The combined effect of handgrip strength and obesity phenotype on the risk of stroke in Chinese middle-aged and elderly: A cohort study.

OBJECTIVE: The aim of this study was to investigate the combined effect of handgrip strength (HGS) and obesity phenotype on the risk of stroke in Chinese middle-aged and elderly people. METHODS: The data was used from the China Health and Retirement Longitudinal Study (CHARLS). Middle-aged and older adults who participated in surveys between 2011 and 2018 were included in the study. They were divided into 4 different types of obesity phenotypes based on obesity and metabolic status: metabolically healthy non-overweight/obesity (MHNO), metabolically healthy overweight/obesity (MHO), metabolically abnormal non-overweight/obesity (MANO), and metabolically abnormal overweight/obesity (MAO). The HGS level was divided into low and high groups according to the median values. Cox proportional risk regression model was used to analyze the joint effect of HGS and obesity phenotype on the risk of stroke among participants. RESULTS: A total of 7904 participants aged 58.89±9.08 years were included in this study. After adjusting for potential confounders, high HGS&MHO (HR=1.86, 95 % CI=1.12-3.09), high HGS&MANO (HR=2.01, 95 %CI=1.42-2.86), high HGS&MAO (HR=2.01, 95 % CI=1.37-2.93), low HGS&MHNO (HR=1.57, 95 % CI=1.00-2.46), low HGS&MHO (HR=2.09, 95 % CI=1.29-3.38), low HGS&MANO (HR=2.02, 95 % CI=1.35-3.03), and low HGS&MAO (HR=2.48, 95 % CI=1.72-3.58) group had significantly higher risks of stroke than the high HGS&MHNO group. CONCLUSION: The coexistence of metabolically unhealthy and low HGS can synergistically increase the risk of stroke in Chinese middle-aged and elderly people.

Analysis of Chemical Constituents of Miao Ethnomedicine Heiguteng Zhuifeng Huoluo Capsule (HZFC) and the Discovery of Active Substances in the Treatment of Rheumatoid Arthritis.

In this study, the chemical substances of Heiguteng Zhuifeng Huoluo Capsule (HZFC) and its potential active ingredients for the treatment of rheumatoid arthritis (RA) were characterized and analyzed by medicinal chemistry combined with bioinformatics methods. Also, the potential active ingredients of HZFC against RA were verified by lipopolysaccharide (LPS)-induced macrophage activation model. The results showed that 79 chemical constituents were successfully identified, mainly including phenylpropanoids, flavonoids, and alkaloids. Among them, 13 active components were closely related to the nine core targets (FASN, ALOX5, EGFR, MMP1, CYP2D6, CNR1, AR, MAOA, and FKBP5) of HZFC in the treatment of RA. Molecular docking further proved that 13 active components had strong docking activity with 9 core targets. In the verification experiment of the LPS-induced RAW 264.7 macrophage model, the verified components (magnoflorine, N-feruloyltyramine, canadine, rutin, quercetin-3-O-glucoside, and pseudocolumbamine) all showed a clear inhibitory effect on the secretion of inflammatory factors in model cells. The above research results suggest that 13 components such as stepharanine, rutin, quercetin-3-O-glucoside, corydine methyl ether, canadine, 8-oxoepiberberine, disinomenine, deosinomenine glucoside, tuduranine, magnoflorine, isosinomenine, pseudocolumbamine, and N-feruloyltyramine may be the main active substances of HZFC in the treatment of RA.

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/ß-Catenin and JAK-2/STAT-3 Signaling Pathways.

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/ß-catenin (wingless-int1/ß-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of ß-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/ß-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

CP41, a novel curcumin analogue, induces apoptosis in endometrial cancer cells by activating the H3F3A/ proteasome-MAPK signaling pathway and enhancing oxidative stress.

AIMS: Curcumin is a natural compound and has good antitumor properties, but its clinical use is limited by its low bioavailability. We constructed the derivative CP41 (3,5-bis(2-chlorobenzylidene)-1-piperidin-4-one) by enhancing the bioavailability of curcumin while retaining its antitumor properties. MAIN METHODS: CCK-8 (Cell Counting Kit-8) was used to detect the effect of CP41 on cell proliferation; Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme-linked immunosorbent assay were used to evaluate the expression of subcutaneous tumor-related molecules in cells and mice. KEY FINDINGS: Our results showed that CP41 inhibited the proliferation of endometrial cancer cells by suppressing the proliferation of AN3CA and HEC-1-B cells. We found that CP41 significantly increased H3F3A and inhibited proteasome activity, which activated MAPK signaling and led to apoptosis. Further experiments showed that H3F3A is a potential target of CP41. Correlation analysis showed that H3F3A was positively correlated with the sensitivity to chemotherapeutic agents in endometrial cancer. CP41 significantly induced reactive oxygen species (ROS) levels and activated endoplasmic reticulum stress, which led to apoptosis. The safety profile of CP41 was also evaluated, and CP41 did not cause significant drug toxicity in mice. SIGNIFICANCE: CP41 showed stronger antitumor potency than curcumin, and its antitumor activity may be achieved by inducing ROS and activating H3F3A-mediated apoptosis.

Association between dietary flavonoid intake and depressive symptoms: A cross-sectional research.

OBJECTIVE: To investigate the relationship between dietary flavonoid intake and depression symptoms in American adults. METHODS: Data sets were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007-2008, 2009-2010, and 2017-2018 survey cycles. Both males and females aged 18 years and older with complete information about dietary flavonoid intake (isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols), depression symptoms, and covariates were included. Logistic regression models were conducted to calculate the odds ratio (OR) of single dietary flavonoid subclass intake on depression, and the restricted cubic spline (RCS) models were utilized to explore the corresponding dose-response relationships. Additionally, we implemented the weighted quantile sum (WQS) regression and quantile g-computation (qgcomp) models to estimate the mixed effects of six flavonoid subclasses and identify the predominant types. RESULTS: After multivariable adjustments, people with higher consumption of flavanones (OR: 0.68, 95% CI: 0.52-0.90, p = 0.008), flavones (OR: 0.63, 95% CI: 0.46-0.87, p = 0.007), flavonols (OR: 0.66, 95% CI: 0.49-0.89, p = 0.008), and total flavonoids (OR: 0.69, 95% CI: 0.50-0.95, p = 0.024) had lower odds of depression symptoms. Meanwhile, significant dose-response relationships were supported by the RCS models. However, no obvious associations between isoflavones, anthocyanidins, flavan-3-ols, and the odds of suffering from depression symptoms were found by the logistic regression models and RCS models. As for the mixed effect, the WQS and qgcomp models both demonstrated that the mixture of six flavonoid subclasses was inversely related to the odds ratios of depression symptoms, and flavones, flavanones, and anthocyanidins were the top 3 contributors. CONCLUSION: Our study implied dietary flavonoid intake was associated with the decreased probability of depression symptoms in U.S. adults, among which flavones, flavanones, and anthocyanidins may occupy the predominant roles.

A nutrient-wide association study for the risk of cardiovascular disease in the China Health and Nutrition Survey (CHNS) and the National Health and Nutrition Examination Survey (NHANES).

Evidence on the association between dietary nutrient-wide intake and cardiovascular disease (CVD) is inconclusive. Therefore, we systematically assessed the association between dietary intake of 29 nutrients and CVD risk using a nutrient-wide association study. Data were obtained from 7878 Chinese adults participating in the China Health and Nutrition Survey (CHNS) wave 2004-2015. We estimated the association of 29 nutrients with CVD risk. Significant findings were replicated in the National Health and Nutrition Examination Survey (NHANES). Four nutrients (selenium, vitamin A, carotenoids, and total protein) were significantly associated with CVD risk in the CHNS. The hazard ratio (HR) and 95% confidence interval (CI) for nutrient intake in the third tertile compared to the first tertile were 0.68 (0.51-0.90), 0.70 (0.54-0.91), 0.64 (0.50-0.83), and 0.54 (0.38-0.77), respectively. In the NHANES replication, selenium maintained a similar direction and strength of association, while the other nutrients were not replicated successfully. Our results provide support for a negative association between selenium intake and CVD risk, while the association of vitamin A, carotenoids and protein with CVD warrants further studies to confirm.

Curcumin derivative NL01 induces ferroptosis in ovarian cancer cells via HCAR1/MCT1 signaling.

OBJECTIVE: Curcumin has been shown to have anti-tumor proliferative properties, but its clinical application is limited by its low bioavailability, etc. Derivatives of curcumin have been developed and tested to improve its therapeutic efficacy. Derivative NL01 could induce ferroptosis through the HCAR1/MCT1 pathway. METHOD: CCK-8 was used to detect curcumin and derivative IC50, crystalline violet staining was used to detect the proliferation inhibition effect of NL01 in ovarian cancer, western blot and qPCR were used to detect downstream related molecular expression changes, Transwell and survival curve assays were used to detect malignant phenotypic. RESULTS: NL01 inhibited cell growth of Anglne and HO8910PM ovarian cancer cells by 13 times more potent than curcumin and induced ferroptosis of these two cells. we found that NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 pathway. Knock-down HCAR1 expression revealed similar phenotype and pathway alterations to NL01 treatment. HCAR1 overexpression promoted a malignant phenotype and resistance to cisplatin in both cancer cells, whereas knockdown of HCAR1 showed the opposite phenotype. Subcutaneous transplantation tumor experiments in nude mice also showed that NL01 induced iron death and inhibited ovarian cancer proliferation. Further study showed that NL01 promoted the downregulation of GPX4 expression, which is related to ferroptosis, and that addition of ferrostatin-1 partially reversed NL01-mediated inhibition of the growth of two cell lines. CONCLUSION: NL01 exhibits better anti-tumor growth properties than curcumin, and NL01 induces ferroptosis in ovarian cancer cells.

Visible Light and Microwave-Mediated Rapid Trapping and Release of Singlet Oxygen Using a Coordination Polymer.

Due to its high reactivity and oxidative strength, singlet oxygen (1 O2 ) is used in a variety of fields including organic synthesis, biomedicine, photodynamic therapy and materials science. Despite its importance, the controlled trapping and release of 1 O2 is extremely challenging. Herein, we describe a one-dimensional coordination polymer, CP1, which upon irradiation with visible light, transforms 3 O2 (triplet oxygen) to 1 O2 . CP1 consists of CdII centers bridged by 9,10-bis((E)-2-(pyridin-4-yl)vinyl)anthracene ligands which undergo a [4+2] cycloaddition reaction with 1 O2 , resulting in the generation of CP1-1 O2 . Using microwave irradiation, CP1-1 O2 displays efficient release of 1 O2 , over a period of 30 s. In addition, CP1 exhibits enhanced fluorescence and has an oxygen detection limit of 97.4 ppm. Theoretical calculations reveal that the fluorescence behaviour is dominated by unique through-space conjugation. In addition to describing a highly efficient approach for the trapping and controlled release of 1 O2 , using coordination polymers, this work also provides encouragement for the development of efficient fluorescent oxygen sensors.

Phase Transition-Promoted Rapid Photomechanical Motions of Single Crystals of a Triene Coordination Polymer.

Molecular crystals with the ability to transform light energy into macroscopic mechanical motions are a promising class of materials with potential applications in actuating and photonic devices. In regard to such materials, coordination polymers that exhibit dynamic photomechanical motion, associated with a phase transition, are unknown. Herein, we report an intriguing photoactive, one-dimensional ZnII coordination polymer, 1, derived from 1,3,5-tri-4-pyridyl-1,2-ethenylbenzene and 3,5-difluorobenzoate. Single crystals of 1 under UV light irradiation exhibit rapid shrinking and bending, violent bursting-jumping, splitting, and cracking behavior. Single-crystal X-ray diffraction analysis and 1 H NMR spectroscopy reveal an unusual photoinduced phase transition involving a single-crystal-to-single-crystal [2+2] cycloaddition reaction that results in photomechanical responses. Interestingly, crystals of 1, which are triclinic with space group P 1 ‾ ${P\bar{1}}$ , are transformed into a higher symmetry, monoclinic cell with space group C2/c. This process represents a rare example of symmetry enhancement upon photoirradiation. The photomechanical activity is likely due to the sudden release of stress associated with strained molecular geometries and significant solid-state molecular movement arising from cleavage and formation of chemical bonds. A composite membrane fabricated from 1 and polyvinyl alcohol (PVA) also displays interesting photomechanical behavior under UV light illumination, indicating the material's potential as a photoactuator.

Identification of a novel mutation in the FGF10 gene in a Chinese family with obvious congenital lacrimal duct dysplasia in lacrimo-auriculo-dento-digital syndrome.

AIM: To identify the pathogenic gene variant in a family with lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] showing congenital lacrimal duct dysplasia as the main clinical manifestation and lay the foundation for future research on the pathogenic gene. METHODS: Ophthalmological examinations, including slit-lamp biomicroscopy and lacrimal duct probing, and computed tomography dacryocystography (CT-DCG) were performed for all participants. The family pedigree was drawn, genetic features were analyzed, and the genomic DNA of the subjects was extracted. Pathogenic genes were screened via whole exome sequencing (WES) and confirmed using Sanger sequencing. RESULTS: Six patients belonged to this three-generation family, and their clinical manifestations included congenital nasolacrimal duct obstruction, congenital absence of lacrimal puncta and canaliculi, lacrimal fistulae, and limb deformities. This pattern indicates autosomal dominant inheritance. Diagnosis was based on the clinical characteristics of LADD syndrome, which presented in all the patients in this family. A novel frameshift mutation in the FGF10 gene (NM_004465.1), c.234dupC (p.Trp79Leus*15), was identified in all patients via WES. The variant was confirmed by Sanger sequencing and classified as a "pathogenic mutation" according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines. CONCLUSION: A novel frameshift mutation in the FGF10 gene is found in all patients. This finding helps this family with LADD syndrome receiving a more accurate clinical diagnosis and genetic counseling by extending the mutation range of the FGF10 gene.

[Analysis of Proliferation Characters of Bone Marrow Mesenchymal Stem Cells Derived from Patients with Myelodysplastic Syndrome].

OBJECTIVE: To analyze the proliferation potential of bone marrow-derived mesenchymal stem cells (MSC) in patients with myelodysplastic syndrome (MDS). METHODS: The MSC derived from the 24 patients with newly diagnosed MDS (MDS-MSC group) and MSC derived from 15 patients with nutritional anemia (control group) in the Affiliated Hospital of Hebei University were used as the research objects. The proliferation potential of MSC was analyzed by colony-forming unit assay, doubling time, cumulative passaging, cell number after 10 days of culture with equal amount of MSC and MTT experiment. The mechanism of abnormal proliferation was analyzed by cell cycle experiment, apoptosis experiment and p21 gene expression assay. RESULTS: In the colony forming unit assay, the number of MDS-MSC colonies was 4.44±2.51, which was significantly lower than that of the control group (12.44±2.55)(P<0.01); the doubling time of MDS-MSC group was significantly longer than that of the control group (7.80±3.26 vs 3.63±0.85) (P<0.01); the number of MDS-MSC in 5×104 culture for 10 days was (39.40±14.18)×104, which was significantly lower than that of the control group ï¼»(85.30±9.49)×104 ï¼½(P<0.01); the number of cumulative passages in MDS-MSC group was 5.20±1.40, which was significantly lower than that in control group (11.60±1.96)(P<0.01); MTT results showed that the proliferation capability of MSC in MDS-MSC group was lower than that in the control group. The cell proportion of G0/G1 phase in MDS-MSC group was higher than that in the control group, while the cell proportion of S phase was lower (P<0.05). The percentage of early apoptotic cells in MDS-MSC group was higher than that in control group (P<0.05); the relative expression level of p21 mRNA in MDS-MSC group was significantly higher than that in control group(P<0.01). CONCLUSION: The proliferative capability of MDS-MSC is significantly reduced, which relates with the arrest of cell cycle in G0/G1 phase, the increase of early apoptotic cells and senescent cells of the MDS-MSC.

FKBP10 promotes proliferation of glioma cells via activating AKT-CREB-PCNA axis.

BACKGROUND: Although the availability of therapeutic options including temozolomide, radiotherapy and some target agents following neurosurgery, the prognosis of glioma patients remains poor. Thus, there is an urgent need to explore possible targets for clinical treatment of this disease. METHODS: Tissue microarrays and immunohistochemistry were used to detect FKBP10, Hsp47, p-AKT (Ser473), p-CREB (Ser133) and PCNA expression in glioma tissues and xenografts. CCK-8 tests, colony formation assays and xenograft model were performed to test proliferation ability of FKBP10 in glioma cells in vitro and in vivo. Quantitative reverse transcriptase-PCR, western-blotting, GST-pull down, co-immunoprecipitation and confocal-immunofluorescence staining assay were used to explore the molecular mechanism underlying the functions of overexpressed FKBP10 in glioma cells. RESULTS: FKBP10 was highly expressed in glioma tissues and its expression was positively correlates with grade, poor prognosis. FKBP10-knockdown suppressed glioma cell proliferation in vitro and subcutaneous/orthotopic xenograft tumor growth in vivo. Silencing of FKBP10 reduced p-AKT (Ser473), p-CREB (Ser133), PCNA mRNA and PCNA protein expression in glioma cells. FKBP10 interacting with Hsp47 enhanced the proliferation ability of glioma cells via AKT-CREB-PCNA cascade. In addition, correlation between these molecules were also found in xenograft tumor and glioma tissues. CONCLUSIONS: We showed for the first time that FKBP10 is overexpressed in glioma and involved in proliferation of glioma cells by interacting with Hsp47 and activating AKT-CREB-PCNA signaling pathways. Our findings suggest that inhibition of FKBP10 related signaling might offer a potential therapeutic option for glioma patients.

Triterpenoid saponins and phenylpropanoid glycoside from the roots of Ardisia crenata and their cytotoxic activities.

Two new triterpenoid saponins, ardisicrenoside R and S (1 and 2), and one new phenylpropanoid glycoside, ardicrephenin (3), along with five known compounds (4-8), were isolated from roots of Ardisia crenata. Their structures were elucidated on the basis of NMR spectroscopic data and chemical methods. Compounds 2-7 were evaluated for their cytotoxic activities against A549, MCF-7, HepG2 and MDA-MB-231 cell lines by MTT assay. Ardicrenin (6) showed significant cytotoxicity, with IC50 values of 1.17 ± 0.01, 1.19 ± 0.06, 3.52 ± 0.23, and 16.61 ± 1.02 µmol·L-1, respectively.

Diosgenin Derivatives as Potential Antitumor Agents: Synthesis, Cytotoxicity, and Mechanism of Action.

Thirty-two new diosgenin derivatives were designed, synthesized, and evaluated for their cytotoxic activities in three human cancer cell lines (A549, MCF-7, and HepG2) and normal human liver cells (L02) using an MTT assay in vitro. Most compounds, especially 8, 18, 26, and 30, were more potent when compared with diosgenin. The structure-activity relationship results suggested that the presence of a succinic acid or glutaric acid linker, a piperazinyl amide terminus, and lipophilic cations are all beneficial for promoting cytotoxic activity. Notably, compound 8 displayed excellent cytotoxic activity against HepG2 cells (IC50 = 1.9 µM) and showed relatively low toxicity against L02 cells (IC50 = 18.6 µM), showing some selectivity between normal and tumor cells. Studies on its cellular mechanism of action showed that compound 8 induces G0/G1 cell cycle arrest and apoptosis in HepG2 cells. Predictive studies indicated that p38α mitogen-activated protein kinase (MAPK) is the optimum target of 8 based on its 3D molecular similarity, and docking studies showed that compound 8 fits well into the active site of p38α-MAPK and forms relatively strong interactions with the surrounding amino acid residues. Accordingly, compound 8 may be used as a promising lead compound for the development of new antitumor agents.

[Clinical observation of dynamic scalp acupuncture combined with task-oriented mirror therapy for upper limbs function impairment in patients with hemiplegia after ischemic stroke].

OBJECTIVE: To explore the effect of dynamic scalp acupuncture combined with task-oriented mirror therapy (TOMT) for upper limb motor function and activity ability of daily living in patients with hemiplegia after ischemic stroke. METHODS: Seventy-eight patients with hemiplegia after ischemic stroke were randomly divided into a dynamic scalp acupuncture group, a TOMT group, and a scalp acupuncture group, 26 cases in each group (1 case dropped off in the TOMT group and the scalp acupuncture group respectively). All three groups received routine rehabilitation training and medication treatment. The TOMT group was treated with TOMT for 40 min a day, 5 days a week for 8 weeks. The scalp acupuncture group was treated with TOMT after the scalp acupuncture, and the dynamic scalp acupuncture group was treated with TOMT during the scalp acupuncture treatment. The scalp acupuncture treatment was applied at ipsilateral up 1/5 and mid 2/5 of Dingnie Qianxiexian and Dingnie Houxiexian, and the needles were retained for 40 min. The scalp acupuncture treatment was given once a day, 5 days a week for 8 weeks. Before treatment and after 4 weeks and 8 weeks of treatment, the functions of upper limb and hand were evaluated by simplified Fugl-Meyer assessment (FMA) scale upper limb part and functional test for the hemiplegic upper extremity-Hong Kong version (FTHUE-HK) grade, the muscle tension of the upper extremity flexor elbow muscle group was assessed by modified Ashworth scale (MAS) and the activity ability of daily living was assessed by modified Barthel index (MBI). RESULTS: After 4 weeks and 8 weeks of treatment, the FMA scores, FTHUE-HK grades and MBI scores in the three groups were better than those before treatment (P<0.01, P<0.05), and MAS scores after 4 weeks of treatment in the three groups were better than those before treatment (P<0.05). After 4 weeks and 8 weeks of treatment, the FMA scores, FTHUE-HK grades and MBI scores in the dynamic scalp acupuncture group were better than those in the TOMT group and the scalp acupuncture group (P<0.05), and these items in the scalp acupuncture group were better than those in the TOMT group (P<0.05). CONCLUSION: The dynamic scalp acupuncture combined with TOMT treatment can effectively improve the upper limb function and the activities ability of daily living in patients with hemiplegia after ischemic stroke, which is better than TOMT after scalp acupuncture and simple TOMT treatment.

High S phase kinase-associated protein 2 expression is a potential prognostic biomarker for glioma.

S phase kinase-associated protein 2 (SKP2), a substrate recognizing protein, serves an important role in promoting cell cycle progression through ubiquitination and degradation of cell cycle inhibitors. In the present study, the clinical significance of SKP2 in gliomas was studied; 395 glioma specimens and 20 non-neoplastic tissues were collected and immunohistochemical analysis was performed. χ2 test was used to assess the associations between SKP2 expression and clinical parameters. Overall survival (OS) curves were plotted according to the Kaplan-Meier method. In the tested glioma samples, SKP2 expression was mainly observed in glioblastomas (GBMs). Survival analysis demonstrated that the overall survival time of the high SKP2 expression group was lower compared with the low SKP2 expression group (median OS, 10.04 months vs. 16.50 months; P=0.003). Moreover, SKP2 was independently associated with an unfavorable prognosis in GBMs. In addition, the expression of SKP2 was associated with the expression of phosphorylated retinoblastoma protein and the epidermal growth factor receptor. A combination of SKP2 expression along with isocitrate dehydrogenase 1 (IDH1) mutations and telomerase reverse transcriptase (TERT) promoter mutations was used to classify glioma patients for survival analysis. Patients with low SKP2 expression, IDH1 mutation and wild-type TERT promoter demonstrated the longest survival time. The findings of the present study, indicate that SKP2 is a potential prognostic biomarker in patients with GBMs.

Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas.

Temozolomide (TMZ) is considered a standard chemotherapeutic agent for glioblastoma (GBM). Characterizing the biological molecules and signaling pathways involved in TMZ sensitivity would be helpful for selecting therapeutic schemes and evaluating prognosis for GBM. Thus, in the present study, we selected 34 glioma cell lines paired with specific IC50 values of TMZ obtained from CancerRxGene and RNA-seq data downloaded from the Cancer Cell Line Encyclopedia to identify genes related to TMZ sensitivity. The results showed that 1,373 genes were related to the response of GBM cells to TMZ. Biological function analysis indicated that epithelial-mesenchymal transition, Wnt signaling, and immune response were the most significantly activated functions in TMZ-resistant cell lines. Additionally, negative regulation of telomere maintenance via telomerase was enriched in TMZ-sensitive glioma cell lines. We also preliminarily observed a synergistic effect of combination treatment comprising TMZ and a telomerase inhibitor in vitro. We identified six genes (MROH8, BET1, PTPRN2, STC1, NKX3-1, and ARMC10) using the random survival forests variable hunting algorithm based on the minimum error rate of the gene combination and constructed a gene expression signature. The signature was strongly related to GBM clinical characteristics and exhibited good prognosis accuracy for both The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Patients in the high score group had a shorter survival time than those in the low score group (11.2 vs. 22.2 months, hazard ratio = 7.31, p = 4.59e-11) of the TCGA dataset. The CGGA dataset was selected as a validation group with 40 patients in the high score set and 43 patients in the low score set (12.5 vs. 28.8 months, hazard ratio = 3.42, p = 8.61e-5). Moreover, the signature showed a better prognostic value than MGMT promoter methylation in both datasets. We also developed a nomogram for clinical use that integrated the TMZ response signature and four other risk factors to individually predict patient survival after TMZ chemotherapy. Overall, our study provides promising therapeutic targets and potential guidance for adjuvant therapy of GBM.

PAI-1 overexpression promotes invasion and migration of esophageal squamous carcinoma cells.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide. Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is highly expressed in various types of tumor tissues, which contributes to cancer progression. The present study explored the role and underlying mechanisms of PAI-1 in ESCC. We found that the PAI-1 protein was extracellularly secreted more from ESCC cells with high PAI-1 expression using Western blotting and enzyme linked immunosorbent assay (ELISA). Knockdown of SERPINE1 expression significantly inhibited the invasion and migration of ESCC KYSE150 and KYSE450 cell lines, which could be restored when adding exogenous human recombinant PAI-1 into the culture medium of the cells stably expressing SERPINE1 shRNA. In vivo experiments showed that SERPINE1 knockdown significantly inhibited xenograft growth and lung metastasis of ESCC cells. Molecular analysis demonstrated that PAI-1 activated AKT and ERK signaling pathways. Co-immunoprecipitation (Co-IP) assays identified that PAI-1 may interact with the membrane receptor LDL receptor related protein 1 (LRP1). These results indicated that overexpression of PAI-1, through interacting with LRP1, might enhance invasion and migration of ESCC cells as well as promote ESCC progression.

Cytotoxic steroidal saponins from the rhizome of Anemarrhena asphodeloides.

Two novel steroidal saponins, timosaponin V and W (1 and 2), together with seven known steroidal saponins (3-9), were isolated from the rhizomes of Anemarrhena asphodeloides Bunge. Their structures were elucidated by extensive 1D NMR and 2D NMR (HSQC, HMBC, 1H-1H COSY, and NOESY), and MS analyses. The cytotoxic activities of the isolates were evaluated. Compound 1 showed a significant cytotoxic activity against MCF-7 and HepG2 cell lines with IC50 values of 2.16 ± 0.19 µM and 2.01 ± 0.19 µM, respectively.

Overexpression of IGFBP2 mRNA predicts poor survival in patients with glioblastoma.

The prognosis of patients with glioblastoma (GBM) is dismal. It has been reported that Insulin-like growth factor (IGF) binding protein 2 (IGFBP2) is associated with the mobility and invasion of tumor cells. We investigated the expression of IGFBP2 mRNA in GBMs and its clinical relevance, using tissue microarrays and RNAscope in situ hybridization in 180 GBMs and 13 normal or edematous tissues. The correlations between the expression and clinical pathological parameters as well as some other biomarkers were analyzed. Overexpression of IGFBP2 mRNA was observed in 23.9% of tumors tested. No expression of IGFBP2 mRNA was detected in normal or edematous tissues. Kaplan-Meier survival analysis showed that the survival time of all the patients with high IGFBP2 tumors had shorter survival than those with low IGFBP2 (P<0.01). Univariate regression and multivariate regression both indicated that the expression of IGFBP2 transcript level was an independent prognostic factor (P=0.008 and 0.007, respectively). Furthermore, expression of IGFBP2 mRNA was related to the occurrence of isocitrate dehydrogenase 1 (IDH1) mutation, high heat shock protein 27 (Hsp27) expression and telomerase reverse transcriptase (TERT) promoter mutation (TERTp+) (P=0.013, 0.015 and 0.016, respectively), and patients with TERTp+/IGFBP2high showed the shortest survival. In conclusion, IGFBP2 mRNA expression status is an independent prognostic biomarker in GBMs, and the combination of IGFBP2 mRNA and TERTp status might serve as a prognostic indicator in patients with GBM.