Poria acid inhibit the growth and metastasis of renal cell carcinoma by inhibiting the PI3K/akt/NF-κb signaling pathway.

Background: Poria acid (PAC) is a triterpene compound found in Poria cocos, a traditional Chinese medicine (TCM). The current study aims to explore the therapeutic effects and potential mechanisms of PAC on the migration and proliferation of human renal cell carcinoma (RCC) cells as well as tumor growth in animal model. Methods: Cell viability and proliferative capacity of normal renal cells and RCC cells were investigated by MTT assay. In addition, 786-O cells were divided into four groups and treated with different concentrations of PAC (0, 20, 40, and 60 µM) for 48 h. Cell scratch test and cell invasion assay were performed to evaluate the effects of PAC on the invasion and migration of RCC cells, respectively. The effects of PAC on apoptosis of RCC cells and expression levels of PI3K/Akt/NF-kB signaling pathway-related biomarkers were investigated using TUNEL staining and Western blotting methods, respectively. Effects of PAC on the inhibitory activity of RCC tumor in mice were evaluated in a 786-O CDX model. Results: The study found that PAC inhibited the viability of RCC cells in a dose-dependent manner, as demonstrated by in vitro cell assays (p < 0.05). However, PAC showed no significant inhibitory effect on normal renal cells (p > 0.05). PAC also significantly inhibited the migration and invasion of RCC via EMT/MMP signaling pathways (p < 0.05). Immunofluorescence and immunoblotting results showed that PAC induced the apoptosis of RCC, which was accompanied by changes in the expression levels of apoptosis-related proteins (p < 0.05). Moreover, PAC significantly downregulated the PI3K/Akt/NF-kB signaling pathway in a concentration-dependent manner (p < 0.05). The effect of PAC on RCC apoptosis was dramatically reversed by 740Y-P (PI3K agonist) (p < 0.05) but significantly enhanced in the presence of LY294002 (PI3K inhibitor) (p < 0.05). The results of in vivo experiment also demonstrated that the antitumor activity of PAC was achieved by affecting the PI3K/Akt/NF-kB signaling pathway. Conclusions: PAC can effectively suppress the proliferation, invasion and migration of RCC cells, and exhibit anti-tumor effects in RCC model by inhibiting the PI3K/Akt/NF-kB signaling pathway.

Efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B exhibiting suboptimal response to entecavir.

BACKGROUND: Entecavir (ETV) is a potent and safe antiviral agent for patients with chronic hepatitis B (CHB); however, some patients may exhibit suboptimal response or resistance to ETV. Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved pharmacokinetics and reduced renal and bone toxicity compared with tenofovir disoproxil fumarate. AIM: To evaluate the efficacy and safety of switching from ETV to TAF in patients with CHB exhibiting suboptimal response to ETV. METHODS: A total of 60 patients with CHB who had been treated with ETV for at least 12 mo and had persistent or recurrent viremia [Hepatitis B virus (HBV) DNA ≥ 20 IU/mL] or partial virologic response (HBV DNA < 20 IU/mL, but detectable) were enrolled in the study. The patients were randomly assigned to either continue ETV (0.5 mg) daily or switch to TAF (25 mg) daily for 48 wk. The primary endpoint was the proportion of patients who achieved a virologic response (HBV DNA level < 20 IU/mL) at week 48. Secondary endpoints included changes in serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and anti-HBe levels, and renal and bone safety parameters. RESULTS: At week 48, the proportion of patients who achieved a virologic response was significantly higher in the TAF group than in the ETV group (93.3% vs 66.7%, P = 0.012). The mean reduction in HBV DNA from baseline was also significantly greater in the TAF group than in the ETV group (-3.8 vs -2.4 Log10 IU/mL, P < 0.001). The rates of ALT normalization, HBeAg loss, HBeAg seroconversion, and HBsAg loss were not found to significantly differ between the two groups. None of the patients developed genotypic resistance to ETV or TAF. Both drugs were well tolerated, with no serious adverse events or discontinuations caused by adverse events. No significant changes were observed in the estimated glomerular filtration rate, serum creatinine level, or urine protein-to-creatinine ratio in either group. The TAF group had a significantly lower decrease in bone mineral density at the lumbar spine and hip than the ETV group (-0.8% vs -2.1%, P = 0.004; -0.6% vs -1.8%, P = 0.007, respectively). CONCLUSION: Switching from ETV to TAF is effective and safe for patients with CHB exhibiting a suboptimal response to ETV and may prevent further viral resistance and reduce renal and bone toxicity.

Systematic investigation for the mechanisms and the substance basis of Yang-Xin-Ding-Ji capsule based on the metabolite profile and network pharmacology.

Because traditional Chinese medicine (TCM) is a complex mixture of multiple components, the application of methodologies for evaluating single-component Western medicine in TCM studies may have certain limitations. Appropriate strategies that recognize the integrality of TCM and connect to TCM theories remain to be developed. Yang-Xin-Ding-Ji (YXDJ) capsule is originally from a classical TCM formula used for the treatment of arrhythmia. In this study, we used UPLC-Q-TOF-MS detection method, coupled with the metabolic research and network pharmacology analysis, to study the scientific connotation of the YXDJ capsule. A total of 33 absorbed constituents and 23 metabolites were identified or tentatively characterized in dosed plasma and urine, and the possible metabolic pathways were mainly methylation, oxidation, sulfation, glucuronidation, and deglucosylation. We optimized the conventional process ways of network pharmacology by collecting targets based on absorbed constituents into the blood. The constituents-target disease and Kyoto Encyclopedia of Genes pathway analysis revealed that 24 absorbed constituents, 32 target genes, and 10 key pathways were probably related to the efficacy of the YXDJ capsule against arrhythmia. The results provided a scientific basis for understanding the bioactive compounds and the pharmacological mechanism of the YXDJ capsule.

Molecular Oxygen-Mediated Radical Alkylation of C(sp3)-H Bonds with Boronic Acids.

A direct and site-specific alkylation of (sp3)C-H bond with aliphatic boronic acid was achieved. By simply heating glycinates and amines together with alkylboronic acids under an oxygen atmosphere, a variety of unnatural α-amino acids and peptides could be obtained in good yields.

Perioperative outcomes and mid-term effects in performing video-assisted thoracoscopic extended thymectomy for myasthenia gravis: subxiphoid versus right thoracic approaches.

BACKGROUND: Approaches of thoracoscopic thymectomy for myasthenia gravis (MG) are debatable. The subxiphoid approach is widely utilized recent years for its better visualization of the anterior mediastinum. In the present study, we compared perioperative outcomes and mid-term effects of the extended thymectomy for MG between the subxiphoid approach and the routine right-thoracic approach. METHODS: One hundred and thirty-one MG patients treated with thoracoscopic extended thymectomy were analyzed. Among them, 68 patients were operated on via the subxiphoid approach and the other 63 via the conventional right-side unilateral approach. The patient outcomes were retrospectively reviewed and evaluated. Mid-term clinical outcome was assessed according to the classification system proposed by the Myasthenia Gravis Foundation of America (MGFA). Clinical efficacy and variables influencing outcome were evaluated by the Kaplan-Meier method and Cox proportional hazards regression analysis. RESULTS: Compared with the right thoracic approach, the duration of the procedure via the subxiphoid approach was significantly shorter (P=0.035), the rates of total thymectomy were higher (P=0.028), and the pain scores on postoperative days 1, 3, and 7 were significantly lower (P<0.001, P<0.001, and P=0.03, respectively). A total of 112 patients with MG were followed up. The subxiphoid approach group reported higher rates of complete stable remission (CSR) and effective treatment of MG, although these differences were not statistically significant (Z=-0.484, P=0.627). By multivariate Cox proportional hazards modes analysis, the chance of CSR was significantly increased when age <40 (OR: 2.623, 95% CI: 1.150-5.983, P=0.022), non-thymomatous MG (OR: 1.078, 95% CI: 1.101-3.316, P=0.021) and MGFA clinical classification (OR: 2.024, 95%:1.164-3.523, P=0.013). CONCLUSIONS: The subxiphoid approach has shorter operation time, higher rates of total thymectomy and better quality of life compared with the lateral thoracoscopic approach. Preoperative age, pathological diagnoses and MGFA Clinical Classification are the independent risk factors for non-complete stable remission (NCSR) after thymectomy.

Norcantharidin regulates ERα signaling and tamoxifen resistance via targeting miR-873/CDK3 in breast cancer cells.

MiR-873/CDK3 has been shown to play a critical role in ERα signaling and tamoxifen resistance. Thus, targeting this pathway may be a potential therapeutic approach for the treatment of ER positive breast cancer especially tamoxifen resistant subtype. Here we report that Norcantharidin (NCTD), currently used clinically as an ani-cancer drug in China, regulates miR-873/CDK3 axis in breast cancer cells. NCTD decreases the transcriptional activity of ERα but not ERß through the modulation of miR-873/CDK3 axis. We also found that NCTD inhibits cell proliferation and tumor growth and miR-873/CDK3 axis mediates cell proliferation suppression of NCTD. More important, we found that NCTD sensitizes resistant cells to tamoxifen. NCTD inhibits tamoxifen induced the transcriptional activity as well ERα downstream gene expressions in tamoxifen resistant breast cancer cells. In addition, we found that NCTD restores tamoxifen induced recruitments of ERα co-repressors N-CoR and SMRT. Knockdown of miR-873 and overexpression of CDK3 diminish the effect of NCTD on tamoxifen resistance. Our data shows that NCTD regulates ERα signaling and tamoxifen resistance by targeting miR-873/CDK3 axis in breast cancer cells. This study may provide an alternative therapy strategy for tamoxifen resistant breast cancer.

Two Approaches for Evaluating the Effects of Galangin on the Activities and mRNA Expression of Seven CYP450.

Galangin is a marker compound of honey and Alpinia officinarum Hance that exhibits great potential for anti-microbial, anti-diabetic, anti-obesity, anti-tumour and anti-inflammatory applications. Galangin is frequently consumed in combination with common clinical drugs. Here, we evaluated the effects of galangin on cytochrome P450 (CYP)-mediated metabolism, using two different approaches, to predict drug⁻drug interactions. Male Sprague Dawley rats were administered galangin daily for 8 weeks. A "cocktail-probes" approach was employed to evaluate the activities of different CYP450 enzymes. Blood samples of seven probe drugs were analysed using liquid chromatography-tandem mass spectrometry in positive and negative electrospray-ionisation modes. Pharmacokinetic parameters were calculated to identify statistical differences. CYP mRNA-expression levels were investigated in real-time quantitative polymerase chain reaction experiments. The galangin-treated group showed significantly decreased AUC0⁻∞ and Cmax values for CYP1A2, and CYP2B3. The galangin-treated group showed significantly increased AUC0⁻∞ and Cmax values for CYP2C13 and CYP3A1. No significant influences were observed in the pharmacokinetic profiles of CYP2C11, CYP2D4 and CYP2E1. The mRNA-expression results were consistent with the pharmacokinetic results. Thus, CYP450 enzyme activities may be altered by long-term galangin administration, suggesting galangin to be a promising candidate molecule for enhancing oral drug bioavailability and chemoprevention and reversing multidrug resistance.

Proton pump inhibitor-induced exfoliative dermatitis: A case report.

A 74-year-old female patient was admitted to hospital following a road accident with pains in the chest, abdomen, waist, back, nose, left wrist and lower limbs. After 1 week, the patient presented with gastrointestinal bleeding, and thus was treated with protein pump inhibitors (PPIs), including lansoprazole, esomeprazole and omeprazole enteric-coated tablets, in order to inhibit acid secretion and attenuate bleeding. However, the patient developed skin rashes on the chest and right lower limb and foot 28 days following treatment initiation. The skin rashes spread and ulcerated after 3 days, and were associated with tracheal mucosal injury and hemoptysis. Subsequently, treatment of the patient with PPIs was terminated, after which the tracheal hemoptysis and skin rashes markedly improved. In addition, no new skin rashes appeared following termination of the PPI treatment. In the present case, long-term treatment of an elderly patient with PPIs may have induced exfoliative dermatitis, due to hepatic ischemia, hypoxia and acute renal failure, which may have decreased the metabolism of PPIs, resulting in the accumulation of PPI metabolites.

FOXO1 silence aggravates oxidative stress-promoted apoptosis in cardiomyocytes by reducing autophagy.

Mechanisms underlining oxidative stress-induced injury to cardiomyocytes during myocardial infarction (MI) or acute ischemia/reperfusion (I/R) are not well recognized. Forkhead box O (FOXO) transcription factors have been defined as critical mediators of oxidative stress resistance in multiple cell types, but their cardioprotective functions have not been reported previously. In the present study, we investigated the promotion to FOXO1 by the treatment with hydrogen peroxide (H2O2) during the H2O2-induced apoptosis in cardiomyocyte H9c2 cells. We then silenced FOXO1 with FOXO1-specific siRNA, and re-evaluated the H2O2-induced apoptosis. In addition, we also examined the H2O2-induced autophagy and the autophagy induction post FOXO1 silence. Results demonstrated that H2O2 induced a significantly high level of apoptosis in H9c2 cells. Interestingly, the FOXO1 in both mRNA and protein levels were not significantly regulated, however, the phosphorylated form of FOXO1 was significantly promoted in the H2O2-treated H9c2 cells. On the other hand, post the significant knockout of FOXO1 with the transfection with FOXO1-specific siRNA, the apoptosis induction was more significant in H9c2 cells subjected to H2O2. In addition, we found a significantly higher level of autophagy induction in the H2O2-treated H9c2 cells. However, the autophagy was markedly reduced by the knockout of FOXO1. In summary, these data support the critical role for FOXO1 in promoting cardiomyocytes against oxidative stress probably through inducing autophagy.

[Prevalence of HIV among men who have sex with men of inland high school and college students in China: a meta-analysis].

OBJECTIVE: To analyze the prevalence of HIV among men who have sex with men (MSM) of inland high school and college students in China, and to analyze the differences between sample size, sampling methods and study period. METHODS: Electronic search strategy was carried out, using WanFang database, China Journal Full-text database, VIP database, CBM and PubMed database to collect data on high school and college students, HIV and MSM, among residents in China. Fixed effects model or random effects model was employed according to statistical tests for homogeneity. Publication bias was assessed by funnel plot. RESULTS: Ten studies were selected with a total of 2014 students-MSM and 106 HIV infected. The overall prevalence of HIV was 4.6% (95% CI 2.9%-6.3%). The prevalence of HIV was stratified by factors as sample size, sampling methods and study period of the study. The pooled prevalence rates of HIV were as follows: 4.7% (95% CI 2.5%-7.0%) and 4.7% (95% CI 1.9%-7.4%) for sample size > 200 and sample size 200, 6.1% (95% CI 3.0%-9.1%) and 2.9% (95% CI 1.7%-4.1%) for snow sampling and non-snow sampling, respectively. The pooled prevalence of HIV were 3.0% (95% CI 1.7%-4.2%) in the study year of 2005-2007 and 6.0% (95% CI 3.1%-9.0%) in 2008-2010, respectively. The pooled prevalence of HIV was higher in snow sampling than non-snow sampling, in the study year of in 2008-2010 than in 2005-2007. CONCLUSION: The prevalence of HIV among MSM of inland high school and college students in China was higher than general population.

Evaluation of a new tuberculosis-related interferon gamma release assay for tuberculosis infection diagnosis in Huzhou, eastern China.

OBJECTIVE: To compare the performance of a new tuberculosis-related interferon gamma release assay (TB-IGRA) with that of QuantiFERON-TB Gold In-Tube (QFT-GIT) for TB infection diagnosis in China. MATERIALS AND METHODS: A total of 458 active TB patients and 378 healthy individuals were enrolled. Among the 458 active TB patients, 395 had pulmonary TB and 63 had extra-pulmonary TB. The blood samples were collected from the active TB patients and health controls; then TB-IGRA and QFT-GIT were used to detect interferon gamma (IFN-γ) levels. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value in TB infection diagnosis for active TB by the TB-IGRA were 83.4%, 94.2%, 94.5%, and 82.4%, respectively. For QFT-GIT, the sensitivity, specificity, positive predictive value, and negative predictive value in TB infection diagnosis for active TB were 81.4%, 97.1%, 97.1%, and 81.2%, respectively. CONCLUSIONS: TB-IGRA had a high sensitivity and specificity for TB infection; it could be comparable with the QFT-GIT assay. It might be a powerful assisting tool for TB infection diagnosis in the Chinese clinical setting.

[The diagnostic value of multichannel intraluminal esophageal impedance and pH monitoring in gastroesophageal reflux-related cough].

OBJECTIVE: To evaluate the diagnostic value and limitation of multichannel intraluminal esophageal impedance and pH (MII-pH) monitoring on the diagnosis of gastroesophageal reflux-related chronic cough (GERC). METHODS: The patients with suspicious GERC consecutively referred to our respiratory clinic between May 2010 and July 2011 underwent a MII-pH monitoring, and received anti-reflux drug therapy, irrespective of the laboratory findings. Chronic cough due to gastroesophageal reflux was determined when there was a favorable response to anti-reflux therapy. Then, the sensitivity, specificity, false positive and negative rate, total consistence, positively and negatively predictive value, the area under the curve of ROC and the Kappa value of the laboratory investigation were calculated for the diagnosis of GERC. RESULTS: During the research period, 56 patients completed MII-pH monitoring. Among them, the abnormal reflux was found in 35 patients, and GERC was finally confirmed in 30 patients (85.7%) including 25 patients (83.3%) due to acid reflux and 5 patients (16.7%) due to non-acid reflux. In the remaining 21 patients with normal reflux episodes, 6 patients (28.6%) could be explained by non-acid reflux for their cough because of a relatively predominant weakly acid reflux and favorable response to empirical anti-reflux therapy. For the diagnosis of GERC, MII-pH monitoring had the sensitivity of 83.3%, the specificity of 75.0%, false positive rate of 25.0%, false negative rate of 16.7%, total consistence of 80.4%, positive predictive value of 85.7%, negative predictive value of 71.4%, the area under the curve of ROC of 0.792 and Kappa value of 0.577 respectively. CONCLUSION: MII-pH is a sensitive and reliable tool for the diagnosis of GERC due to its ability to detect both acid and non-acid reflux.

Cough reflex sensitivity and airway inflammation in patients with chronic cough due to non-acid gastro-oesophageal reflux.

BACKGROUND AND OBJECTIVE: The aim of this study was to explore the pathogenesis of chronic cough caused by non-acid reflux. METHODS: Seven patients with chronic cough due to non-acid reflux, 12 patients with chronic cough due to acid reflux, 10 patients with gastro-oesophageal reflux disease without cough and 12 healthy volunteers were recruited for the study. All subjects underwent oesophageal multi-channel intraluminal impedance measurements combined with pH monitoring, and assessment of cough reflex sensitivity to capsaicin and induced sputum cytology. The concentrations of substance P, mast cell tryptase, prostaglandin D2 and histamine in induced sputum were measured by ELISA. RESULTS: Cough threshold C2 and C5 did not differ between patients with chronic cough due to non-acid or acid reflux, but the values were significantly lower than those for patients with gastro-oesophageal reflux disease without cough and healthy volunteers. Weakly acidic reflux episodes were obviously more frequent in patients with chronic cough due to non-acid reflux than in the other three groups. Sputum substance P and mast cell tryptase concentrations were remarkably increased in patients with chronic cough, but were similar for those with cough due to non-acid or acid reflux. There were significant inverse correlations between substance P levels and cough threshold C2 or C5 in patients with cough due to non-acid or acid reflux, and between mast cell tryptase levels and cough threshold C2 in patients with cough due to acid reflux. CONCLUSIONS: Chronic cough due to non-acid reflux may be related to cough reflex hypersensitivity caused by neurogenic airway inflammation and mast cell activation, in which weakly acidic reflux is possibly a major factor.

Discrepancy between presumptive and definite causes of chronic cough.

BACKGROUND: The current diagnostic algorithms for chronic cough require the establishment of the primary presumptive causes followed by the confirmation of diagnosis with the specific therapies. The aim of the study was to investigate the discrepancy between presumptive and definite causes and its clinical implication. METHODS: A total of 109 patients with chronic cough underwent laboratory investigations to identify the cause of cough; including sinus computerized tomography (if needed), histamine bronchial provocation, induced sputum cytology and 24-hour esophageal pH or multi-channel intraluminal impedance combined with pH monitoring. The presumptive causes were confirmed by treating them sequentially. The difference between presumptive and definite causes of chronic cough was compared. RESULTS: Single cause was more frequent in the definite diagnosis than in the presumptive diagnosis (78.9% vs. 54.1%, χ(2) = 15.01, P = 0.0001). In contrast, multiple causes were significantly fewer in definite diagnosis than in the presumptive diagnosis (15.6% vs. 37.6%, χ(2) = 13.53, P = 0.0002). There was a discrepancy between definite and presumptive causes in 30 patients (27.5%). Compared with the presumptive causes, definite upper airway cough syndrome (24.8% vs. 11.9%, χ(2) = 6.0, P = 0.01) and gastroesophageal reflux disease (6.4% vs. 0, χ(2) = 7.23, P = 0.007) was more frequent as a single cause of chronic cough while cough variant asthma plus gastroesophageal reflux disease (3.7% vs. 11.9%, χ(2) = 5.17, P = 0.02) and upper airway cough syndrome plus nonasthmatic eosinophilic bronchitis (0 vs. 9.2%, χ(2) = 10.48, P = 0.001) were fewer as multiple causes of chronic cough. CONCLUSIONS: A discrepancy was common between presumptive and definite causes of chronic cough. To treat presumptive causes sequentially may be a suitable solution for avoidance of erroneous multiple causes and possible over-treatment.

Efficacy and safety of modified sequential three-step empirical therapy for chronic cough.

BACKGROUND AND OBJECTIVE: Sequential three-step empirical therapy is useful for the management of chronic cough. The purpose of this study was to evaluate the efficacy and safety of modified sequential three-step empirical therapy. METHODS: Consecutive patients (n = 240) with chronic cough were recruited and randomly assigned to receive modified (modified group) or primary (primary group) sequential three-step empirical therapy. The primary end-point was the overall rate of control of chronic cough. Secondary end-points were the rate of control of chronic cough at each step of therapy, the duration of treatment required, changes in cough symptom score, health-related quality of life and possible adverse effects. RESULTS: The study was completed by 106 patients in the modified group and 108 patients in the primary group. The overall rate of control of chronic cough was 88.7% in the modified group and 91.7% in the primary group (chi(2) = 0.54, P > 0.05). There were no obvious differences in the rate of control of cough at each step of therapy, the duration of treatment required, patterns of cough symptom scores or improvements in the health-related quality of life between the modified and primary groups. However, the incidence of drowsiness was significantly lower in the modified group than in the primary group (11.7% vs 21.7%, chi(2) = 4.32, P = 0.04). CONCLUSIONS: Modified three-step empirical therapy was as efficacious as primary three-step therapy for chronic cough, but was preferable because it had fewer side-effects.