Diagnosis of Esophageal Squamous Cell Carcinoma by High-Performance Serum Metabolic Fingerprints: A Retrospective Study.

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy, and timely diagnosis of ESCC contributes to an increased cancer survival rate. However, current detection methods for ESCC mainly rely on endoscopic examination, limited by a relatively low participation rate. Herein, ferric-particle-enhanced laser desorption/ionization mass spectrometry (FPELDI MS) is utilized to record the serum metabolic fingerprints (SMFs) from a retrospective cohort (523 non-ESCC participants and 462 ESCC patients) to build diagnostic models toward ESCC. The PFELDI MS achieved high speed (≈30 s per sample), desirable reproducibility (coefficients of variation < 15%), and high throughput (985 samples with ≈124 200 data points for each spectrum). Desirable diagnostic performance with area-under-the-curves (AUCs) of 0.925-0.966 is obtained through machine learning of SMFs. Further, a metabolic biomarker panel is constructed, exhibiting superior diagnostic sensitivity (72.2-79.4%, p < 0.05) as compared with clinical protein biomarker tests (4.3-22.9%). Notably, the biomarker panel afforded an AUC of 0.844 (95% confidence interval [CI]: 0.806-0.880) toward early ESCC diagnosis. This work highlighted the potential of metabolic analysis for accurate screening and early detection of ESCC and offered insights into the metabolic characterization of diseases including but not limited to ESCC.

Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression.

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates. Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates. Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration. However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo. Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression. Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression. Results: We show that loss of Kindlin-2 markedly inhibits KrasG12D-driven pancreatic cancer progression in vivo as well as in vitro. Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation. Loss of Kindlin-2 blocked DDX3X from binding to the 5'-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth. Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2. Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression.

Late Cambrian geomagnetic instability after the onset of inner core nucleation.

The Ediacaran Period marks a pivotal time in geodynamo evolution when the geomagnetic field is thought to approach the weak state where kinetic energy exceeds magnetic energy, as manifested by an extremely high frequency of polarity reversals, high secular variation, and an ultralow dipole field strength. However, how the geodynamo transitioned from this state into one with more stable field behavior is unknown. Here, we address this issue through a high-resolution magnetostratigraphic investigation of the ~494.5 million-year-old Jiangshanian Global Standard Stratotype and Point (GSSP) section in South China. Our paleomagnetic results document zones with rapid reversals, stable polarity and a ~80 thousand-year-long interval without a geocentric axial dipole field. From these changes, we suggest that for most of the Cambrian, the solid inner core had not yet grown to a size sufficiently large to stabilize the geodynamo. This unusual field behavior can explain paleomagnetic data used to define paradoxical true polar wander, supporting instead the rotational stability of the solid Earth during the great radiation of life in the Cambrian.

Clinical experiences of final-year nursing students during the COVID-19 pandemic: A systematic review and meta-synthesis.

OBJECTIVES: This systematic review aimed to qualitatively synthesise existing literature to examine the clinical nursing experiences of final-year nursing students during the COVID-19 pandemic and provide recommendations for the effective management of clinical placement of nursing students. DESIGN: A qualitative systematic review was conducted and reported following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. DATA SOURCES: Five electronic databases were searched and qualitative studies were included for analysis if they focussed on the clinical nursing experiences of final-year nursing students during the COVID-19 pandemic. REVIEW METHODS: Data synthesis was conducted by extracting all findings, developing categories, and producing synthesised findings. RESULTS: Four synthesised findings were concluded: 1) facing the unknown and willingness to help, 2) challenging the clinical environment, 3) transition improving professional identity, and 4) finding ways out of the pandemic. CONCLUSIONS: The transition of nursing students to clinical nursing practice during the pandemic is a personally and professionally challenging process, while nursing students try to adapt to the changing clinical environment and enhance their professional identity. Nursing managers and health policymakers should acknowledge the challenges encountered by nursing students during the pandemic and support the professional growth of future nursing teams by providing high-quality supervision.

CHILKBP protects against podocyte injury by preserving ZO-1 expression.

Glomerular diseases afflict millions of people and impose an enormous burden on public healthcare costs worldwide. Identification of potential therapeutic targets for preventing glomerular diseases is of considerable clinical importance. CHILKBP is a focal adhesion protein and modulates a wide array of biological functions. However, little is known about the role of CHILKBP in glomerular diseases. To investigate the function of CHILKBP in maintaining the structure and function of podocytes in a physiologic setting, a mouse model (CHILKBP cKO) was generated in which CHILKBP gene was conditionally deleted in podocytes using the Cre-LoxP system. Ablation of CHILKBP in podocytes resulted in massive proteinuria and kidney failure in mice. Histologically, typical podocyte injury including podocyte loss, foot process effacement, and glomerulosclerosis was observed in CHILKBP cKO mice. Mechanistically, we identified ZO-1 as a key junctional protein that interacted with CHILKBP. Loss of CHILKBP in podocytes exhibited a significant reduction of ZO-1 expression, leading to abnormal actin organization, aberrant slit diaphragm protein expression and compromised podocyte filtration capacity. Restoration of CHILKBP or ZO-1 in CHILKBP-deficient podocytes effectively alleviated podocyte injury induced by the loss of CHILKBP in vitro and in vivo. Finally, we showed the glomerular expression of CHILKBP and ZO-1 was decreased in patients with proteinuric kidney diseases. Our findings reveal a novel signaling pathway consisting of CHILKBP and ZO-1 that plays an essential role in maintaining podocyte homeostasis and suggest novel therapeutic approaches to alleviate glomerular diseases.

Optimization of Nanofiber Wearable Heart Rate Sensor Module for Human Motion Detection.

In order to further improve the detection performance of the wearable heart rate sensor for human physiological and biochemical signals and body kinematics performance, the wearable heart rate sensor module was optimized by using nanofibers. Nanoparticle-doped graphene films were prepared by adding nanoparticles to a graphene oxide solution. The prepared film was placed in toluene, and the nanoparticles were removed to complete the preparation of a graphene film with a porous microstructure. The graphene film and the conductive film together formed a wearable heart rate sensor module. The strain response test of the porous graphene film wearable heart rate sensor module verifies the validity of the research in this paper. The resistance change of the wearable heart rate sensor module based on the PGF-2 film is 8 to 16 times higher than that of the RGO film, and the sensitivity is better, proving that the sensor module designed by this method shows significant application potential in human motion detection.

6,7-Dimethoxycoumarin Influences the Erythroid Differentiation of Human Chronic Myelogenous Leukemia K562 Cells through Regulating FOXO3/p27 Signal Pathway.

Objective: To study the pharmacological activity and the mechanism of action of natural compounds derived from 6,7-dimethoxycoumarin on the differentiation of human chronic myeloid leukemia K562 cells. Methods: We use MTT assay (Sigma-Aldrich, USA) to detect cell viability; use flow cytometry to analyze DNA content for cell cycle analysis; use benzidine staining to synthesize hemoglobin to determine K562 cell differentiation; use western blot analysis and qPCR to detect the expression levels of FOX03, P27, CDK4, and their phosphorylation; and use the AOBS laser scanning confocal system (Leica, Wetzlar, Germany) to analyze and quantify the number of positive green spots. The statistical methods used are one-way analysis of variance (ANOVA) and Dunnett's test to analyze within and between groups. Results: In order to explore the effect of 6,7-dimethoxycoumarin on the differentiation of K562 cell erythrocytes, it was concluded that 6,7-dimethoxycoumarin promotes the differentiation of K562 cell erythrocytes; the proliferation of K562 cells was detected by MTT method, and the results showed that 6,7-dimethoxycoumarin can inhibit the proliferation of K562 cells; to evaluate the effect of 6,7-dimethoxycoumarin on the proliferation of K562 cells, the results showed that 6,7-dimethoxycoumarin increased the expression of FOXO3, P27, CDK4, and CDK65, and decreased the phosphorylation of CDK4 and CDK6 proteins. To further explore the effect of knocking out FOXO3 on cell differentiation, the results show that 6,7-dimethoxycoumarin can reduce the differentiation and proliferation of K562 cells by increasing the expression of FOXO3. Conclusion: This study extended the understanding of the pharmacological activity of 6,7-dimethoxycoumarin and may provide a potential new target for the treatment of chronic myelogenous leukemia. However, we still need to further study the specific molecular capabilities of 6.7 dimethylcoumarin to understand their possible capture mechanism.

Palladium-Catalyzed Carbonylative Sonogashira/Annulation Reaction: Synthesis of Indolo[1,2-b]isoquinolines.

A palladium-catalyzed carbonylative Sonogashira/annulation reaction for the synthesis of indolo[1,2-b]isoquinolines has been developed. Tetracyclic 6/5/6/6 indoline skeletons were synthesized in moderate to good yields from easily available 2-bromo-N-(2-iodophenyl)benzamides and terminal alkynes. Notably, this efficient methodology established three C-C bonds and a C-N bond through a one-step transformation and provided a new method for the synthesis of indolo[1,2-b]isoquinoline derivatives.

Identification of novel biomarkers involved in doxorubicin-induced acute and chronic cardiotoxicity, respectively, by integrated bioinformatics.

Background: The mechanisms of doxorubicin (DOX) cardiotoxicity were complex and controversial, with various contradictions between experimental and clinical data. Understanding the differences in the molecular mechanism between DOX-induced acute and chronic cardiotoxicity may be an ideal entry point to solve this dilemma. Methods: Mice were injected intraperitoneally with DOX [(20 mg/kg, once) or (5 mg/kg/week, three times)] to construct acute and chronic cardiotoxicity models, respectively. Survival record and ultrasound monitored the cardiac function. The corresponding left ventricular (LV) myocardium tissues were analyzed by RNA-seq to identify differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) found the key biological processes and signaling pathways. DOX cardiotoxicity datasets from the Gene expression omnibus (GEO) database were combined with RNA-seq to identify the common genes. Cytoscape analyzed the hub genes, which were validated by quantitative real-time PCR. ImmuCo and ImmGen databases analyzed the correlations between hub genes and immunity-relative markers in immune cells. Cibersort analyzed the immune infiltration and correlations between the hub genes and the immune cells. Logistic regression, receiver operator characteristic curve, and artificial neural network analysis evaluated the diagnosis ability of hub genes for clinical data in the GEO dataset. Results: The survival curves and ultrasound monitoring demonstrated that cardiotoxicity models were constructed successfully. In the acute model, 788 DEGs were enriched in the activated metabolism and the suppressed immunity-associated signaling pathways. Three hub genes (Alas1, Atp5g1, and Ptgds) were upregulated and were negatively correlated with a colony of immune-activating cells. However, in the chronic model, 281 DEGs showed that G protein-coupled receptor (GPCR)-related signaling pathways were the critical events. Three hub genes (Hsph1, Abcb1a, and Vegfa) were increased in the chronic model. Furthermore, Hsph1 combined with Vegfa was positively correlated with dilated cardiomyopathy (DCM)-induced heart failure (HF) and had high accuracy in the diagnosis of DCM-induced HF (AUC = 0.898, P = 0.000). Conclusion: Alas1, Atp5g1, and Ptgds were ideal biomarkers in DOX acute cardiotoxicity. However, Hsph1 and Vegfa were potential biomarkers in the myocardium in the chronic model. Our research, first, provided bioinformatics and clinical evidence for the discovery of the differences in mechanism and potential biomarkers of DOX-induced acute and chronic cardiotoxicity to find a therapeutic strategy precisely.

Serum nuclear factor IB as a novel and noninvasive indicator in the diagnosis of secondary hyperparathyroidism.

BACKGROUND: Chronic renal failure (CRF) referred to chronic progressive renal parenchymal damage caused by various causes, with metabolite retention and imbalance of water, electrolyte, and acid-base balance as the main clinical manifestations. Secondary hyperparathyroidism (sHPT) was a common complication in maintenance hemodialysis patients with CRF. Nuclear factor IB (NFIB) was a newly found tumor suppressor gene in various cancers. The present study aimed to illustrate the role of NFIB in sHPT clinical diagnosis and treatment response. METHODS: A retrospective, case-control study, including 189 patients with sHPT and 106 CRF patients without sHPT, compared with 95 controls. Serum NFIB and 1,25(OH)2 D3 levels were measured by RT-qPCR and ELISAs, respectively. ROC analysis was conducted to verify the diagnostic value of NFIB in sHPT. Spearman's correlation analysis was conducted to verify the association between NFIB and bone mineral density (BMD) scores. After 6 months of treatment, the variance of NFIB and 1,25(OH)2 D3 in different groups was recorded. RESULTS: The expression of NFIB was significantly lower in serum samples from sHPT and non-sHPT CRF patients, compared to controls. Clinicopathological information verified sHPT was associated with NFIB, parathyroid hormone (PTH), serum calcium, serum phosphorus, time of dialysis, and serum 1,25(OH)2 D3 levels. Spearman's correlation analysis illustrated the positive correlation between NFIB levels and BMD scores. At receiver operator characteristic (ROC) curve analysis, the cutoff of 1.6508 for NFIB was able to identify patients with sHPT from healthy controls; meanwhile, NFIB could also discriminate sHPT among CRF patients as well (cutoff = 1.4741). Furthermore, we found that during 6 months of treatment, NFIB levels were gradually increased, while PTH and serum P levels were decreased. CONCLUSIONS: Serum NFIB was a highly accurate tool to identify sHPT from healthy controls and CRF patients. Due to its simplicity, specificity, and sensitivity, this candidate can be proposed as a first-line examination in the diagnostic workup in sHPT.

Physcion 8-O-ß-glucopyranoside ameliorates liver fibrosis through inflammation inhibition by regulating SIRT3-mediated NF-κB P65 nuclear expression.

Physcion 8-O-ß-glucopyranoside (PSG), an anthraquinone extracted from Rumex japonicus Houtt, has various pharmacological effects, however, the effect of PSG on liver fibrosis and its related mechanism remain to be determined. We here showed that PSG ameliorated liver injury and liver fibrosis, decreased collagen deposition and inhibited inflammation in carbon tetrachloride (CCl4)-induced rats. Consistent with the in vivo results, PSG suppressed the transforming growth factor-ß1 (TGF-ß1)-induced cell viability, liver fibrosis and secretion of inflammatory factors in hepatic stellate cells (HSCs). Interestingly, PSG increased the enzyme activity and promoter activity of sirtuin 3 (SIRT3) in fibrotic liver and activated HSCs. In addition, PSG notably increased the mRNA and protein expression of SIRT3 both in vivo and in vitro. Depletion of SIRT3 either by using 3-TYP (SIRT3 selective inhibitor) or SIRT3 siRNA attenuated the anti-inflammatory effect of PSG in activated HSCs. Further study found that TGF-ß1 increased the nuclear expression of NF-κB p65, but showed no obvious effect on the total NF-κB p65 expression. Compared to the control adenovirus (Ad.mk), overexpression of SIRT3 by infecting adenovirus encoding SIRT3 (Ad.SIRT3) notably decreased the nuclear expression of NF-κB p65 in activated HSCs. Our results demonstrated that PSG attenuated inflammation by regulating SIRT3-mediated NF-κB P65 nuclear expression in liver fibrosis, providing novel molecular insights into the anti-fibrotic effect of PSG.

Association Between Dietary Fiber Intake and Non-alcoholic Fatty Liver Disease in Adults.

Background: Evidence on the association of non-alcoholic fatty liver disease (NAFLD), a public health concern, with dietary fiber intake is inconsistent. Objective: To investigate the relationship between dietary fiber intake from different sources and NAFLD risk in US adults. Methods: Data were collected from the 2007-2014 National Health and Nutrition Examination Survey. NAFLD was defined as a United States Fatty Liver Index ≥30, and dietary fiber intake was assessed through two 24-h dietary recall interviews. Logistic regression and restricted cubic spline models were used to explore the relationship of dietary intakes of total, cereal, fruit, and vegetable fiber with NAFLD risk. Results: A total of 6,613 participants, aged more than 20 years, were included in this study. After adjusting for multiple confounding factors, the odds ratios and 95% confidence intervals of NAFLD for the highest quartile vs. lowest quartile intakes of total, cereal, fruit, and vegetable fiber were 0.12 (0.08-0.16), 0.25 (0.19-0.33), 0.41 (0.33-0.52), and 0.42 (0.32-0.56), respectively. In stratified analyses by sex and age, statistically significant negative associations of dietary intakes of total, cereal, fruit, and vegetable fiber with NAFLD risk were observed in all participants. Dose-response analysis indicated a non-linear correlation between NAFLD risk and dietary intake of total fiber, whereas the relationship was linear for cereal, fruit, and vegetable fiber intakes. Conclusion: Total, cereal, fruit, and vegetable fiber intakes exhibit negative correlations with NAFLD risk in the general adult population in the United States.

Comparative in vivo pharmacokinetics study of affeic acid, isoferulic acid and ferulic acid in crude and three different prepared Cimicifuga foetida L.

Our study investigated the differences in pharmacokinetics of three major components of crude Cimicifuga foetida L. and its fried product and honey- and liquor-prepared products. A rapid and sensitive ultra-high performance liquid chromatography with tandem mass spectrometry approach was established for determing caffeic acid, isoferulic acid and ferulic acid in rat plasma. The approach has good linearity, precision, accuracy, recovery and stability. Phenolic acid was rapidly absorbed. The times to peak concentration were shorter in the processed group than those for the crude product, with their values of <30 min. The peak concentration values of caffeic acid and isoferulic acid were higher in the crude group than in the processed groups (p < 0.05). Area under the curve values of the three phenolics in the crude group were significantly higher than those of the processed groups (p < 0.05).

Possible links between extreme oxygen perturbations and the Cambrian radiation of animals.

The role of oxygen as a driver for early animal evolution is widely debated. During the Cambrian explosion, episodic radiations of major animal phyla occurred coincident with repeated carbon isotope fluctuations. However, the driver of these isotope fluctuations and potential links to environmental oxygenation are unclear. Here, we report high-resolution carbon and sulphur isotope data for marine carbonates from the southeastern Siberian Platform that document the canonical explosive phase of the Cambrian radiation from ~524 to ~514 Myr ago. These analyses demonstrate a strong positive covariation between carbonate δ13C and carbonate-associated sulphate δ34S through five isotope cycles. Biogeochemical modelling suggests that this isotopic coupling reflects periodic oscillations in atmospheric O2 and the extent of shallow ocean oxygenation. Episodic maxima in the biodiversity of animal phyla directly coincided with these extreme oxygen perturbations. Conversely, the subsequent Botoman-Toyonian animal extinction events (~514 to ~512 Myr ago) coincided with decoupled isotope records that suggest a shrinking marine sulphate reservoir and expanded shallow marine anoxia. We suggest that fluctuations in oxygen availability in the shallow marine realm exerted a primary control on the timing and tempo of biodiversity radiations at a crucial phase in the early history of animal life.

Fast compensation for arbitrary focusing through scattering media.

We introduce a fast compensation scheme to realize arbitrary focusing after propagation through a scattering sample. Theoretical analysis of the effect of cross terms on multi-point focusing is conducted based on the transmission matrix theory. The results show that the cross-term influence is very significant, which needs to be considered. The Multi-Population Genetic Algorithm is adopted to retrieve the input mode for the suppression of the cross-term effect. In order to realize fast compensation and reduce measurement noise, the off-axis holographic method is used to measure the large transmission matrix, which reduces the number of measurements compared with the traditional method. In the experiment, after retrieving the input phase, we obtain a high-quality focal output, and the signal-to-noise ratio is increased by 13.6 dB.

Cryptotanshinone inhibits the growth and invasion of colon cancer by suppressing inflammation and tumor angiogenesis through modulating MMP/TIMP system, PI3K/Akt/mTOR signaling and HIF-1α nuclear translocation.

The aim of this study was to evaluate the pharmacological effects of CPT on CT26 colon cancer cells in vivo and in vitro, and to reveal the potential mechanism. CPT suppressed the proliferation and growth of CT26 colon cancer in vitro and in vivo. CPT inhibited the invasion of CT26 cells in vitro, and decreased the protein expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 but increased those of tissue inhibitor of metallopeptidase-1 (TIMP-1) and TIMP-2 in vitro and in vivo. It also inhibited tumor cell-induced angiogenesis of endothelial cells in vitro and rat aortic ring angiogenesis ex vivo, and possibly by suppressing angiogenesis-associated factors. CPT suppressed the expressions of inflammatory factors in vivo and in vitro. Mechanism studies showed that CPT inhibited the PI3K/AKT/mTOR signaling pathway, as evidenced by decreased expressions of phospho-PI3K (p-PI3K), p-Akt and p-mTOR. Moreover, CPT significantly suppressed the nuclear expression but increased the cytosolic expression of hypoxia inducible factor-1α (HIF-1α). Collectively, CPT inhibited the growth, invasion, inflammation and angiogenesis in CT26 colon cancer, and at least partly, by regulating the PI3K/Akt/mTOR signaling and the nuclear translocation of HIF-1α.

Stachydrine ameliorates carbon tetrachloride-induced hepatic fibrosis by inhibiting inflammation, oxidative stress and regulating MMPs/TIMPs system in rats.

Inflammation and oxidative stress are two crucial factors mediating liver fibrosis. Stachydrine (STA) is a naturally occurring compound extracted from a medicinal plant Leonuru heterophyllus, which can inhibit the proliferation and induce the apoptosis of breast cancer cells, relieve high glucose-induced endothelial cell senescence and isoproterenol-induced cardiac hypertrophy, and exert antitumor effects. However, its roles in hepatic fibrosis remain largely unknown. We aimed to evaluate the effect of STA on carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats and to elucidate the possible mechanisms. STA alleviated the pathological changes caused by CCl4 injection in livers compared to the normal liver. Hematoxylin-eosin staining further showed that STA treatment remarkably improved the liver histology, as evidenced by mitigated hepatic steatosis, necrosis, and fibrotic septa. STA reduced the liver/body weight ratio and the serum levels of aminotransferase, aspartate aminotransferase and alkaline phosphatase. It also significantly decreased collagen deposition and hydroxyproline level. Both mRNA and protein levels of α-SMA, α1(I)-procollagen and fibronectin were decreased by STA compared to those of the model group. STA significantly inhibited the expressions of inflammatory factors interleukin-6 (IL-6), IL-8, IL-1ß, tumor necrosis factor-α, inducible nitric oxide synthase and cyclooxygenase-2. It suppressed oxidative stress by decreasing malondialdehyde level as well as increasing glutathione level and enzymatic activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase. STA also significantly increased the protein expressions of tissue inhibitor of metallopeptidase-1 (TIMP-1) and TIMP-2 but decreased those of matrix metalloproteinase-2 (MMP-2) and MMP-9, indicating excessive basement membrane in the fibrotic liver. Collectively, STA has potent protective effects on the liver, with therapeutic implication for liver fibrosis.

Catalpol suppressed proliferation, growth and invasion of CT26 colon cancer by inhibiting inflammation and tumor angiogenesis.

Tumor angiogenesis and inflammation, which play important roles in mediating tumor proliferation and growth, should be inhibited to effectively regulate tumor progression. Catalpol, a main active ingredient extracted from Rehmannia glutinosa, has various pharmacological actions including anti-apoptotic, anti-inflammatory, hypoglycemic and anti-cancer properties. However, the pharmacological effect of catalpol on colon cancer remains largely unknown. The aim of this study was to investigate the effects of catalpol on the proliferation, growth, invasion, tumor angiogenesis and inflammation of CT26 colon cancer in vitro and in vivo. Catalpol inhibited the proliferation and growth of CT26 cells in concentration- and dose-dependent manners in vitro and in vivo, respectively. Catalpol suppressed the invasion of CT26 cells in vitro. Tumor cell-induced vascularization of endothelial cells and rat aortic ring angiogenesis were impaired by catalpol. Catalpol reduced the secretions of several angiogenic markers in the culture supernatant of CT26 cells. Immunohistochemical assay showed that catalpol inhibited the expressions of angiogenic markers vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), hypoxia inducible factor-1α (HIF-1α) and basic fibroblast growth factor (bFGF) in colon cancer tissues. Moreover, catalpol inhibited the expressions of inflammatory factors interleukin-1ß (IL-1ß), IL-6, IL-8, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS). Taken together, catalpol suppressed the growth and invasion of CT26 colon cancer cells mainly by inhibiting inflammation and tumor angiogenesis, as a promising candidate compound for treating colon cancer.

Attenuation of ß-Amyloid Toxicity In Vitro and In Vivo by Accelerated Aggregation.

Accumulation and aggregation of ß-amyloid (Aß) peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer's disease. The self-assembled Aß molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate Aß toxicity is to facilitate the conversion of Aß intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of Aß by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of Aß monomers, accompanying reduced Aß cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of Aß oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the Aß aggregation-promotion effect can potentially be useful for developing strategies to reduce Aß toxicity.