Unveiling the anti-senescence effects and senescence-associated secretory phenotype (SASP) inhibitory mechanisms of Scutellaria baicalensis Georgi in low glucose-induced astrocytes based on boolean network.

BACKGROUND: Astrocytes senescence has been demonstrated in the aging brain and Alzheimer's disease (AD). Moreover, lower glucose metabolism has been confirmed in the early stage of AD. However, whether low glucose could induce astrocytes senescence remain ambiguous. Studies have shown that the ethanol extracts of Scutellaria baicalensis Georgi (SGE) exert neuroprotective and anti-aging effects, while whether SGE could delay astrocytes senescence was unclear. PURPOSE: This study investigated the anti-senescence effect of SGE in low glucose-induced T98G cells and primary astrocytes, and explored the possible mechanisms based on boolean network. METHODS: The neuroprotective effects of SGE in low glucose-induced T98G cells were evaluated by measurement of cell viability, LDH, ROS and ATP. The anti-senescence effects of SGE were investigated by detection of senescence-associated ß-galactosidase (SA-ß-Gal), senescence-associated secretory phenotype (SASP), cell cycle and senescence-related markers. The possible mechanisms of SGE in delaying astrocytes senescence were discovered through integrating transcriptomics with boolean network, and validation experiments were further performed. RESULTS: Our results revealed that low glucose could induce astrocytes senescence, and SGE could delay astrocytes senescence by decreasing the staining rate of SA-ß-gal, reducing secretions of SASP factors (IL-6, CXCL1, MMP-1), alleviating cell cycle arrest in G0/G1 phase, decreasing the formation of punctate DNA foci and down-regulating the expression of p16INK4A, p21 and γH2A.X. Transcriptomics and further verification results showed that SGE could markedly inhibit the mRNA expression levels of SASP factors (CXCL10, CXCL2, CCL2, IL-6, CXCR4, CCR7). Moreover, C-X-C motif chemokine 10 (CXCL10) was predicted to be the key SASP factor affecting the network stability by using boolean network. Further experiments validated that SGE could markedly reduce CXCL10 level, decrease the secretion of IL-6 and inhibit cell migration in CXCL10 induced primary astrocytes. CONCLUSION: In summary, our research unmasks that the anti-senescence effects of SGE were highly correlated with the suppression of SASP secretions, and CXCL10 mediated the SASP inhibition effect of SGE in low glucose-induced astrocytes. Our study highlights that the delay of astrocytes senescence and the inhibition of SASP might be a new mechanism of SGE for alleviating neurodegenerative diseases such as AD.

Effects of Composite Warm Mix Additive (CAR) on the Physical and Rheological Performance of Bitumen and the Pavement Performance of Its Concrete.

Warm mix asphalt received increasing attention in recent years, and this technology aims to increase the fluidity of bitumen in the process of mixing and construction. To characterize the physical and rheological properties of bitumen and the pavement performance of bituminous mixtures, it was modified by a composite additive Rediset. Rediset consists of both the cationic surfactants and organic additive-based rheology modifiers. Commonly used materials such as Pen 60/80 bitumen and bituminous concrete (AC-20) were selected. The results show that Rediset can improve the penetration and softening point of the bitumen, making the bitumen stiffer and harder. All Rediset-modified bituminous concretes are in the same low-temperature performance grade (PG) as the bitumen without Rediset. Although Rediset can decrease the rutting and crack resistance of Rediset-modified bituminous concrete, all the Rediset-modified bituminous concrete with less than 2% Rediset still satisfied the requirement of the maximum bending strain being higher than 2000 µÎµ, and the dynamic stability of Rediset-modified bituminous concrete with 3% Rediset was still higher than 1000 cycles/mm. The cationic surfactants in the Rediset can play the role of an anti-stripping agent and improve the adhesion between the interfaces of the aggregate and bituminous binder, which enhances the moisture resistance of Rediset-modified bituminous concrete.

Is correction of segmental kyphosis necessary in single-level anterior cervical fusion surgery? An observational study.

BACKGROUND: This study was conducted to determine whether sagittal lordotic alignment and clinical outcomes could be improved by the correction of segmental kyphosis after single-level anterior cervical discectomy and fusion (ACDF) surgery. PATIENTS AND METHODS: We retrospectively reviewed patients who underwent single-level ACDF surgery in our hospital between January 2014 and February 2017. Basic characteristics of patients included age at surgery, gender, diagnosis, duration of symptoms, and location of target level. Pre- and postoperative radiographs at the 6-month follow-up were used to evaluate the following parameters, such as segmental angle, C2-C7 angle, T1 slope, and C2-C7 sagittal vertical axis (SVA). Postoperative clinical outcomes were assessed by the Neck Disability Index and VAS. According to the segmental angle of postoperative radiographs, patients were divided into noncorrection group and correction group. RESULTS: A total of 181 patients (99 males and 82 females) were analyzed in our study. There were 32 patients in the noncorrection group and 149 patients in the correction group. There was no significant difference in demographic and clinical data between the two groups before surgery. However, patients in the correction group showed larger C2-C7 angle and lower C2-C7 SVA after surgery in comparison with those in the noncorrection group. Besides, changes in the segmental angle were positively correlated with changes in C2-C7 angle and negatively correlated with changes in C2-C7 SVA. CONCLUSION: Surgical correction of segmental kyphosis in single-level cervical surgery contributed to balanced cervical alignment in comparison with those without satisfactory correction. However, we could not demonstrate that the correction of segmental alignment is associated with a better recovery in clinical outcomes.

Risk factors associated with clinical adjacent segment pathology following multi-level cervical fusion surgery.

Few clinical studies investigate risk factors associated with clinical adjacent segment pathology (CASP) following multi-level cervical fusion surgery. The aim is to record the incidence of postoperative CASP in patients after at least 2 years' follow-up and to identify possible risk factors that may be associated with the CASP after multi-level cervical surgery.We retrospectively reviewed patients who underwent multi-level cervical surgery in our hospital from January 2004 to February 2016. All patients underwent more than 2 years' follow-up. The diagnosis of CASP is according to clinical symptoms as well as image findings. Potential risk factors were collected from demographic data and radiographic images.A total of 301 patients after multi-level cervical surgery were analyzed. During follow-up, 28 patients (9.3%) were diagnosed as having CASP. Among these patients, 7 showed symptoms of CASP within 3 years after surgery, 6 showed symptoms between 3 and 5 years, 14 showed symptoms between 5 and 10 years, and the last one showed symptoms more than 10 years later. In the multivariate analysis, degeneration of adjacent segment (OR, 1.592; 95% CI, 1.113-2.277), decreased Cobb angle in fused vertebrae (OR, 2.113; 95% CI, 1.338-3.334) and decreased Cobb angle in cervical spine (OR, 1.896; 95% CI, 1.246-2.886) were correlated with the incidence of CASP during follow-up.The incidence of CASP following multi-level cervical surgery was 9.3% with a mean of about 70 months' follow-up. Patients with preoperative degeneration of adjacent segment and postoperative imbalance of sagittal alignment have a higher risk of developing CASP after multi-level cervical surgery.

Rational drug design of indazole-based diarylurea derivatives as anticancer agents.

A series of novel indazole-based diarylurea derivatives targeting c-kit were designed by structure-based drug design. The derivatives were prepared, and their antiproliferative activities were evaluated against human colon cancer HCT-116 cell line and hepatocellular carcinoma PLC/PRF/5 cell line. The antiproliferative activities demonstrated that six of nine compounds exhibited comparable activities with sorafenib against HCT-116. The structure-activity relationship (SAR) analysis indicated that the indazole ring part tolerated different kinds of substituents, and the N position of the central pyridine ring played key roles in antiproliferative activity. The SAR and interaction mechanisms were further explored using molecular docking method. Compound 1i with N-(2-(pyrrolidin-1-yl)ethyl)-carboxamide possessed improved solubility, 596.1 ng/ml and best activities, IC50 at 1.0 µm against HCT-116, and 3.48 µm against PLC/PRF/5. It is a promising anticancer agent for further development.

Pharmacokinetics and metabolism of SL-01, a prodrug of gemcitabine, in rats.

PURPOSE: SL-01, dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl) carbamoyl) pyrazine-2-carboxylate, is a prodrug of gemcitabine. Our previous reports suggested that SL-01 possesses superior bioavailability and anticancer activity to gemcitabine in mice. In this study, its pharmacokinetics and metabolisms were investigated in rats. METHODS: The pharmacokinetics of SL-01 was studied following intravenous or oral administration of SL-01 to Sprague-Dawley rats. The metabolites profile of SL-01 was further determined in rats receiving intravenous administration of SL-01. Blood samples were analyzed by using LC-MS or LC-MS/MS assay. RESULTS: Following administration with SL-01 intravenously or orally, SL-01, plasma gemcitabine released from SL-01 as well as the sum of gemcitabine (gemcitabine converted from SL-01 and plasma gemcitabine) exhibited higher values of V z /F and CL z /F, and longer MRT and t 1/2 than those of gemcitabine administered intravenously. The C max of gemcitabine produced by intravenous SL-01 was higher than that of gemcitabine dosed intravenously. The absolute bioavailability for the sum of gemcitabine was 32.2 % for intravenous and 22.2 % for oral administration with SL-01, respectively. After a single intravenous administration, a total of 5 components (M1, M2, M3, M4, and M5) were detected and identified as the metabolites of SL-01 in the plasma of rats. M1 and M2 were formed from the methylation and reduction of SL-01, respectively. Hydrolysis of the amide bond of SL-01 gave M3 and M4. M5 was produced from further dealkylation of M3. CONCLUSIONS: SL-01 displayed improved absorption, good distribution, high clearance, long mean residence time, and moderate bioavailability after administered intravenously or orally to rats. The major metabolic pathways of SL-01 involved methylation, reduction, hydrolysis, and dealkylation. These results suggested that SL-01 acts as a prodrug of gemcitabine in rats.

Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines.

New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity.

Synthesis and biological evaluation of oral prodrugs based on the structure of gemcitabine.

A series of oral prodrugs based on the structure of gemcitabine (2',2'-difluorodeoxycytidine) were synthesised by introducing an amide group at the N4-position of the cytidine ring. A total of 16 compounds were obtained, and their chemical and biological characteristics were evaluated. The half-maximal inhibitory concentrations (IC(50)s) for most of these compounds were higher than that of gemcitabine in vitro. Compounds 5d and 5m, the representative compounds, were examined in terms of their physiological stabilities and pharmacokinetics. Compound 5d showed good stability in PBS and simulated intestinal fluid, and an analysis of its pharmacokinetics in mice suggested that the introduction of an amide group to gemcitabine could greatly improve its bioavailability. Further evaluation of compound 5d in vivo showed that this compound possesses higher activity than gemcitabine against the growth of HepG2 human hepatocellular carcinoma cells and HCT-116 colon adenocarcinoma cells with less toxicity to animals. These results suggest that compound 5d could be further developed as a potential oral anticancer agent for clinical applications in which gemcitabine is currently used.