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Human induced pluripotent stem cells (hiPSCs) may provide potential resource for regenerative medicine research, including generation of insulin-producing cells for diabetes research and insulin production. Testosterone (T) is an androgen hormone which promotes protein synthesis and improves the management of type 2 diabetes in clinical studies. Concurrently, co-existed hyperandrogenism and hyperinsulinism is frequently observed in polycystic ovary syndrome, congenital adrenal hyperplasia and some of Wermer's syndrome. However, the relationship among androgens, insulin and the differentiation of pancreatic β cells is still not fully clear. Here we find that T improves the differentiation efficiency of insulin-producing cells from hiPSCs. The addition of T into routine differentiation formula for pancreatic β cells increases the differentiation efficiency from 12% to 35%. The administration of T promotes the expression of key genes associated with β cells differentiation including NGN3, NEUROD1 and INS. This finding benefits the ongoing process to optimize the differentiation protocol of pancreatic β cells from hiPSCs, and provides some degree of understanding the clinical management of T for type 2 diabetes. [ABSTRACT FROM AUTHOR]

This work introduced an eco-friendly approach for the synthesis of sliver nanoparticles (AgNPs) with a water-soluble fraction of polysaccharides extracted from the roots of Astragalus membranaceus (AMWP). AMWP mediated AgNPs (AMWP-AgNPs) were successfully synthesized using 1.0 mM AgNO 3 and 1.25 mg/mL AMWP, reacting in aqueous environment at 25 °C for 6 h. The synthesized AMWP-AgNPs exhibited a broad surface plasmon resonance peak (SPR) at 445 nm in Ultraviolet-visible (UV–vis) spectrum, which was characteristic of a poly-dispersed AMWP-AgNPs. Transmission electron microscopy (TEM) and Dynamic light scattering (DLS) analysis revealed that the AMWP-AgNPs were almost spherical shaped with an average diameter of 65.08 nm. The antibacterial activities of AMWP-AgNPs were assessed on four strains of clinical isolated multidrug resistant (MDR) bacteria and four relative reference strains using modified agar disk diffusion and tetrazolium methods. All strains, especially the resistant strains, were significantly inhibited by AMWP-AgNPs at comparatively low concentration (minimum inhibition concentrations (MICs) ranging from 0.032 to 0.063 mg/mL). Therefore, we propose that the AMWP-AgNPs will have a great potential in anti-MDR bacterial applications. [ABSTRACT FROM AUTHOR]

Chlorogenic acid (CGA), a polyphenolic compound, exists widely in medicinal herbs, which has been shown a strong antioxidant and anti-inflammatory effect. This study investigated the protective effects and mechanism of CGA on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Treatment of CGA successfully ameliorates LPS-induced renal function and pathological damage. Moreover, CGA dose-dependently suppressed LPS-induced blood urea nitrogen (BUN), creatinine levels, and inflammatory cytokines TNF-α, IL-6, and IL-1β in serum and tissue. The relative proteins' expression of TLR4/NF-κB signal pathway was assessed by western blot analysis. Our results showed that CGA dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. CGA also suppressed LPS-induced TNF-α, IL-6, and IL-1β production both in serum and kidney tissues. Furthermore, our results showed that CGA significantly inhibited the LPS-induced expression of phosphorylated NF-κB p65 and IκB as well as the expression of TLR4 signal. In conclusion, our results provide a mechanistic explanation for the anti-inflammatory effects of CGA in LPS-induced AKI mice through inhibiting TLR4/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins. Carfilzomib inhibited growth and induced apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells occurred in a caspase-dependent manner through both intrinsic and extrinsic caspase pathways. In addition, carfilzomib inhibited constitutive activation of the NF-κB signaling cascade, both in MCL cell lines and primary MCL cells, by completely blocking the phosphorylation of IκBα. Our results demonstrate that carfilzomib can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Chemotherapy is critical for the treatment of liver cancer. Despite the pro-apoptotic effects of corosolic acid (CA) have been revealed, the methods to enhance its efficacy are unclear. The aim of this study is to investigate the target that might reduce CA efficacy and figure out the way to conquer it. We found reduction of Yes-associated protein (YAP) might be a critical event that suppresses efficacy of CA. Treatment of CA accelerated degradation of YAP via enhancing its phosphorylation by LATS1. Moreover, we found CA boosts βTrCP-dependent Ubiquitination of YAP. Interestingly, the protein stability of βTrCP per se could be enhanced by CA. Notably, ActionomycinD (AD) strengthened CA-induced apoptosis of liver cancer cells via elevating YAP while down-regulating βTrCP. Importantly, combined treatment of CA and AD had much more obvious influences against transformative phenotypes of liver cancer cells than those under treatment of CA alone. Combined usage of AD successfully reduced IC50 value of CA. In summary, we have first uncovered that suppression of YAP might reduce efficacy of CA to treat liver cancer, combined treatment of AD and CA might solve this problem. [ABSTRACT FROM AUTHOR]

Background: ALK rearrangement-advanced NSCLC patients respond to crizotinib. ALK rearrangement is currently determined with RT-PCR. VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC; however, VENTANA IHC has rarely been used to determine the response to crizotinib in Chinese patients with NSCLC and ALK overexpression. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangements, we conducted this study to analyze VENTANA IHC and RT-PCR in a large cohort of Chinese patients with NSCLC undergoing screening for ALK rearrangements.Methods: A total of 1720 patients with NSCLC who had ALK rearrangements detected by VENTANA IHC and/or RT-PCR were included in this analysis. We compared the efficacy and survival of ALK-positive patients detected by VENTANA IHC and RT-PCR. We used NGS to identify patients in whom the two methods were inconsistent.Results: Among 1720 patients, 187 (10.87%) were shown to be ALK-positive by VENTANA IHC and/or RT-PCR, and 66 received crizotinib treatment. We identified 10.27% (172/1674) of patients as ALK-positive by the VENTANA IHC method, and 12.73% (41/322) of patients had ALK rearrangements by the RT-PCR method. Twenty-nine of 276 (10.51%) ALK-positive patients were simultaneously analyzed using VENTANA IHC and RT-PCR. The overall response rates were 65.90% (29/44) by VENTANA IHC and 55.88% (19/34) by RT-PCR. The disease control rates were 86.36% (38/44) by VENTANA IHC and 76.47% (26/34) by RT-PCR. In contrast, the median progression-free survival for VENTANA IHC and RT-PCR was 8.5 and 9.2 months, respectively. The VENTANA IHC and RT-PCR results obtained for 6 of 17 ALK-positive patients were inconsistent based on NGS; specifically, 4 patients had EML4-ALK fusions, 2 patients had non EML4-ALK fusions, 1 patient had a KCL1-ALK fusion, and one patient had a FBXO36-ALK fusion.Conclusions: VENTANA IHC is a reliable and rapid screening tool used in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy. VENTANA IHC has moderate sensitivity and a slightly higher association with response to therapy with ALK inhibitors, and some VENTANA IHC-positive, but RT-PCR-negative cases may benefit from crizotinib. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition (EMT) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. TWIST activated by intra-tumoral hypoxia functions to promote the EMT. We hypothesized that TWIST and the downstream gene pathway could mediate PDAC progression under hypoxia. Therefore, 90 PDAC tissue specimens were immunostained for TWIST and other proteins. Pancreatic cancer cell lines were used for in vitro experiments and nude mice were used to confirm the in vivo data. Expression of TWIST and HIF-1α proteins was significantly upregulated, whereas expression of E-cadherin and p16 was down-regulated in PDAC tissues compared to that of non-tumor tissues and in tumor tissues obtained from patients with tumor involving splenic artery than those without splenic artery involvement. Up-regulated TWIST in tumor tissues were associated with worse prognosis in PDAC patients. The in vitro data showed that HIF-1α-induced TWIST overexpression promoted tumor cell growth and EMT under a hypoxic condition via TWIST interaction with Ring1B and EZH2. In vivo data showed that TWIST overexpression or a hypoxic condition induce xenograft growth, abdominal metastasis and low mouse survival, whereas knockdown of either Ring1B or EZH2 expression suppressed tumor xenograft growth and metastasis and prolonged survival of nude mice. TWIST was the key player in promotion of pancreatic cancer development and metastasis under a hypoxic condition through interaction with Ring1B and EZH2 to regulate expression of E-cadherin and p16 proteins in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of the combination of topical 20% autologous serum eye drops (ASEs) and silicone-hydrogel soft contact lenses (SCLs) for the treatment of corneal persistent epithelial defects (PEDs), and to compare the recurrence of epithelial breakdown with or without continuous use of ASEs after silicone-hydrogel SCLs removal.Methods: We conducted a prospective interventional study of 21 eyes of 21 patients with PEDs treated with combined ASEs and silicone-hydrogel SCLs from September 2014 to August 2015. SCLs were removed after total re-epithelialization and patients were subsequently randomized divided into two groups: (1) with and (2) without continuous use of ASEs for an additional 2 weeks. PEDs healing rate and epithelial defect recurrence were evaluated.Results: PEDs healed in all eyes within 3 weeks. Recurrence was noted in five eyes (50%) in patients without continued use of ASEs for 2weeks after total re-epithelialization and SCLs removal during a 3-month follow-up (odds ratio: 23.0; P<0.05). Recurrent epithelial defects were successfully treated with secondary SCLs application combined with autologous serum use. No adverse events were noted during the entire treatment period.Conclusions: The combined use of ASEs and silicone-hydrogel SCLs can successfully treat recalcitrant PEDs. Prolonged use of ASEs after total re-epithelialization can decrease recurrence rates. [ABSTRACT FROM AUTHOR]

Background Methane has been reported to play a protective role in ischemia-reperfusion injury via anti -oxidation, anti-inflammatory and anti-apoptotic activities. This study was designed to determine the protective effects of methane-rich saline (MRS) on acute carbon monoxide (CO) poisoning. Methods A total of 36 male Sprague-Dawley rats were randomly divided into 3 groups: sham group, CO group and MRS group. Acute CO poisoning was induced by exposing rats to 1000 ppm CO in air for 40 min and then to 3000 ppm CO for an additional 20 min until they lost consciousness. MRS at 10 ml/kg was intraperitoneally administered at 0 h, 8 h and 16 h after CO exposure. Rats were sacrificed 24 h after CO exposure. Brains were collected for Nissl staining. The cortex and hippocampus were separated for the detections of malondialdehyde (MDA), 3-nitrotyrosine (3-NT), 8-hydroxydeoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin1-β (IL-1β), interleukin-6 (IL-6) and superoxide dismutase (SOD) activities. Results The results showed that MRS treatment improved neuronal injury, reduced MDA, 3-NT and 8-OHdG, and increased SOD activity of the hippocampus and cortex compared with normal saline-treated rats. In addition, MRS reduced the expression of TNF-α and IL-1β in the brain but had no effect on IL-6 expression. Conclusion These findings suggest that MRS may protect the brain against acute CO poisoning-induced injury via its anti -oxidative and anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

Context: Sea cucumbers have been consumed as tonic, food, and nutrition supplements for many years. Objective: The objective of this study is to investigate the antiobesity and lipid-lowering effects of sea cucumber extracts inin vitroandin vivomodels and elucidate the mechanism of action of the extracts on obesity and dyslipidemia. Materials and methods: The 60% ethanol extracts from the body walls of 10 different sea cucumbers were investigated for the inhibition of pancreatic lipase (PL) activityin vitro. The optimal active extract (SC-3) was further chemically analyzed by LC-MS and UV. And 0.1% and 0.2% of SC-3 was mixed with a high-fat diet to treat C57/BL6 mice for 6 weeks or 2 weeks as preventive and therapeutic study. The body weight, serum, and liver lipid profile in the mice were investigated. Results: The crude extract ofPearsonothuria graeffeiSemper (Holothuriidae) inhibited the PL activity by 36.44% of control at 0.5 μg/mL. SC-3 and echinoside A inhibited PL with an IC50value at 2.86 μg/mL and 0.76 μM. 0.1% of SC-3 reduced the body weight (23.0 ± 0.62 versus 26.3 ± 0.76 g), the serum TC (2.46 ± 0.04 versus 2.83 ± 0.12 mmol/L), TG (0.19 ± 0.08 versus 0.40 ± 0.03 mmo/L), and LDL-c (0.48 ± 0.02 versus 0.51 ± 0.02 mmol/L), and liver TC (1.19 ± 0.17 versus 1.85 ± 0.13 mmol/mg) and TG (6.18 ± 0.92 versus 10.87 ± 0.97 mmol/mg) contents of the obese C57BL/six mice on a high-fat diet. Discussion and conclusion: Sea cucumber may be used for developing antiobesity and antihyperlipidemia drugs. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic total extraperitoneal (TEP) hernia repair has been confirmed as an effective procedure in several studies but is considered technically demanding. Separating the hernial sac and spermatic cord is difficult when a large sac inguinal hernia is encountered. This study aimed to investigate the feasibility and effectiveness of a combined open and laparoscopic TEP repair of large sac inguinal hernias.Methods: From June 2012 to May 2015, laparoscopic TEP (112 cases) and combined open and laparoscopic TEP (COL-TEP) (44 cases) were performed in patients with large sac hernia. There was no clear definition of large sac inguinal hernia; therefore, we defined a large sac as one with the sac base cranial to or over outer ring that could not be easily resected laparoscopically. Using this definition, the laparoscopic TEP group was divided into a small sac TEP (SS-TEP) group (68 cases) and a large sac TEP (LS-TEP) group (44 cases). Direct hernias were included in the SS-TEP group because the hernial sac was easily dissected laparoscopically. The patient demographics, perioperative parameters, complications, and recurrence were compared between the three groups.Results: No significant differences were found between the groups in mean age, gender, body mass index, comorbidities, number of previous laparotomies, or recurrence rate. Compared with the LS-TEP group, both the SS-TEP and COL-TEP groups had a significantly lower surgical duration (51.4 ± 10.9 vs. 32.8 ± 13.1 and 36.2 ± 11.2 min, respectively), conversion rate (13.6 vs. 0 and 0 %, respectively), and total complication rate (27.3 vs. 13.2 and 11.3 %, respectively).Conclusion: The combined technique was safe and effective for repair of large sac inguinal hernias. The combined technique was associated with decreased technical difficulty, surgical duration, and conversion and total complication rates. [ABSTRACT FROM AUTHOR]

Aims: Angiotensin II (Ang II) aggravates hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Angiotensin-(1-7) [Ang-(1-7)], which counter-regulates Ang II, has been evidenced to protect against hepatic fibrosis. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, being activated by reactive oxygen species (ROS), is identified as a novel mechanism of liver fibrosis. However, whether the NLRP3 inflammasome involves in regulation of Ang II-induced hepatic fibrosis remains unclear. This study investigates the different effects of the Ang II and Ang-(1-7) on collagen synthesis by regulating the NLRP3 inflammasome/Smad pathway via redox balance modulation. Results: In vivo, Ang-(1-7) improved bile duct ligation-induced hepatic fibrosis, reduced H2O2 content, protein levels of NOX4, and the NLRP3 inflammasome, whereas it increased glutathione (GSH) and nuclear erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE). In vitro, Ang II treatment elevated NOX4 protein expression and ROS production in hepatic stellate cells (HSCs), whereas it inhibited GSH and Nrf2-ARE, resulting in the activation of the NLRP3 inflammasome in the mitochondria of HSCs. NLRP3 depletion inhibited Ang II-induced collagen synthesis. Furthermore, Ang II increased NLRP3 and pro-IL-1β levels by activating the Toll-like receptor 4 (TLR4)/MyD88/NF-κB pathway. Treatment with antioxidants, NOX4 small interference RNA (siRNA), or Nrf2 activator inhibited Ang II-induced NLRP3 inflammasome activation and collagen synthesis. In contrast, the action of Ang-(1-7) opposed the effects of Ang II. Innovation and Conclusions: Ang-(1-7) improved liver fibrosis by regulating NLRP3 inflammasome activation induced by Ang II-mediated ROS via redox balance modulation. Antioxid. Redox Signal. 24, 795-812. [ABSTRACT FROM AUTHOR]

Purpose: We report two cases of Alternaria keratitis refractory to the conventional antifungal medical treatment successfully treated with subconjunctival fluconazole injection.Methods: Report of two cases.Results: After subconjunctival injection of fluconazole (2 mg/mL) 0.5 mL twice a day for 5 days then once a day till 14 days, two cases of Alternaria keratitis refractory to the conventional antifungal medical treatment were successfully treated. No severe local and systemic side effects were found in these two patients.Conclusions: Alternaria keratitis has a varied clinical presentation and suspicion must be maintained for unusual causes of infectious keratitis. Alternaria keratitis can be difficult to eradicate even with traditional antifungals such as amphotericin B and natamycin. Subconjunctival injection of fluconazole could be effective for Alternaria keratitis unresponsive to conventional antifungal medical treatment. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported that natriuretic peptides in the blood and pleural fluid (PF) are effective diagnostic markers for heart failure (HF). These natriuretic peptides include N-terminal pro-brain natriuretic peptide (NT-proBNP), brain natriuretic peptide (BNP), and midregion pro-atrial natriuretic peptide (MR-proANP). This systematic review and meta-analysis evaluates the diagnostic accuracy of blood and PF natriuretic peptides for HF in patients with pleural effusion. Methods: PubMed and EMBASE databases were searched to identify articles published in English that investigated the diagnostic accuracy of BNP, NT-proBNP, and MR-proANP for HF. The last search was performed on 9 October 2014. The quality of the eligible studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. The diagnostic performance characteristics (sensitivity, specificity, and other measures of accuracy) were pooled and examined using a bivariate model. Results: In total, 14 studies were included in the meta-analysis, including 12 studies reporting the diagnostic accuracy of PF NT-proBNP and 4 studies evaluating blood NT-proBNP. The summary estimates of PF NT-proBNP for HF had a diagnostic sensitivity of 0.94 (95% confidence interval [CI]: 0.90–0.96), specificity of 0.91 (95% CI: 0.86–0.95), positive likelihood ratio of 10.9 (95% CI: 6.4–18.6), negative likelihood ratio of 0.07 (95% CI: 0.04–0.12), and diagnostic odds ratio of 157 (95% CI: 57–430). The overall sensitivity of blood NT-proBNP for diagnosis of HF was 0.92 (95% CI: 0.86–0.95), with a specificity of 0.88 (95% CI: 0.77–0.94), positive likelihood ratio of 7.8 (95% CI: 3.7–16.3), negative likelihood ratio of 0.10 (95% CI: 0.06–0.16), and diagnostic odds ratio of 81 (95% CI: 27–241). The diagnostic accuracy of PF MR-proANP and blood and PF BNP was not analyzed due to the small number of related studies. Conclusions: BNP, NT-proBNP, and MR-proANP, either in blood or PF, are effective tools for diagnosis of HF. Additional studies are needed to rigorously evaluate the diagnostic accuracy of PF and blood MR-proANP and BNP for the diagnosis of HF. [ABSTRACT FROM AUTHOR]

Pterostilbene (3,5-dimethoxy-4-hydroxystilbene) is a component of blueberry. It has been reported that long-term treatment with blueberry has a neuroprotective effect. However, it has not been reported whether pterostilbene is effective in attenuating cerebral ischemia/reperfusion (I/R) injury. In the present study, focal cerebral ischemia was induced by middle cerebral artery occlusion for 90 min followed by reperfusion. To observe the dose-dependent effect, pterostilbene (2.5–80 mg/kg, ig ) was administered for 3 days before ischemia. To determine the time-dependent effect, pterostilbene (10 mg/kg, ig ) was administered as a single dose at 0, 1, or 3 h after reperfusion. Twenty-four hours after I/R, pterostilbene dose-dependently improved neurological function, reduced brain infarct volume, and alleviated brain edema. The most effective dose was 10 mg/kg; the therapeutic time window was within 1 h after I/R and treatment immediately after reperfusion showed the best protective effect. The protective effect is further confirmed by the results that post-ischemic treatment with pterostilbene (10 mg/kg) significantly improved motor function, alleviated blood brain barrier disruption, increased neurons survival and reduced cell apoptosis in cortical penumbra after cerebral I/R. We also found that pterostilbene (10 mg/kg) significantly reversed the increased content of malondialdehyde and the decreased activity of superoxide dismutase in the ipsilateral hemisphere. Furthermore, pterostilbene decreased the oxidative stress markers 4-hydroxynonenal and 8-hydroxyguanosine positive cells in the cortical penumbra. All these findings indicate that pterostilbene dose- and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury. This neuroprotective effect of pterostilbene may be associated with its inhibition of oxidative stress and subsequent neuronal apoptosis in the cortical penumbra. [ABSTRACT FROM AUTHOR]

Guizhi Fuling Capsule (GFC) is a famous traditional Chinese medicine (TCM) formula recorded in Synopsis of the Golden Chamber, which has achieved obvious effects in the treatment of uterine fibroids (UFs). Mediator complex subunit 12 (Med12) mutations were closely related to UFs in 85% of fibroid cases. The Wnt/β-Catenin signaling pathway plays an important role in the occurrence and development of UFs. This study aims to explore the pharmacological mechanism of GFC against UFs in which the Med12-mediated Wnt/β-Catenin pathway is involved. Med12 was silenced in uterine fibroid cells (UFCs) using a lentivirus-based Med12 gene-specific RNA interference (RNAi) strategy. Cell proliferation was performed by CCK-8 assay, cell apoptosis and cell cycle were measured by flow cytometry. The rat model of UFs was established by injecting estradiol benzoate and progesterone. Forty-eight rats were divided into six groups, the low-dose GFC (L-GFC) group, the medium-dose GFC (M-GFC) group and the high-dose GFC (H-GFC) group were intragastrically treated with GFC solution at 0.25 g/kg, 0.50 g/kg and 1.00 g/kg per day for 8 weeks, the positive control (PC) group was administrated with mifepristone (2.70 mg/kg/day), the normal control (NC) group and the model control (MC) group were given equal volume of normal saline once a day for 8 weeks. The histopathological changes of uterine tissues were evaluated by H&E staining. The expression of Med12 in uterine tissues were detected by immunohistochemistry. The protein and mRNA levels of associated genes were evaluated by western bolt and real time-PCR, respectively. Related indicators involved in Wnt/β-Catenin pathway, such as Wnt1, β-Catenin, Cyclin D1, TCF1/TCF7 and C-myc, were compared among different groups. The Wnt/β-Catenin signaling pathway was inhibited after Med12 gene was knocked out in UFCs. GFC-containing serum could induce cell apoptosis, make the cell cycle stagnated in G0/G1 phase to inhibiting the proliferation and reduce the expression of Wnt1, β-Catenin, Cyclin D1, TCF1/TCF7, and C-myc in control-shRNA cells, while had no significant effect on Med12-shRNA cells. Compared with the MC group, the weight, endometrial thickness, and pathological structure of the uterus in the GFC treated groups were significantly improved. The expression of Med12, Wnt1, β-Catenin, Cyclin D1, TCF1/TCF7, and C-myc that related to Wnt/β-Catenin pathway in the GFC treated groups were decreased with the increase of dosage administration. GFC inhibited UFs growth, which was directly associated with Med12 modulated Wnt/β-Catenin signaling pathway. This study provided new perspective to understand the therapeutic mechanism of UFs. [Display omitted] • Guizhi Fuling Capsule (GFC) inhibited the proliferation of uterine fibroid cells by disrupting the normal Med12 expression. • GFC induced apoptosis and made the cell cycle stagnated in G0/G1 phase of uterine fibroid cells. • GFC improved the weight, endometrial thickness, and pathological structure of the uterus in uterine fibroids model rats. • GFC regulated the Med12-mediated Wnt/β-Catenin pathway to treating uterine fibroids in model rats. [ABSTRACT FROM AUTHOR]

Angiogenesisis a key restorative mechanism in response to ischemia, and pro-angiogenic therapy could be beneficial in stroke. Accumulating experimental and clinical evidence suggest that human urinary kallidinogenase (HUK) improves stroke outcome, but the underlying mechanisms are not clear. The aim of current study was to verify roles of HUK in post-ischemic angiogenesis and identify relevant mediators. In rat middle cerebral artery occlusion (MCAO) model, we confirmed that HUK treatment could improve stroke outcome, indicated by reduced infarct size and improved neurological function. Notably, the 18F-FDG micro-PET scan indicated that HUK enhanced cerebral perfusion in rats after MCAO treatment. In addition, HUK promotespost-ischemic angiogenesis, with increased vessel density as well as up-regulated VEGF andapelin/APJ expression in HUK-treated MCAO mice. In endothelial cell cultures, induction of VEGF and apelin/APJ expression, and ERK1/2 phosphorylation by HUK was further confirmed. These changes were abrogated by U0126, a selective ERK1/2 inhibitor. Moreover, F13A, a competitive antagonist of APJ receptor, significantly suppressed HUK-induced VEGF expression. Furthermore, angiogenic functions of HUK were inhibited in the presence of selective bradykinin B1 or B2 receptor antagonist both in vitro and in vivo. Our findings indicate that HUK treatment promotes post-ischemic angiogenesis and cerebral perfusion via activation of bradykinin B1 and B2 receptors, which is potentially due to enhancement expression of VEGF and apelin/APJ in ERK1/2 dependent way. [ABSTRACT FROM AUTHOR]

The emergence of extensively drug-resistant tuberculosis (XDR-TB) in China is a great threat to TB control. To determine the molecular characterisation of XDR-TB isolates from China and the correlations between specific drug resistance-associated mutations and different genotype strains, 58 XDR-TB isolates were sequenced in eight drug loci, including katG , inhA , oxyR–ahpC intergenic region, rpoB , eis , rrs , gyrA and gyrB , and were genotyped using spoligotyping and analysis of the noise transfer function region. Compared with the phenotypic data, the sensitivities and specificities for DNA sequencing were 87.9% and 100.0% for isoniazid (INH), 91.4% and 98.3% for rifampicin (RIF), 60.4% and 100.0% for kanamycin (KAN) and 81.0% and 100.0% for ofloxacin (OFX), respectively. A combination of eight drug loci predicted XDR-TB phenotypes with 53.4% sensitivity (31/58 isolates) and 100.0% specificity. The most frequent mutations among these XDR-TB isolates were katG 315 and inhA -15 (for INH), 531, 526 and 516 in rpoB (for RIF), rrs 1401 and eis –10 (for KAN) and 94, 90 and 91 in gyrA (for OFX). Also, among these XDR-TB isolates, 44 (75.9%) were identified as Beijing genotype strain, of which 31 (70.5%) belonged to the modern Beijing sublineage. inhA -8, rpoB 526 and rpoB 531 mutations demonstrated significant statistical associations with ancient and modern Beijing family sublineage ( P < 0.05). However, Beijing and non-Beijing genotypes showed no association with specific resistance-conferring mutations. These results will be helpful in designing new molecular biology-based techniques to diagnose XDR-TB in China. [ABSTRACT FROM AUTHOR]

This study was undertaken to investigate the synergistic effects of methylprednisolone (MP) administration and transplantation of amniotic membrane mesenchymal stem cells (AM-MSCs) following T11 spinal cord clip compressive injury in rats. The combination treatment with MP (50 mg/kg) and delayed transplantation of AM-MSCs after rat spinal cord injury, significantly reduced (1) myeloperoxidase activity, (2) the proinflammatory cytokines: tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-17, interferon-γ and (3) the cell apoptosis [terminal deoxynucleotidyl transferase, dUTP nick end labeling (TUNEL) staining, and caspase-3, Bax and Bcl-2 expressions]; increased: (1) the levels of the anti-inflammatory cytokines (IL-10 and transforming growth factor-β1) and (2) the survival rate of AM-MSCs in the injury site. The combination therapy significantly ameliorated the recovery of limb function (evaluated by Basso, Beattie and Bresnahan score). Taken together, our results demonstrate that MP in combination with AM-MSCs transplantation is a potential strategy for reducing secondary damage and promoting functional recovery following spinal cord injury. [ABSTRACT FROM AUTHOR]

Background: N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. Methods: We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250–750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer’s Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. Results: Sodium benzoate produced a better improvement than placebo in Alzheimer’s Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. Conclusions: Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. [ABSTRACT FROM AUTHOR]

Objective: To investigate the outcome between the primary and secondary hypospadias with severe chordee in older patients by the transverse preputial island flap (TPIF). Materials and methods: We retrospectively analyzed 53 hypospadias patients who were performed with TPIF for urethroplasty, including 25 primary hypospadias (Group 1) and 28 secondary hypospadias (Group 2). The mean age in Group 1 was 12.12 ± 10.709 and 18.64 ± 8.727 in Group 2 ( P = 0.0181). The mean follow-up time was 38.7 months (22-60 months). Results: All of the foreskin flaps survived after the operation without necrosis. The overall complication rate was 24 % in Group 1 and 53.57 % in Group 2 ( P = 0.0280). All the patients were also divided into two cohorts according to their ages in surgery. In the 0-10-yr cohort, there was a significant difference in the overall complication rate between the primary and secondary groups ( P = 0.0173). But in the cases who were over 11 year old, there was no significant difference in the overall complications between two groups ( P = 0.1603). Also no significant difference was found in the mean length of the urethral defect between two groups ( P = 0.8312). Conclusion: The Duckett technique is an optional choice for some older Chinese patients undergoing primary operations, but it has a higher complication rate in those who have undergone previous failed urethroplasties. The unsatisfactory results found in the reoperative group were supposed to be linked to the older age, the lack of subcutaneous flap coverage and local scar tissue, but not to the length of the urethral defect. [ABSTRACT FROM AUTHOR]

This study compared the effects on glycaemic variability and glucose control between saxagliptin and acarbose as add-on therapies for aged T2DM inadequately controlled with metformin alone. The results showed that compared with acarbose–metformin, saxagliptin–metformin was more effective in glucose control with similar glycaemic variability. [ABSTRACT FROM AUTHOR]

During cancer development, tumor suppressor genes were silenced by promoter methylation or histone deacetylation. Histone deacetylases (HDACs) are important to maintain histone deacetylation. HDAC inhibitors (HDACis) were thus proposed as a new therapeutic approach to cancer. The current study aims to understand the effect and molecular mechanisms of HDACis on gastric cancer cells. Trichostatin A (TSA) significantly inhibited the growth of gastric cancer cells by inducing apoptosis. Gene profiling results showed PUMA (p53 upregulated modulator of apoptosis) as one of 122 genes upregulated in TSA-treated gastric cancer cells. PUMA was downregulated in gastric cancer cell lines and primary gastric carcinoma tissues. Patients with low PUMA expression had significant decreases in overall survival (HR, 2.04; p = 0.047). Ectopic PUMA expression inhibited the growth of gastric cancer cells while PUMA depletion promoted cellular growth. The knockdown of HDAC3 but not other HDACs upregulated PUMA expression. HDAC3 could bind to PUMA promoter, which was abrogated after TSA treatment. In contrast to TSA and SB, HDAC3 siRNA failed to upregulate p53 expression but promoted the interaction of p53 with PUMA promoter. In summary, proapoptotic PUMA was downregulated in gastric cancer and its mRNA expression level is a valuable prognosis factor for gastric cancer. HDAC3 is important to downregulate PUMA expression in gastric cancer and HDACis, like TSA, promoted PUMA expression through stabilizing p53 in addition to HDAC3 inhibition. In combination with chemotherapy, targeting HDAC3 might be a promising strategy to induce apoptosis of gastric cancer cells. [ABSTRACT FROM AUTHOR]

Survivin is overexpressed in major types of cancer and is considered an ideal 'universal' tumor-associated antigen that can be targeted by immunotherapeutic vaccines. However, its anti-apoptosis function raises certain safety concerns. Here, a new truncated human survivin, devoid of the anti-apoptosis function, was generated as a candidate tumor vaccine. Interleukin 2 (IL-2) has been widely used as an adjuvant for vaccination against various diseases. Meanwhile, the DNA prime and recombinant adenovirus (rAd) boost heterologous immunization strategy has been proven to be highly effective in enhancing immune responses. Therefore, the efficacy of a new cancer vaccine based on a truncated form of survivin, combined with IL-2, DNA prime, and rAd boost, was tested. As prophylaxis, immunization with the DNA vaccine alone resulted in a weak immune response and modest anti-tumor effect, whereas the tumor inhibition ratio with the DNA vaccine administered with IL-2 increased to 89 % and was further increased to nearly 100 % by rAd boosting. Moreover, complete tumor rejection was observed in 5 of 15 mice. Efficacy of the vaccine administered therapeutically was enhanced by nearly 300 % when combined with carboplatin. These results indicated that vaccination with a truncated survivin vaccine using DNA prime-rAd boost combined with IL-2 adjuvant and carboplatin represents an attractive strategy to overcoming immune tolerance to tumors and has potential therapeutic benefits in melanoma cancer. [ABSTRACT FROM AUTHOR]

Objective: To improve the hemocompatibility of chitosan/soy protein isolate composite membranes by heparinization. Methods: Chitosan/soy protein isolate membranes (ChS-n, n=0, 10 and 30, corresponding to the soy protein isolate content in the membranes) and heparinized ChS-n membranes (HChS-n) were prepared by blending in dilute HAc/NaAc solution. The hemocompatibility of ChS-n and HChS-n membranes were comparatively evaluated by measuring surface heparin density, blood platelet adhesion, plasma recalcification time (PRT), thrombus formation and hemolysis assay. Results: The surface heparin density analysis showed that heparinized chitosan/SPI soy protein isolate membranes have been successfully prepared by blending. The density of heparin on the surface of HChS-n membranes was in the range of 0.67-1.29 μg/cm2. The results of platelet adhesion measurement showed that the platelet adhesion numbers of HChS-n membranes were lower than those of the corresponding ChS-n membranes. The PRT of the HChS-0, HChS-10 and HChS-30 membranes were around 292, 306 and 295 s, respectively, which were longer than the corresponding ChS-0 (152 s), ChS-10 (204 s) and ChS-30 (273 s) membranes. The hemolysis rate of HChS-n membranes was lower than 1%. Conclusion: The hemocompatibility of ChS membranes could be improved by blending with heparin. Compared with ChS membranes, HChS membranes showed lower platelet adhesion, longer PRT, higher BCI, significant thromboresistivity and a lower hemolysis rate due to the heparinization. This widens the application of chitosan and soy protein-based biomaterials that may come in contact with blood. [ABSTRACT FROM AUTHOR]

Abstract: Wogonin, a naturally occurring monoflavonoid extracted from Scutellariae radix, has been shown to possess tumor therapeutic potential in vitro and in vivo. However, the effects of wogonin on tumor cells invasion remains poorly understood. In this study, we performed in vitro experiments to investigate the anti-invasive and anti-metastatic activity of wogonin in MDA-MB-231 human breast carcinoma cells. Wogonin caused a concentration-dependent suppression of cell migration, adhesion and invasion. The mechanism revealed that wogonin significantly inhibited the expression and activity of both endogenous and phorbol-12-myristate-13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) potentially associating with the suppression of translocation of protein kinase C (PKC) δ and phosphorylation of extracellular signal-regulated kinase (ERK1/2). These results suggested that wogonin could inhibit the invasion of tumor cells by downregulating the expression and activity of MMP-9, the possible targets may be PKCδ and ERK1/2. [Copyright &y& Elsevier]

Abstract: Three polysaccharides PS1-1, PS1-2 and PS2-1 were successfully isolated from marine fungus Penicillium sp. F23-2 and the chemical characteristics were determined. Antioxidant properties of the three polysaccharides were evaluated by assays of various antioxidant in vitro systems. The results showed that PS1-1, PS1-2 and PS2-1 were primarily consisted of mannose with variable amounts of glucose and galactose, whereas their glucuronic acid contents, molecular weights and glycosidic linkage pattern were different. The three polysaccharides possessed good antioxidant properties, especially scavenging abilities on superoxide radicals and hydroxyl radicals. Moreover, PS2-1 showed higher antioxidant properties than PS1-1 and PS1-2 and should be explored as a potential antioxidant. [Copyright &y& Elsevier]

Abstract: Our previous study revealed that oroxylin A, a naturally occurring monoflavonoid isolated from Scutellariae radix, could inhibit the proliferation of human hepatocellular carcinoma HepG2 cells through inducing the apoptosis in these cells. However, the molecular mechanism of its anticancer activity remains poorly understood and warrants further investigations. In this study, we examined the anti-invasive activities of oroxylin A in vitro. The results showed that oroxylin A suppressed MDA-MB-435 cell adhesion to the fibronectin-coated substrate in a concentration-dependent manner. It inhibited the wound healing migration of MDA-MB-435 cells and invasion of MDA-MB-435 cells through reconstituted extracellular matrix (matrigel). Zymography revealed that oroxylin A decreased the secretion of matrix metalloproteinases-2 (MMP-2) and metalloproteinases-9 (MMP-9). Oroxylin A also inhibited the expressions of MMP-2 and MMP-9 in MDA-MB-435 cells. Additionally, oroxylin A exerted an inhibitory effect on the phosphorylation of extracellular regulated proteinkinases1/2 (ERK1/2). Collectively, these data provided a molecular basis for the antiinvasive effects of oroxylin A. Taken together, these findings strongly suggest that oroxylin A had potential anti-metastatic effect in vitro and shed light on the investigation of oroxylin A on breast cancer metastasis in vivo. [Copyright &y& Elsevier]

Active-fixation pacing leads allow the use of selective pacing sites. We evaluated their long-term performance versus passive-fixation leads in 199 newly implanted patients (n = 100 active and n = 99 passive). Postoperative pacing thresholds in the active group were higher than in the passive group (0.85 ± 0.31 V vs. 0.53 ± 0.21 V at baseline, P < 0.001). The active thresholds fell to 0.72 ± 0.23 V at 5 years with a significant drop at one month (0.68 ± 0.53 V, P = 0.003). The passive thresholds slightly increased to 0.72 ± 0.31 V at five years. Differences between groups were significant until three years (all P < 0.05). Active impedances were generally lower than passive impedances (600.44 ± 94.31Ω vs. 683.14 ± 110.98Ω at baseline), and both showed significant reductions at one month to 537.96 ± 147.43Ω in the active group, and after three months to 643.85 ± 82.40Ω in the passive group (both P < 0.01 vs. baseline). Impedance differences between groups were significant until four years (all P < 0.05). Adverse events included thresholds over 1 V, 5 of 6 active and 2 of 5 passive leads returned to below 1 V. One active left ventricular lead dislodged. One passive left subclavian lead insulation fracture occurred. Thus Active fixation pacing leads are stable in a five-year long-term follow up. There was no difference between active and passive leads in terms of electrical performance. [ABSTRACT FROM AUTHOR]