationships of these derivatives were briefly discussed.