Functional Axis of PDE5/cGMP Mediates Timosaponin-AIII-Elicited Growth Suppression of Glioblastoma U87MG Cells.

Glioblastoma (GBM) is the most aggressive brain tumor, with high mortality. Timosaponin AIII (TIA), a steroidal saponin isolated from the medicinal plant Anemarrhena asphodeloides Bge., has been shown to possess anticancer properties in various cancer types. However, the effect of TIA on GBM is unknown. In this study, we reveal that TIA not only inhibited U87MG in vitro cell growth but also in vivo tumor development. Moreover, we found that the cause of TIA-induced cell growth suppression was apoptosis. When seeking to uncover antitumor mechanisms of TIA, we found that TIA diminished the expression of cGMP-specific phosphodiesterase 5(PDE5) while elevating the levels of guanylate cyclases (sGCß), cellular cGMP, and phosphorylation of VASPser239. Following the knockdown of PDE5, PDE5 inhibitor tadalafil and cGMP analog 8-Bro-cGMP both inhibited cell growth and inactivated ß-catenin; we reason that TIA elicited an antitumor effect by suppressing PDE5, leading to the activation of the cGMP signaling pathway, which, in turn, impeded ß-catenin expression. As ß-catenin is key for cell growth and survival in GBM, this study suggests that TIA elicits its anti-tumorigenic effect by interfering with ß-catenin function through the activation of a PDE5/cGMP functional axis.

Effect of using electronic medication monitors on tuberculosis treatment outcomes in China: a longitudinal ecological study.

BACKGROUND: In China, an indigenously developed electronic medication monitor (EMM) was designed and used in 138 counties from three provinces. Previous studies showed positive results on accuracy, effectiveness, acceptability, and feasibility, but also found some ineffective implementations. In this paper, we assessed the effect of implementation of EMMs on treatment outcomes. METHODS: The longitudinal ecological method was used at the county level with aggregate secondary programmatic data. All the notified TB cases in 138 counties were involved in this study from April 2017 to June 2019, and rifampicin-resistant cases were excluded. We fitted a multilevel model to assess the relative change in the quarterly treatment success rate with increasing quarterly EMM coverage rate, in which a mixed effects maximum likelihood regression using random intercept model was applied, by adjusting for seasonal trends, population size, sociodemographic and clinical characteristics, and clustering within counties. RESULTS: Among all 69 678 notified TB cases, the treatment success rate was slightly increased from 93.5% [95% confidence interval (CI): 93.0-94.0] in second quarter of 2018 to 94.9% (95% CI: 94.4-95.4) in second quarter of 2019 after implementing EMMs. There was a statistically significant effect between quarterly EMM coverage and treatment success rate after adjusting for potential confounders (P = 0.0036), increasing 10% of EMM coverage rate will lead to 0.2% treatment success rate augment. Besides, an increase of 10% of elderly or bacteriologically confirmed TB will lead to a decrease of 0.4% and 0.9% of the treatment success rate. CONCLUSIONS: Under programmatic settings, we found a statistically significant effect between increasing coverage of EMM and treatment success rate at the county level. More prospective studies are needed to confirm the effect of using EMM on TB treatment outcomes. We suggest performing operational research on EMMs that provides real-time data under programmatic conditions in the future.

MiR-26a-5p Inhibits Cell Proliferation and Enhances Doxorubicin Sensitivity in HCC Cells via Targeting AURKA.

OBJECTIVE: To investigate the role of miR-26a-5p in cell proliferation and doxorubicin sensitivity in hepatocellular carcinoma. METHODS: We evaluated miR-26a-5p expression in hepatocellular carcinoma tissues and cell lines by reverse transcription polymerase chain reaction. Cell Counting Kit-8 was used to examine cell proliferation. Relationship between miR-26a-5p and aurora kinase A was evaluated by luciferase report system. Western blot was used to detect expression of aurora kinase A. RESULTS: In this study, we observed miR-26a-5p was downregulated in hepatocellular carcinoma tissues and cell lines. Gain-of-function experiments showed that proliferation rate of hepatocellular carcinoma cells decreased under condition of miR-26a-5p mimics. We found miR-26a-5p mimics could enhance doxorubicin sensitivity of hepatocellular carcinoma cells. Further study showed that aurora kinase A was target gene of miR-26a-5p. Suppression of aurora kinase A could lead to lower cell proliferation and higher doxorubicin sensitivity of hepatocellular carcinoma cells. CONCLUSION: Our study found that miR-26a-5p could inhibit cell proliferation and enhance doxorubicin sensitivity in hepatocellular carcinoma cells by targeting aurora kinase A.

SHCBP1 is a novel target and exhibits tumor­promoting effects in gastric cancer.

The present study investigated the expression and potential influence of SHC SH2 domain­binding protein 1 (SHCBP1) in gastric cancer (GC) cells. SHCBP1 is closely related to cell proliferation and cell cycle progression, but its role in GC remains unclear. The TCGA database revealed that SHCBP1 is highly expressed in GC tissues. Furthermore, SHCBP1 was revealed to be highly expressed in GC cell lines MGC­803 and SGC­7901 cells, and downregulation of SHCBP1 significantly inhibited GC cell proliferation. Furthermore, SHCBP1 expression promoted cell cycle progression and inhibition of apoptosis. Since the CDK4, cyclin D1 and caspase family proteins play important roles in cell cycle and apoptosis regulation, it was examined whether there was an association between SHCBP1 and these signaling pathways in GC. Our results revealed that SHCBP1 promoted cell cycle progression by regulating the CDK4­cyclin D1 cascade and suppressed caspase­3, caspase PARP­dependent apoptotic pathways. Cell invasion and metastasis experiments also revealed that SHCBP1 promoted tumor growth and invasiveness. These tumor­promoting functions of SHCBP1 may provide a potential molecular basis for the diagnosis and targeted therapy of GC.

Antinociceptive Effects of Prim-O-Glucosylcimifugin in Inflammatory Nociception via Reducing Spinal COX-2

We measured anti-nociceptive activity of prim-o-glucosylcimifugin (POG), a molecule from Saposhnikovia divaricate (Turcz) Schischk. Anti-nociceptive or anti-inflammatory effects of POG on a formalin-induced tonic nociceptive response and a complete Freund's adjuvant (CFA) inoculation-induced rat arthritis pain model were studied. Single subcutaneous injections of POG produced potent anti-nociception in both models that was comparable to indomethacin analgesia. Anti-nociceptive activity of POG was dose-dependent, maximally reducing pain 56.6% with an ED₅₀ of 1.6 mg. Rats given POG over time did not develop tolerance. POG also time-dependently reduced serum TNFα, IL-1β and IL-6 in arthritic rats and both POG and indomethacin reduced spinal prostaglandin E2 (PGE₂). Like indomethacin which inhibits cyclooxygenase-2 (COX-2) activity, POG dose-dependently decreased spinal COX-2 content in arthritic rats. Additionally, POG, and its metabolite cimifugin, downregulated COX-2 expression in vitro. Thus, POG produced potent anti-nociception by downregulating spinal COX-2 expression.

Genetic ablation of receptor for advanced glycation end products promotes functional recovery in mouse model of spinal cord injury.

Spinal cord injury (SCI) results in a loss of normal motor and sensory function, leading to severe disability and reduced quality of life. The aim of this work was to investigate the effect of receptor for advanced glycation end products (RAGE) deficiency on the function recovery in a mouse model of SCI. Mice received a mid-thoracic spinal contusion injury. Upregulation of RAGE protein expression in spinal cord tissue was evident at 12 h after SCI and continued at 2 and 5 days. Furthermore, we showed that locomotor recovery was improved and lesion pathology was reduced after SCI in RAGE-deficient mice. RAGE deficiency in mice attenuated apoptosis after SCI through inhibiting p53/Bax/caspase-3 pathway. RAGE deficiency in mice inhibited inflammation after SCI, marked by reduced myeloperoxidase activity, NFκB nuclear translocation, and TNF-α, IL-1ß, and IL-6 mRNA and protein levels. RAGE deficiency in mice exposed to SCI suppressed the upregulation of inducible nitric oxide synthase (iNOS) and gp91-phox and attenuated oxidative and nitrosative stresses, marked by reduced formation of malondialdehyde, reactive oxygen species, peroxynitrite (OONO(-)), and 3-nitrotyrosine. RAGE deficiency in mice exposed to SCI attenuated glial scar at the injury site, marked by decreased expression of glial fibrillary acidic protein. These data indicate that the RAGE plays an important role in the development of SCI and might provide a therapeutic target to promote recovery from SCI.

[Study of an adherence rating score system for tuberculosis patients in China].

OBJECTIVE: To develop an adherence rating score (ARS) system specific for tuberculosis (TB) patients. METHODS: A cross-sectional survey of 124 TB patients was conducted to figure out risk factors for adherence to treatment. The step-wise logistic regression models were used for selecting adherence-related variables. ARS was developed based on the weighting scores of the parameters of all the predicted variables in the logistic model. The reliability and responsibility of ARS was evaluated by using external data from an open label randomized controlled trial on 574 TB patients. The patients were grouped as adherence group (247 patients) and non-adherence group (327 patients) based on the predicted ARS. And the non-adherence group was randomized divided into a trail group (146 patients) and a control group (181 patients). The intervention for the trail group was custom health educational material aimed to reduce ARS, while the intervention for control groups was general TB education material, which was routinely used in the current local TB control settings. The cumulative non-adherence rates of the three groups were compared with each other after six-month follow-up period of treatment. RESULTS: The ARS system had 7 items which covered the following domains: disease status, psychology, patients' KAP (knowledge, attitude, and practice), regularly life-style and social supports. The score of ARS was 2.38+/-0.18 (mean+/-SD) for adherence patients, and 4.69 +/-0.20 (mean+/-SD) for non-adherence patients (t=8.52, P<0.01). In the randomized controlled trial, the six months cumulative non-adherence rates ware 24.7% for the trail group and it was 41.4% for the control group(P<0.01); while the six months cumulative non-adherence rates were not statistical significant difference between trail group and adherence group (P>0.05). CONCLUSION: The ARS system was reliability and validity for evaluating the adherence of TB treatment in the stop TB settings in China.

Design of the anti-tuberculosis drugs induced adverse reactions in China National Tuberculosis Prevention and Control Scheme Study (ADACS).

BACKGROUND: More than 1 million tuberculosis (TB) patients are receiving the standard anti-TB treatment provided by China National Tuberculosis Prevention and Control Scheme (CNTS) in China every year. Adverse reactions (ADRs) induced by anti-TB drugs could both do harm to patients and lead to anti-TB treatment failure. The ADACS aimed to explore ADRs' incidences, prognoses, economical and public health impacts for TB patients and TB control, and build a DNA bank of TB patients. METHODS/DESIGN: Multiple study designs were adopted. Firstly, a prospective cohort with 4488 sputum smears positive pulmonary tuberculosis patients was established. Patients were followed up for 6-9 months in 52 counties of four regions. Those suspected ADRs should be checked and confirmed by Chinese State Food and Drug Administration (SFDA). Secondly, if the suspected ADR was anti-TB drug induced liver injury (ATLI), a nested case-control study would be performed which comprised choosing a matched control and doing a plus questionnaire inquiry. Thirdly, health economical data of ADRs would be collected to analyze financial burdens brought by ADRs and cost-effectiveness of ADRs' treatments. Fourthly, a drop of intravenous blood for each patient was taken and saved in FTA card for DNA banking and genotyping. Finally, the demographic, clinical, environmental, administrative and genetic data would be merged for the comprehensive analysis. DISCUSSION: ADACS will give an overview of anti-TB drugs induced ADRs' incidences, risk factors, treatments, prognoses, and clinical, economical and public health impacts for TB patients applying CNTS regimen in China, and provide suggestions for individualized health care and TB control policy.

[Genetic polymorphism of glutathione-S-transferase M1 and T1: a systematic review in Chinese population and a pilot study in smear-positive pulmonary tuberculosis cases of Jilin province].

OBJECTIVE: To investigate the distribution of glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) genes polymorphisms in Chinese population and smear-positive pulmonary tuberculosis cases of Jilin province. METHODS: Articles about GSTM1 and GSTT1 genes polymorphisms published before 2009 in China were searched. The study population was obtained from fourteen counties (or districts) of Jilin province, which included all cases from November, 2007 to May, 2008, totally 1120. The genotypes of GSTM1 and GSTT1 were detected by multiplex PCR technique. RESULTS: The frequencies of GSTM1 and GSTT1 'null' genotypes and combination M1-T1 'null' genotype acquired from systematic review were 54.2%, 46.8% and 26.2%, respectively, in Chinese Hans they were 53.4%, 44.9% and 25.5%, and in our research they are 57.2%, 20.4% and 13.7%, respectively. No significant differences between the frequencies of males and females as well as among that of different age groups were observed (P > 0.05). The frequency of GSTM1 'null' genotype in our research is slightly higher than that in systematic review (P = 0.016) , and the frequencies of GSTT1 'null' genotype and combination M1-T1 'null' genotype and are significantly lower than those in systematic review (both P < 0.001). CONCLUSION: The frequencies of GSTM1 and GSTT1 'null' genotypes were different among ethnic. The statistical difference between systematic review and our research may due to our large sample size and mostly Southern people in previous studies.