Predictive Value and Immunological Role of the HSPA5 Gene in Cervical Cancer.

Cervical cancer (CC) ranks fourth among women's malignancies worldwide and seriously affects women's health. HSPA5 is a heat shock protein, also known as glucose regulatory protein 78 (GRP78). Upregulation of HSPA5 has been reported to be closely associated with multiple types of tumors. However, the specific role of HSPA5 in cervical cancer has not been discovered. In our study, we explored the prognostic value of HSPA5 in CC. Here, we analyzed the (TCGA) and (UCSC) databases, the analysis of HSPA5 in many tumors types was conducted with the "wilcox. test" method. A False Discovery Rate (FDR) value < 0.05 and Log2 | (fold change, FC) |> 1 were set as the cutoffs. "*", "**", and "***" indicate FDR < 0.05, < 0.01, and < 0.001, respectively, and further used human cervical cancer cells for q-PCR and western blotting detection. q-PCR and western blotting results showed that HSPA5 was highly expressed in cervical cancer cells, while it was expressed at low levels in normal cells (P < 0.05).We also analyzed the immunohistochemical data. immunohistochemical analysis results showed that HSPA5 was highly expressed in human cervical cancer, while it was expressed at low levels in normal tissues (P < 0.05). Analysis in TCGA-UCSC showed that the proportion of G3 in the group with high expression of HSPA5 was relatively high (P < 0.05). Enrichment analysis and survival analysis showed that the increased expression of HSPA5 in cervical cancer was related to the survival of CC and was involved in the regulation of biological behavior and molecular signaling pathways of cervical cancer. The correlation analysis of immune checkpoint and immune infiltration showed that HSPA5 was involved in the regulation of immune process of cervical cancer (P < 0.05). Drug sensitivity correlation analysis showed that HSPA5 was a sensitive target for tumor drugs (P < 0.05). In brief, those results suggest that HSPA5 can act as an oncogene of CC development and can serve as an effective predictive biomarker in cervical cancer.

ANXA2 and Rac1 negatively regulates autophagy and osteogenic differentiation in osteosarcoma cells to confer CDDP resistance.

BACKGROUND: Cisplatin (CDDP) is a mainstay chemotherapeutic agent for OS treatment, but drug resistance has become a hurdle to limit its clinical effect. Autophagy plays an important role in CDDP resistance in OS, and in the present study we explored the role of ANXA2 and Rac1 in dictating CDDP sensitivity in OS cells. METHODS: ANXA2 and Rac1 expression levels were examined by Western blot and autophagy induction was detected by transmission electron miscroscope (TEM) in the clinical samples and OS cell lines. CDDP resistant cells were established by exposing OS cells to increasing doses of CDDP. The effects of ANXA2 and Rac1 knockdown on CDDP sensitivity were evaluated in the cell and animal models. RESULTS: Reduced autophagy was associated with the increased expression of ANXA2 and Rac1 in CDDP resistant OS tumor samples and cells. Autophagy suppression promoted CDDP resistance and inducing autophagy re-sensitized the resistant cells to CDDP treatment in vitro and in vivo. Further, knocking down ANXA2 or Rac1 re-activated autophagy and attenuated CDDP resistance in OS cells. We further demonstrated that CDDP resistant OS cells displayed a poorer osteogenic differentiation state when compared to the parental cell lines, which was significantly reversed by autophagy re-activation and ANXA2 or Rac1 silencing. CONCLUSION: Our findings revealed a complicated interplay of ANXA2/Rac1, autophagy induction, and osteogenic differentiation in dictating CDDP resistance in OS cells, suggesting ANXA2 and Rac1 as promising targets to modulate autophagy and overcome CDDP resistance in OS cells.

The effect and apoptosis mechanism of 6-methoxyflavone in HeLa cells.

INTRODUCTION: Tumour cell apoptosis is a crucial indicator for judging the antiproliferative effects of anti-cancer drugs. The detection of optical and macromolecular biomarkers is the most common method for assessing the level of apoptosis. We aimed to explore the anti-tumour mechanisms of 6-methoxyflavone. MATERIALS AND METHODS: Three optical methods, including the percentage of apoptotic cells, cell morphology, and subcellular ultrastructure changes, were obtained using flow cytometry, inverted fluorescence microscopy, and transmission electron microscope imaging. The mRNA or protein expression of macromolecular biomarkers related to common apoptotic pathways was determined via polymerase chain reactions or western blot assays. The functional role of the core gene biomarker was investigated through overexpression, knockdown, and phosphorylation inhibitor (GSK2656157). RESULTS: Transcriptome sequencing and the optical biomarkers assays demonstrated that 6-methoxyflavone could induce apoptosis in HeLa cells. The expression of macromolecular biomarkers indicated that 6-methoxyflavone induced apoptosis through the PERK/EIF2α/ATF4/CHOP pathway. Phosphorylated PERK was identified as the core biomarker of this pathway. Both overexpression and GSK2656157 significantly altered the expression level of phosphorylated PERK in 6-methoxyflavone-treated HeLa cells. DISCUSSION AND CONCLUSION: Macromolecular biomarkers, such as phosphorylated PERK and phosphorylated EIF2α are of great significance for assessing the therapeutic effects of 6-methoxyflavone.

Sparse-aperture photonics-integrated interferometer (SPIN) imaging system: structural design and imaging quality analysis.

The burgeoning field of astrophotonics, the interface between astronomy and photonics, is redefining astronomical instrumentation to replace traditional bulk optical systems with integrated optics. This drives the development of a new promising photonics-integrated interferometric imaging technique, called the segmented planar imaging detector for electro-optical reconnaissance (SPIDER). Compared to conventional imaging systems, SPIDER can reduce the size, weight, and power (SWaP) by one to two orders of magnitude for an equivalent imaging resolution in virtue of photonics-integrated technology. However, SPIDER has a dense lens distribution and tens of separated narrow wavebands demultiplexed by array waveguide gratings. In this paper, we developed a new simplified sparse-aperture photonics-integrated interferometer (SPIN) imaging system. The SPIN imaging system was no more a Michelson configuration interferometer as SPIDER and was designed as a Fizeau configuration interferometer imaging system. This transfer of configuration type affords a more concise structure; the SPIN was designed with much less apertures and fewer wavebands than those of SPIDER. Further, the SPIN yields enhanced modulation transfer function and imaging quality with equivalent aperture diameter, compared with SPIDER. The main barrier of this transfer is the elimination of coupling restriction at the tip of a waveguide, namely the apodization effect. This effect, which is caused by the coupling effect between Fourier lens and waveguide, hinders SPIN imaging systems from getting finer resolution. However, a microscope could be used to eliminate this effect. Moreover, a waveguide array is used to receive these finer details and enlarges the field of view in SPIN. The coupling efficiency of the waveguides and crosstalk errors between waveguides of array were analyzed, which are important for proper parameters setting in SPIN imaging system. Based on these analyses, the imaging principle was derived and a hyper-Laplacian-based imaging reconstruction algorithm was developed. A simulation of the SPIN imaging system with seven apertures and one imaging waveband demonstrated the high imaging quality.

Overexpression of BMP9 promotes ovarian cancer progression via Notch1 signaling.

Cell proliferation and migration play important parts in ovarian cancer progression. BMP9, as one of the members of the TGF-ß superfamily and BMP family, plays a diverse and significant array of biological roles, including cell differentiation, proliferation, apoptosis, tumorigenesis, and metabolism. However, the role and mechanism of BMP9 in ovarian cancer progression remains uncertain. We found that the expression of BMP9 was increased in human ovarian cancer cell lines, which induced Notch1 intracellular domain (NICD1) accumulation. And we also found the expression abundance of BMP9 is low in ovarian cancer cells. Thus, we generated recombinant adenoviruses overexpressing BMP9 to perform the research. We found that overexpression of BMP9 promoted ovarian cancer cell proliferative viability, cell cycle progression, cell migration in vitro, and accelerated subcutaneous tumor growth in vivo, which was inhibited by dominant-negative mutant Notch1 recombinant adenoviruses. Besides, we also demonstrated that silencing of BMP9 by recombinant adenoviruses inhibited ovarian cancer cell viability and migration in vitro. Additionally, BMP9-induced ovarian cancer cell progression also involved the elevation of HES2, c-Myc, MMP9, and Cyclin D1, as well as repressed expression of p27. Together, these results revealed that BMP9 acts as a promoting factor in ovarian cancer progression, and overexpression of BMP9 promotes ovarian cancer progression and growth via Notch1 signaling. Thereby our research may provide new insight into the pathogenesis of ovarian cancer and BMP9-Notch1 signaling may serve as a novel therapeutic target axis for ovarian cancer treatment.

Knockdown of diacylglycerol kinase zeta (DGKZ) induces apoptosis and G2/M phase arrest in human acute myeloid leukemia HL-60 cells through MAPK/survivin/caspase pathway.

Diacylglycerol kinase zeta (DGKZ) is associated with the pathogenesis of a variety of malignant diseases, but its biological function on acute myeloid leukemia (AML) has not been explored. The aim of this study was to analyze apoptosis induced by knockdown of DGKZ and its mechanism in human acute myeloid leukemia HL-60 cells. qRT-PCR was carried out to detect the expression of DGKZ in HL-60, THP-1, Jurkat, K562, and CD34 cell lines. Additionally the expression of DGKZ in AML cells obtained from patients were detected by qRT-PCR. Cell Counting Kit-8 (CCK-8) assay was used to determine the viability of HL-60 cells DGKZ knocked down. Apoptosis and cell cycle phase of HL-60 cells after DGKZ knockdown were evaluated by flow cytometry. Western blot analysis was performed to investigate expressions of the proteins related to apoptosis and cell cycle. Results showed that expression of DGKZ was significantly higher in HL-60 and AML cells obtained from patients than those of Jurkat, THP-1, K562 and human CD34 cell. Compared with the shCtrl group, DGKZ was markedly knocked down in HL-60 cells transfected with lentivirus encoding shRNA. DGKZ knockdown significantly inhibited the proliferation and induced cycle arrest at the G2/M phase in HL-60 cells. The expressions of MAPK, caspase-3, caspase-8, cytochrome C markedly increased and p-MAPK and survivin decreased in HL-60 cells after DGKZ knockdown. The results suggest that knockdown of DGKZ can induce apoptosis and G2/M phase arrest in human acute myeloid leukemia HL-60 cells through the MAPK/survivin/caspase pathway.

Noninvasive Identification of Renal Hypoxia in Experimental Myocardial Infarctions of Different Sizes by Using BOLD MR Imaging in a Mouse Model.

Purpose To test the feasibility of using blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging to measure alterations in renal oxygenation in a mouse model with experimental myocardial infarctions (MIs) of different sizes. Materials and Methods The study was approved by the local animal ethics committee. One hundred eighty-nine male C57BL/6 J mice were randomly subjected to MI surgery (with different locations of left anterior descending coronary artery occlusion) or sham surgery, defined as the exposure of the heart but no ligation. Mice with MI underwent late gadolinium enhancement imaging 1 day after occlusion to confirm infarct size. Mice were sorted into three groups: those with large MI (n = 48), those with small MI (n = 48), and those with sham operation (n = 36). Renal BOLD MR imaging was performed before and 1, 7, 14, 28, and 60 days after MI, and histologic analysis of renal hypoxia-inducible factor-1α (HIF-1α) and kidney injury molecule-1 (KIM-1) was performed to evaluate tissue hypoxia and kidney injury in subgroups imaged at each time point. The relationships between the BOLD R2* and HIF-1α expression and between HIF-1α and KIM-1 expression were assessed. Statistical analyses were performed with one-way analysis of variance or the Kruskal-Wallis test and Spearman correlation test. Results A significant elevation in R2* was detected in the MI groups compared with the sham group in the cortex (P < .001 for large MI vs sham group; P = .007 for small MI vs sham group) and medulla (P < .001 for large MI vs sham group; P = .003 for small MI vs sham group) on day 60, and R2* was higher in the large MI group than in the small MI group (P < .001). Renal HIF-1α expression was increased after MI and showed linear correlation with R2* in the cortex (R2 = 0.56) and medulla (R2 = 0.63). In addition, an increase in renal KIM-1 was observed in the MI groups compared with the sham group on day 60 (sham group, 53.9 × 103 arbitrary units [au] ± 35.2; large MI group, 389.3 × 103 au ± 99.8; and small MI group, 185.8 × 103 au ± 91.9; P < .001 for large MI group vs sham group; P = .037 for small MI group vs sham group), and renal KIM-1 showed a positive correlation with HIF-1α (R2 = 0.68). Conclusion The magnitude of renal hypoxia with MIs of different sizes can be noninvasively measured with BOLD MR imaging, and increased renal hypoxia is a potential risk factor for progressive tubulointerstitial injury in mouse kidneys. © RSNA, 2017 Online supplemental material is available for this article.

Noninvasive assessment of age, gender, and exercise effects on skeletal muscle: Initial experience with T1 ρ MRI of calf muscle.

PURPOSE: To prospectively investigate age- and gender-related changes in the fast-twitch (tibialis anterior, TA) and slow-twitch (soleus, SOL) skeletal muscle of healthy rats and volunteers and to compare the exercise-related difference in health volunteers with T1 ρ magnetic resonance imaging (MRI). MATERIALS AND METHODS: In all, 18 rats and 70 humans were involved in this study. For the animal study, T1 ρ relaxation times were measured in the TA and SOL rat muscle with a 3.0T MRI scanner and compared to histological data. For the human study, three groups (young, middle-aged, and elderly) of volunteers underwent T1 ρ MRI scans (3.0T) of their calves. To further differentiate the human scans, 18 volunteers were recruited, half of them (n = 9) routinely trained with high-intensity sports, while the other half (n = 9) with no physical training. Statistical analysis was performed via paired t-test, independent-sample t-test, and analysis of variance (ANOVA). Correlations between T1 ρ and age/gender/physical endurance were calculated. RESULTS: The average T1 ρ relaxation times of the TA and SOL of female rats were higher than that of male rats (P < 0.001). The T1 ρ relaxation time of TA was significantly lower compared to SOL (P < 0.001). A significant linear correlation was observed between T1 ρ and the type I slow-twitch fiber proportion (%) in SOL (R2 = 0.837, P < 0.001). Similarly, in human studies the average T1 ρ relaxation times of TA were significantly lower than SOL for all age groups (P < 0.001). The higher T1 ρ relaxation times of TA and SOL in the elderly volunteers (P < 0.001) and in the females (P < 0.05) indicated significant age- and gender-dependent differences. In high-intensity sports groups, the higher T1 ρ in SOL (P < 0.01) and lower in TA (P < 0.05) were observed compared with the control group. CONCLUSION: This study demonstrated that T1 ρ MRI can be used to display the differences in fast- and slow-twitch skeletal muscle as well as potentially age-, gender-, and exercise-related differences. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:61-70.

Overexpression of Jagged1 Ameliorates Aged Rat-Derived Endothelial Progenitor Cell Functions and Improves Its Transfusion Efficiency for Rat Balloon-Induced Arterial Injury.

BACKGROUND: Endothelial progenitor cell (EPC) has significant age-dependent alterations in properties, but the role of Jagged1 in aging-induced decline of EPC functions remains unclear. METHODS: 2- and 20-month old healthy male Sprague-Dawley rats were used in present study. Jagged1 gene transfection was performed in EPC isolated from aged (AEPC) and young rats (YEPC), respectively. Experiments were divided into 4 groups: (1) pIRES2-EGFP (PE) group, (2) PE-combined N-[N-(3, 5-difluoro-phenacetyl)-1- alany1]-S-phenyglycine t-butyl ester (DAPT) (PE + D) group, (3) pIRES2 EGFP-Jagged1 (PEJ) group, and (4) PEJ combined DAPT (PEJ + D) group. Notch molecules were detected by real-time quantitative polymerase chain reaction or Western blotting. CD34, CD133, CD45, and KDR markers were detected by flow cytometry. EPC migration and proliferation were detected with a modified Boyden chamber and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, respectively; the tube formation ability was assayed by in vitro angiogenesis kit; EPC transfusion after Jagged1 gene transfection was performed in rat carotid artery injury models. RESULTS: Jagged1 gene transfection effectively activates notch-signaling pathway. Compared with PE groups, overexpression of Jagged1 significantly promoted AEPC functions including proliferation, migration, the tube formation ability, and cell differentiation, these effects could be reasonably diminished by DAPT. In vivo study demonstrated that Jagged1 overexpressing also significantly promoted AEPC homing to the vascular injury sites and decreases the neointima formation after vascular injury. CONCLUSIONS: Overexpression of Jagged1 ameliorates aged rat-derived EPC functions and increases its transfusion efficiency for balloon-induced rat arterial injury.

Synergistic Effects of Transplanted Endothelial Progenitor Cells and RWJ 67657 in Diabetic Ischemic Stroke Models.

BACKGROUND AND PURPOSE: An immature vascular phenotype in diabetes mellitus may cause more severe vascular damage and poorer functional outcomes after stroke, and it would be feasible to repair damaged functional vessels using endothelial progenitor cell (EPC) transplantation. However, high glucose induces p38 mitogen-activated protein kinase activation, which can accelerate the senescence and apoptosis of EPCs. The aim of this study was to investigate the combined effects of EPC transplantation and p38 mitogen-activated protein kinase inhibitor administration on diabetic stroke outcomes. METHODS: Bone marrow-derived EPCs were injected intra-arterially into db/db mice after ischemic stroke induction. RWJ 67657 (RWJ), a p38 mitogen-activated protein kinase inhibitor, was administered orally for 7 consecutive days, with the first dose given 30 minutes before stroke induction. Functional outcome was determined at days 0, 1, 7, 14, and 21. Angiogenesis, neurogenesis, infarct volume, and Western blotting assays were performed on day 7, and white matter remodeling was determined on day 14. RESULTS: Neither EPC transplantation nor RWJ administration alone significantly improved diabetic stroke outcome although RWJ displayed a potent anti-inflammatory effect. By both improving the functioning of EPCs and reducing inflammation, EPC transplantation plus RWJ administration in vivo synergistically promoted angiogenesis and neurogenesis after diabetic stroke. In addition, the white matter remodeling, behavioral scores, and expressions of vascular endothelial growth factor and brain-derived neurotrophic factor were significantly increased in diabetic mice treated with both EPCs and RWJ. CONCLUSIONS: The combination of EPC transplantation and RWJ administration accelerated recovery from diabetic stroke, which might have been caused by increased levels of proangiogenic and neurotrophic factors.

Renal lipids and oxygenation in diabetic mice: noninvasive quantification with MR imaging.

PURPOSE: To determine the relationship between renal lipid content and intrarenal oxygenation in diabetic nephropathy by using noninvasive chemical shift-selective (CSS) imaging and blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging. MATERIALS AND METHODS: The study was approved by the institutional Committee on Animal Research. Lipid and water phantoms for CSS imaging were made, and BOLD MR imaging phantoms from arterial and venous blood samples were collected from rats. CSS imaging and BOLD imaging were performed to measure lipid contents and T2* in phantoms and kidneys of diabetic gene (db) db/db mice and wild-type mice after exposure to nitrogen (four per group) and injection of furosemide (four per group). Results of MR imaging-measured lipid contents and oxygen tension were compared with known values in phantoms and reference standard from mice with histologic data. Statistical analysis was performed with independent sample and paired sample t tests and Pearson correlation test. RESULTS: Renal lipid content in db/db mice was significantly higher compared with that in control mice (9.40% ± 1.89 and 3.11% ± 0.57, respectively; P < .001). In addition, the lipid content in the cortex of db/db mice was significantly higher than that in medulla (12.73% ± 0.94 and 3.16% ± 0.50, respectively; P < .001). Correlation was significant between T2* measured with BOLD and oxygen tension in blood phantoms (r = 0.958; P < .001). Lower baseline T2* in diabetic kidney suggested lower oxygenation that reserved excess oxygen supply. Lower oxygenation in diabetic kidney cortex was observed after nitrogen exposure and furosemide injection. CONCLUSION: Noninvasive CSS imaging and MR imaging of db/db diabetic mice revealed the relationship between the renal lipid content and intrarenal oxygenation in diabetic kidney. Lipid accumulation in diabetic kidney compromises the oxygenation of the renal tissue and made it more susceptible to renal hypoxia. Online supplemental material is available for this article.

Research progress on the GRP78 gene in the diagnosis, treatment and immunity of cervical cancer.

BACKGROUND: GRP78 is a molecular chaperone protein in the endoplasmic reticulum that is involved in protein assembly and quality control, and it participates in ER stress regulation of endoplasmic reticulum stress pathways. Studies have confirmed that GRP78 gene is highly expressed in a variety of tumors and is involved in different biological functions. PURPOSE: The present review highlights the involvement of the GRP78 gene in regulating the development of cervical cancer by promoting the proliferation and invasion of cervical cancer cells as well as by inhibiting apoptosis and promoting the Warburg effect. High expression of GRP78 is positively correlated with chemotherapy resistance in cervical cancer. GRP78 plays an anticancer role in cervical cancer by regulating autophagy and apoptosis. Mediated immune CD8 + T cells regulate tumor cell immunity and play a role in the application of the HPV vaccine. CONCLUSIONS: GRP78 plays a multifunctional role in cervical cancer and has important therapeutic and diagnostic value.

Mesenchymal stem cells with p38 mitogen-activated protein kinase interference ameliorate mouse ischemic stroke.

Mesenchymal stem cells (MSCs) have been widely used in the treatment of ischemic stroke. However, factors such as high glucose, oxidative stress, and aging can lead to the reduced function of donor MSCs. The p38 mitogen-activated protein kinase (MAPK) signaling pathway is associated with various functions, such as cell proliferation, apoptosis, senescence, differentiation, and paracrine secretion. This study examined the hypothesis that the downregulation of p38 MAPK expression in MSCs improves the prognosis of mice with ischemic stroke. Lentiviral vector-mediated short hairpin RNA (shRNA) was constructed to downregulate the expression level of p38 MAPK in mouse bone marrow-derived MSCs. The growth cycle, apoptosis, and senescence of MSCs after infection were examined. A mouse model of ischemic stroke was constructed. After MSC transplantation, the recovery of neurological function in the mice was evaluated. Lentivirus-mediated shRNA significantly downregulated the mRNA and protein expression levels of p38 MAPK. The senescence of MSCs in the p38 MAPK downregulation group was significantly reduced, but the growth cycle and apoptosis did not significantly change. Compared with the control group, the infarct volume was reduced, and the neurological function and the axonal remodeling were improved in mice with ischemic stroke after transplantation of MSCs with downregulated p38 MAPK. Immunohistochemistry confirmed that in the p38 MAPK downregulation group, apoptotic cells were reduced, and the number of neuronal precursors and the formation of white matter myelin were increased. In conclusion, downregulation of p38 MAPK expression in MSCs improves the therapeutic effect in mice with ischemic stroke, an effect that may be related to a reduction in MSC senescence. This method is expected to improve the efficacy of MSCs in patients, especially in patients with underlying diseases such as diabetes, thus providing a basis for clinical individualized treatment for cerebral infarction.

[Effects of telmisartan on the level of Aß1-42, interleukin-1ß, tumor necrosis factor α and cognition in hypertensive patients with Alzheimer's disease].

OBJECTIVE: To explore the effects of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor γ-stimulating activity, on the levels of Aß1-42, interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α) and cognition in elderly hypertensive patients with Alzheimer's disease (AD). METHODS: A total of 48 patients with probable AD and essential hypertension were randomly assigned into telmisartan group (n = 24, 40 - 80 mg qd) or amlodipine group (n = 24, 5 - 10 mg qd) for 6 months at Henan Provincial People's Hospital during 2008 - 2011. Cognitive evaluations were assessed at pre-treatment and 24 weeks post-treatment by clinical assessment, rating scales and neuropsychological tests while the cerebrospinal fluid (CSF) levels of Aß1-42, IL-1ß and TNF-α by enzyme-linked immunosorbent assay (ELISA). RESULTS: After 6 months, mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) significantly decreased compared with baseline values to a similar extent in both groups. No significant differences existed between two groups in SBP or DBP. The patients displayed significantly higher Aß1-42 and greatly lower levels of IL-1ß and TNF-α in the telmisartan group versus the amlodipine group (P < 0.05). At 24 weeks, the patients in the telmisartan group had better mini-mental state examination (MMSE) (22.0 ± 3.4) and Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) (15 ± 5) scales scores than those taking amlodipine (MMSE (19.5 ± 2.8) and ADAS-cog (18 ± 5). Patients treated with telmisartan had better improvement on the MMSE (P < 0.05) and ADAS-cog (P < 0.05) scales compared with the amlodipine group by the end of study week 24. CONCLUSION: Telmisartan may delay the decreased level of Aß1-42 and reduce the levels IL-1ß and TNF-α in CSF so as to improve the cognitive function of elderly hypertensive patients with AD. With additional benefits in comparison with common antihypertensive drugs, it may offer a novel therapeutic strategy of AD.

6-Methoxyflavone induces S-phase arrest through the CCNA2/CDK2/p21CIP1 signaling pathway in HeLa cells.

This study aimed to elucidate the specific anticancer mechanism of 6-methoxyflavone in HeLa cells. A total of 178 putative targets of 6-methoxyflavone were obtained from the PharmMapper database. Microarray analyses, transcriptome sequencing analyses, functional enrichment analyses, and gene set enrichment analyses were performed to preliminarily explore the roles and mechanisms of the 178 targets in cervical cancer. Cell counting kit-8, cell cycle assays, polymerase chain reactions, and western blotting were used to clarify the mechanism of action of 6-methoxyflavone. Molecular docking and noncovalent interaction analyses were performed to further confirm the mechanism of action in three-dimensional structures. Functional enrichment analyses and gene set enrichment analyses indicated that high mRNA expression of cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2) stimulated cell cycle progression in cervical cancer. Cell proliferation and cycle assays, transcriptome sequencing, polymerase chain reactions, and western blotting revealed that 6-methoxyflavone inhibited HeLa cell proliferation and induced S-phase arrest via the CCNA2/CDK2/ cyclin-dependent kinase inhibitor 1A (p21CIP1) pathway. Molecular docking and noncovalent interaction analyses showed that 6-methoxyflavone had the strongest affinity toward, inhibitory effect on, and noncovalent interactions with CDK2, and that the combination of CDK2 and CCNA2 enhanced these effects. An analysis of clinical characteristics showed that 6-methoxyflavone might be related to six clinicopathological parameters of cervical cancer patients. 6-Methoxyflavone induces S-phase arrest in HeLa cells via the CCNA2/CDK2/p21CIP1 pathway.

Comparative Study on Topological Properties of the Whole-Brain Functional Connectome in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinson's Disease Without RBD.

Purpose: Idiopathic rapid eye movement Sleep Behavior Disorder (iRBD) is considered as a prodromal and most valuable warning symptom for Parkinson's disease (PD). Although iRBD and PD without RBD (nRBD-PD) are both α-synucleinopathies, whether they share the same neurodegeneration process is not clear enough. In this study, the pattern and extent of neurodegeneration were investigated and compared between early-stage nRBD-PD and iRBD from the perspective of whole-brain functional network changes. Methods: Twenty-one patients with iRBD, 23 patients with early-stage nRBD-PD, and 22 matched healthy controls (HCs) were enrolled. Functional networks were constructed using resting-state functional MRI (fMRI) data. Network topological properties were analyzed and compared among groups by graph theory approaches. Correlation analyses were performed between network topological properties and cognition in the iRBD and nRBD-PD groups. Results: Both patients with iRBD and patients with early-stage nRBD-PD had attention, executive function, and some memory deficits. On global topological organization, iRBD and nRBD-PD groups still presented small-worldness, but both groups exhibited decreased global/local efficiency and increased characteristic path length. On regional topological organization, compared with HC, nRBD-PD presented decreased nodal efficiency, decreased degree centrality, and increased nodal shortest path length, while iRBD presented decreased nodal efficiency and nodal shortest path. For iRBD, brain regions with decreased nodal efficiency were included in the corresponding regions of nRBD-PD. Nodal shortest path changes were significantly different in terms of brain regions and directions between nRBD-PD and iRBD. Attention deficits were correlated with local topological properties of the occipital lobe in both iRBD and nRBD-PD groups. Conclusion: Both global and local efficiency of functional networks declined in nRBD-PD and iRBD groups. The overlaps and differences in local topological properties between nRBD-PD and iRBD indicate that iRBD not only shares functional changes of PD but also presents distinct features.

Resting-State Functional Network Topology Alterations of the Occipital Lobe Associated With Attention Impairment in Isolated Rapid Eye Movement Behavior Disorder.

Purpose: This study investigates the topological properties of brain functional networks in patients with isolated rapid eye movement sleep behavior disorder (iRBD). Participants and Methods: A total of 21 patients with iRBD (iRBD group) and 22 healthy controls (HCs) were evaluated using resting-state functional MRI (rs-fMRI) and neuropsychological measures in cognitive and motor function. Data from rs-fMRI were analyzed using graph theory, which included small-world properties, network efficiency, network local efficiency, nodal shortest path, node efficiency, and network connectivity, as well as the relationship between behavioral characteristics and altered brain topological features. Results: Rey-Osterrieth complex figure test (ROCFT-copy), symbol digital modalities test (SDMT), auditory verbal learning test (AVLT)-N1, AVLT-N2, AVLT-N3, and AVLT-N1-3 scores were significantly lower in patients with iRBD than in HC (P < 0.05), while trail making test A (TMT-A), TMT-B, and Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III) scores were higher in patients with iRBD (P < 0.05). Compared with the HCs, patients with iRBD had no difference in the small-world attributes (P > 0.05). However, there was a significant decrease in network global efficiency (P = 0.0052) and network local efficiency (P = 0.0146), while an increase in characteristic path length (P = 0.0071). There was lower nodal efficiency in occipital gyrus and nodal shortest path in frontal, parietal, temporal lobe, and cingulate gyrus. Functional connectivities were decreased between the nodes of occipital with the regions where they had declined nodal shortest path. There was a positive correlation between TMT-A scores and the nodal efficiency of the right middle occipital gyrus (R = 0.602, P = 0.014). Conclusion: These results suggest that abnormal behaviors may be associated with disrupted brain network topology and functional connectivity in patients with iRBD and also provide novel insights to understand pathophysiological mechanisms in iRBD.

Studies on the Mechanism of Alloimperatorin on the Proliferation and Apoptosis of HeLa Cells.

Alloimperatorin is a compound extracted from the traditional Chinese medicine (Angelica dahurica), which has exhibited anticancer activity. However, its precise molecular mechanism of anticancer remains unclear. Alloimperatorin-induced apoptosis of cervical cancer cells and its molecular mechanism were investigated in the present study. Cholecystokinin octapeptide (CCK-8) was employed to evaluate the cytotoxicity of alloimperatorin on HeLa, SiHa, and MS-751 cells. Flow cytometry was used to assess apoptosis induced by alloimperatorin. The mechanism of apoptosis was verified by mitochondrial membrane potential, Western blotting, and fluorescent PCR. The results of the study showed that alloimperatorin reduced the activity of HeLa cells. The calculated IC50 at 48 hours was 116.9 µM. Compared with the control group, alloimperatorin increased the apoptotic rate of HeLa cells and reduced the mitochondrial membrane potential of HeLa cells. The Western blot results showed that alloimperatorin promotes the expression of caspase3, 8, 9 and that Bax apoptotic proteins reduce PARP expression, procaspase3, 8, 9, and BCL-2 proteins and reduces the cyt-c in the mitochondria expression. The results demonstrated that alloimperatorin can induce HeLa cell apoptosis through mitochondria and extrinsic apoptotic pathways.