Topotecan reduces sepsis-induced acute lung injury and decreases the inflammatory response via the inhibition of the NF-κB signaling pathway.

This study aims to determine the function of topotecan (TPT) in acute lung injury (ALI) induced by sepsis. The mouse sepsis model was constructed through cecal ligation and puncture (CLP). The ALI score and lung wet/dry (W/D) weight ratio were applied to evaluate the level of lung injury. Hematoxylin-eosin staining was used to examine the role of TPT in lung tissue in a CLP-induced ALI mouse model. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction were used to detect the concentrations of inflammatory factors, such as interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α. Western blot was used to detect relevant protein levels in the nuclear factor-κB (NF-κB) pathway. Moreover, 10-day survival was recorded by constructing the CLP model. The results indicated that TPT could improve lung tissue damage in mice and could significantly reduce lung injury scores (p < 0.01) and the W/D ratio (p < 0.05). Treatment with ammonium pyrrolidinedithiocarbamate obtained the similar results with the TPT treatment. Both significantly reduced the inflammatory response in the lungs, including reducing the number of neutrophils and total cells in the bronchoalveolar lavage fluid (BALF), significantly reducing the total protein concentration of the BALF, and significantly inhibiting the activity of MPO. Both also inhibited inflammatory cytokine expression and the levels of NF-κB pathway proteins induced by sepsis. Furthermore, TPT significantly improved survival in sepsis. TPT improves ALI in the CLP model by inhibiting the NF-κB pathway, preventing fatal inflammation.

Autophagy-related signaling pathways in non-small cell lung cancer.

Lung cancer is one of the most prevalent causes of morbidity and mortality in both men and women across the globe. The disease has a quiet phenotype at first, which leads to chronic tumor development. Non-small cell lung cancer (NSCLC) is the most common kind of lung cancer, accounting for 85 percent of all lung malignancies. Autophagy has been described as an intracellular "recycle bin" where damaged proteins and molecules are degraded. Autophagy regulation is mainly dependent on signaling pathways such as phosphoinositide 3-kinases (PI3K), AKT, and the mammalian target of rapamycin (mTOR). In the context of NSCLC, studies on these signaling pathways are inconsistent, but our literature review suggests that the inhibition of mTOR, PI3K/AKT, and epidermal growth factor receptor signaling pathways by different medications can active autophagy and inhibit NSCLC progression. In conclusion, signaling pathways related to autophagy are effective therapeutic approaches for the treatment of NSCLC.

Dual targeting of MEK and PI3K effectively controls the proliferation of human EGFR-TKI resistant non-small cell lung carcinoma cell lines with different genetic backgrounds.

BACKGROUND: Molecular targeted therapy for non-small cell lung carcinoma (NSCLC) is restricted due to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This study evaluated the effects of dual targeting of MEK and PI3K in human EGFR-TKI resistant NSCLC cell lines. METHODS: EGFR-TKI resistant NSCLC cell lines H1975, H460, and A549, with different mutation and amplification status in EGFR, K-RAS, PIK3CA, and MET genes, were treated with a MEK162 (MEK inhibitor) and BKM120 (PI3K inhibitor) combination or a BIBW2992 (EGFR inhibitor) and ARQ197 (MET inhibitor) combination and assayed for cell proliferation, apoptosis, and cell cycle distribution. RESULTS: Dual targeting of MEK and PI3K efficiently inhibited the cell proliferation, induced apoptosis and the G0/G1 cell cycle, and decreased the phosphorylation of ERK1/2, AKT, S6, and 4E-BP1. H460 cells with K-RAS and PIK3CA mutation were most sensitive to MEK162 and BKM120 combinations. H1975 cells with EGFR and PIK3CA mutation and MET amplification were sensitive to BIBW2992 and ARQ197 combinations. CONCLUSION: Dual targeting regulated the proliferation of EGFR-TKI-resistant NSCLC cells, especially mutants in K-RAS and PIK3CA that are promising for EGFR-TKI-resistant NSCLC therapeutics.

Accelerating ESD-induced gastric ulcer healing using a pH-responsive polyurethane/small intestinal submucosa hydrogel delivered by endoscopic catheter.

Endoscopic submucosal dissection (ESD) is the standard treatment for early-stage gastric cancer, but the large post-operative ulcers caused by ESD often lead to serious side effects. Post-ESD mucosal repair materials provide a new option for the treatment of post-ESD ulcers. In this study, we developed a polyurethane/small intestinal submucosa (PU/SIS) hydrogel and investigated its efficacy for accelerating ESD-induced ulcer healing in a canine model. PU/SIS hydrogel possessed great biocompatibility and distinctive pH-sensitive swelling properties and protected GES-1 cells from acid attack through forming a dense film in acidic conditions in vitro. Besides, PU/SIS gels present a strong bio-adhesion to gastric tissues under acidic conditions, thus ensuring the retention time of PU/SIS gels in vivo. In a canine model, PU/SIS hydrogel was easily delivered via endoscopy and adhered to the ulcer sites. PU/SIS hydrogel accelerated gastric ulcer healing at an early stage with more epithelium regeneration and slight inflammation. Our findings reveal PU/SIS hydrogel is a promising and attractive candidate for ESD-induced ulcer repair.

[Relationship of ADC histogram parameters with pathological grade and lymph node metastasis of prostate cancer].

OBJECTIVE: To investigate the relationship between the apparent diffusion coefficient (ADC) histogram parameters based on the whole tumor and the pathological grade and lymph node metastasis (LNM) of PCa. METHODS: This retrospective study included 82 cases of PCa confirmed pathologically and subjected to MRI preoperatively. We obtained a series of ADC histogram parameters, such as ADCmean, ADCmedian, ADC25%, ADC75%, entropy, and histogram width, by processing the ADC images via the Firevoxel Post-Processing and the SPSS24 software. We compared the parameters between the high-risk and low- or moderate-risk groups as well as between the LNM-positive and LNM-negative groups of the patients, and analyzed the diagnostic performance of the parameters with statistically significant differences. RESULTS: The high-risk group, compared with the low- or moderate-risk one, showed a significantly lower ADCmean (ï¼»590 ± 120ï¼½ vs ï¼»837 ± 142ï¼½ ×10－6 mm2/s, P < 0.01), ADCmedian (ï¼»560 ± 117ï¼½ vs ï¼»804 ± 139ï¼½ ×10－6 mm2/s, P < 0.01), ADC25% (ï¼»446.5 ± 98ï¼½ vs ï¼»717 ± 118ï¼½ ×10－6 mm2/, P < 0.01) and ADC75% (ï¼»667 ± 132ï¼½ vs ï¼»931 ± 167ï¼½ ×10－6 mm2/s, P < 0.01). The ADCmean manifested the highest diagnostic performance, with an AUC of 0.907, a sensitivity of 0.933 and a specificity of 0.796. No statistically significant difference was found between the high-risk and the low- or moderate-risk one in entropy (3.58 ± 0.39 vs 3.63 ± 0.42, P = 0.238) or the histogram width (ï¼»540 ± 73ï¼½ vs ï¼»520 ± 65ï¼½ ×10－6 mm2/s, P = 0.086). Both entropy and the histogram width were remarkably higher in the LNM-positive than in the LNM-negative group (3.95 ± 0.41 vs 3.12 ± 0.45, P < 0.01; ï¼»578 ± 59ï¼½ vs ï¼»455 ± 68ï¼½ ×10－6 mm2/s, P < 0.01), and the former had an even higher diagnostic performance, with an AUC of 0.836, a sensitivity of 0.887 and a specificity of 0.781. There were no statistically significant differences between the LNM-positive and LNM-negative groups in the ADCmean (ï¼»768 ± 135ï¼½ vs ï¼»790±128ï¼½ ×10－6 mm2/s, P = 0.402), ADCmedian (ï¼»759 ± 110ï¼½ vs ï¼»775 ± 121ï¼½ ×10－6 mm2/s, P = 0.225), ADC25% (ï¼»643 ± 91ï¼½ vs ï¼»657 ± 89ï¼½ ×10－6 mm2/s, P = 0.654) or ADC75% (ï¼»895 ± 127ï¼½ vs ï¼»872 ± 129ï¼½ ×10－6 mm2/s, P = 0.926). CONCLUSIONS: ADC histogram parameters are related to pathological grade and LNM of PCa, and the analysis of the ADC histogram based on the whole tumor has an important value for preoperative evaluation and prognostic estimation of the malignancy.

Alcelaphine herpesvirus 1 genes A7 and A8 regulate viral spread and are essential for malignant catarrhal fever.

Alcelaphine herpesvirus 1 (AlHV-1) is a gammaherpesvirus that is carried asymptomatically by wildebeest. Upon cross-species transmission to other ruminants, including domestic cattle, AlHV-1 induces malignant catarrhal fever (MCF), which is a fatal lymphoproliferative disease resulting from proliferation and uncontrolled activation of latently infected CD8+ T cells. Two laboratory strains of AlHV-1 are used commonly in research: C500, which is pathogenic, and WC11, which has been attenuated by long-term maintenance in cell culture. The published genome sequence of a WC11 seed stock from a German laboratory revealed the deletion of two major regions. The sequence of a WC11 seed stock used in our laboratory also bears these deletions and, in addition, the duplication of an internal sequence in the terminal region. The larger of the two deletions has resulted in the absence of gene A7 and a large portion of gene A8. These genes are positional orthologs of the Epstein-Barr virus genes encoding envelope glycoproteins gp42 and gp350, respectively, which are involved in viral propagation and switching of cell tropism. To investigate the degree to which the absence of A7 and A8 participates in WC11 attenuation, recombinant viruses lacking these individual functions were generated in C500. Using bovine nasal turbinate and embryonic lung cell lines, increased cell-free viral propagation and impaired syncytia formation were observed in the absence of A7, whereas cell-free viral spread was inhibited in the absence of A8. Therefore, A7 appears to be involved in cell-to-cell viral spread, and A8 in viral cell-free propagation. Finally, infection of rabbits with either mutant did not induce the signs of MCF or the expansion of infected CD8+ T cells. These results demonstrate that A7 and A8 are both essential for regulating viral spread and suggest that AlHV-1 requires both genes to efficiently spread in vivo and reach CD8+ T lymphocytes and induce MCF.

Sex-differential effects of olanzapine vs. aripiprazole on glucose and lipid metabolism in first-episode schizophrenia

Abstract Objective To compare sex difference in metabolic effect of olanzapine versus aripiprazole on schizophrenia. Methods A twelve-week prospective open-label cohort study to compare four subgroups according to first-episode schizophrenia patients' type of drug usage and sex: female aripiprazole (n = 11), male aripiprazole (n = 11), female olanzapine (n = 10), and male olanzapine (n = 11) for body mass index, fasting serum triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and fasting glucose. Results Aripiprazole may be associated with weight gain in female patients with low-baseline weight. Aripiprazole may have an adverse effect of weight and favorable effects of circulating glucose and lipid on female over male schizophrenia patients. The aripiprazole-induced changes in glucose and lipid may be independent of body fat storage, especially for female schizophrenia patients. Olanzapine may have adverse effects of weight, glucose and lipid profiles on female over male schizophrenic patients. Discussion Our findings fill the gap in knowledge and provide a sex-specific guidance to psychiatrist better tailoring treatment to individual sex-differential characteristics and a key clue to understand the sex-differential mechanism of antipsychotics-induced metabolic dysfunction.

Nanostructured titanium surfaces fabricated by hydrothermal method: Influence of alkali conditions on the osteogenic performance of implants.

Hydrothermal method is an easy-to-use approach for creating nanostructured surfaces on titanium (Ti). However, whether the alkali conditions of this method influence the osteogenic potential of the modified surfaces remains unknown. In this study, we fabricated nanostructured surfaces, termed the Ti-1, Ti-5, and Ti-10 groups, by using the hydrothermal method in 1 M, 5 M, and 10 M NaOH aqueous solutions, respectively. An untreated Ti surface served as a control. The osteogenic performance of modified surfaces was systemically investigated, including the proliferation and osteogenic differentiation of human osteoblast-like MG63 cells in vitro and the osteointegration of implants in a rabbit femoral condyle defect model. After hydrothermal treatment, the hydrophilicity of modified surfaces was greatly enhanced. The Ti-1 group showed a nanowire-like topography, while the Ti-5 and Ti-10 groups exhibited a nanopetal-like topography with different pore sizes. Compared with the untreated Ti surface, the modified surfaces showed good cytocompatibility and enhanced the osteogenic differentiation of MG-63 cells. Compared with the other modified surfaces, the Ti-5 group was the most favourable for the osteogenic differentiation of cells, showing higher levels of alkaline phosphatase activity, osteogenic gene expression, mineralization and osteoprotegerin secretion. Twelve weeks after implantation at the bone defects, the Ti-5 group showed superior peri-implant bone regeneration and higher peak push-out force than the other groups. Overall, this study revealed the crucial role of alkali conditions of hydrothermal method in modulating the material characteristics of modified surfaces and their osteogenic performance in vitro and in vivo, highlighting the need for optimizing the processing conditions of hydrothermal method for enhanced osteointegration.

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection.

The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-ß, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.

Synergistic activity of the histone deacetylase inhibitor trichostatin A and the proteasome inhibitor PS-341 against taxane-resistant ovarian cancer cell lines.

Although a combination of platinum- and taxane-based chemotherapy is recommended for at least 70% patients with ovarian cancer as treatment subsequent to surgery, the initial response to the chemotherapy is not durable and tumors become resistant. Histone deacetylase and proteasome inhibitors are novel therapeutic agents. However, the moderate antitumoral effect of the inhibitors has restricted their clinical use when used as single agents. The aim of the present study was to investigate the synergistic activity of trichostatin A (TSA) and PS-341 in ovarian cancer cells, along with the investigation of the molecular mechanisms of taxane resistance. The taxane-sensitive ovarian cancer A2780 cell line and its resistant variant, A2780T, were treated with taxane, TSA and PS-341 at various concentrations. An Annexin V assay was performed to determine the levels of cell viability and apoptosis, while flow cytometry and immunofluorescence staining for the mitotic phase-specific protein phosphorylated-histone H3 (Ser10) were used for cell cycle detection. The effects of combined TSA and PS-341 on cell cycle-associated proteins were tested by western blot analysis. Furthermore, the present study examined the apoptosis and cell cycle arrest induced by the 3 agents subsequent to overexpression or downregulation of cyclin B1 in A2780 and A2780T cells, respectively. It was found that TSA interacted synergistically with PS-341, resulting in a marked increase in apoptosis and the rate of G2/M arrest in A2780T cells. A lower basal level of cyclin B1 expression and the incompetence of the upregulation of the cyclin may explain the taxane resistance found in A2780T cells. Collectively, the combination of TSA and PS-341 increased cyclin B1 expression level regardless of the basal expression level, resulting in the proliferation inhibition and apoptosis in A2780 and A2780T cells, which raised the possibility that a combination of the two drugs may represent a novel strategy for the treatment of ovarian cancer, particularly in taxane-resistant ovarian cancer.

New tris(dopamine) derivative as an iron chelator. Synthesis, solution thermodynamic stability, and antioxidant research.

A new tris(dopamine) derivative, containing three dopamine chelate moieties which were attached to a trimesic acid molecular scaffold, has been prepared and fully characterized by NMR, FTIR and HRMS. The solution thermodynamic stability of the chelator with Fe(III), Mg(II), Zn(II) and Fe(II) ions was investigated. Results demonstrated that the chelator exhibited effective binding ability and improved selectivity to Fe(III) ion. The chelator possessed affinity similar to that of diethylenetriaminepentaacetic acid chelator for Fe(III) ion. The high affinity could be attributed to the favorable geometric arrangement between the chelator and Fe(III) ion coordination preference. The chelator also exhibited high antioxidant activity and nontoxicity to neuron-like rat pheochromocytoma cells. Hence, the chelator could be used as chelating agent for iron overload situations without depleting essential metal ions, such as Mg(II) and Zn(II) ions.

Accelerating effects of genipin-crosslinked small intestinal submucosa for defected gastric mucosa repair.

Slow healing of gastric mucosa defects caused by endoscopic surgery is a common but severe clinical problem for lack of an effective treatment. Small intestinal submucosa (SIS) is a bio-derived extracellular matrix scaffold with remarkable repairing ability for soft tissue, but its rapid degradation and poor mechanical properties in the stomach environment limit its application for gastric mucosa regeneration. Herein, we modified SIS by genipin, a natural crosslinking agent, to improve its resistance against degradation in gastric juice and to promote the healing of gastric mucosa defects. The crosslinking characteristics of genipin-crosslinked SIS (GP-CR SIS) were evaluated by crosslinking degree, swelling ratio and FITR, respectively. GP-CR SIS was highly resistant to gastric juice digestion and had a great improvement in mechanical properties. Additionally, GP-CR SIS maintained excellent biocompatibility according to a cytotoxicity test, hemolysis test, and rat subcutaneous implant assay. In an in vivo study, we treated defected gastric mucosa with GP-CR SIS in a rabbit endoscopic submucosal dissection (ESD)-related ulcer model. After two weeks of surgical treatment, GP-CR SIS significantly expedited wound closure and ameliorated newly constructed tissue by providing a protective microenvironment for rapid granulation tissue formation and accelerating angiogenesis/re-epithelialization. In conclusion, this study demonstrates the huge therapeutic potential of GP-CR SIS scaffolds for accelerating defected gastric mucosa regeneration.

[Protective effects of Genistein on human renal tubular epithelial cells damage of microwave radiation].

OBJECTIVE: To observe the effects of microwave irradiation on human proximal renal tubular epithelial cells (HKC) and protec-tive effects of genistein. METHODS: HKC cells were divided into control group, microwave irradiation group and genistein group(n=6) re-spectively. The genistein group cells were pre-incubated with 30µmol/L genistein in DMEM for 2 hours. After irradiation for 24 hours, the concentrations of lactate dehydrogenase(LDH) and ß-N-acetyl glucosaminidase(NAG) in culture solution were measured to evaluate cell injury. Cells were curetted to measure the levels of malondialdehyde (MDA) and superoxide dismutase (SOD). Cell apoptosis and necrosis were de-tected with Hoechst 33258 stain. RESULTS: Compared with the control group, the NAG activity of the microwave irradiation group was signifi-cantly increased(P < 0.01), and NAG activity of genistein pre-incubated group was significantly decreased(P < 0.01). The levels of LDH in microwave irradiation group were also increased significantly (P < 0.01 vs control group). LDH levels could be decreased obviously (P < 0.01 vs microwave irradiation group) after genistein pre-incubate. Hoechst 33258 fluorescent staining revealed that the nucleus crimpled, cres-cent liked and chromatin condensed, even nucleus disintegrated. Our research showed that microwave irradiation could lead to large amount of cell apoptosis and necrosis, and genistein pre-treatment could reduce the ratio of apoptosis and necrosis than that in microwave irradiation group (P < 0.01). The concentration of MDA in microwave irradiation group was higher than that in control group (P < 0.01). At the same time, the activity of SOD was significantly reduced (P < 0.01). Pre-incubated with genistein could not decrease the MDA levels, but could increase the activities of SOD (P < 0.01 vs microwave irradiation group). CONCLUSIONS: microwave irradiation can induce human proximal renal tubular epithelial cells injury. The protective effects of genistein may partly correlated with decreasing oxidative stress damage and cell apoptosis in HKC cells.

Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells.

Despite the impressive rates of clinical response to programmed death 1 (PD-1) blockade in multiple cancers, the majority of patients still fail to respond to this therapy. The CT26 tumor in mice showed similar heterogeneity, with most tumors unaffected by anti-PD-1. As in humans, response of CT26 to anti-PD-1 correlated with increased T- and B-cell infiltration and IFN expression. We show that intratumoral injection of a highly interferogenic TLR9 agonist, SD-101, in anti-PD-1 nonresponders led to a complete, durable rejection of essentially all injected tumors and a majority of uninjected, distant-site tumors. Therapeutic efficacy of the combination was also observed with the TSA mammary adenocarcinoma and MCA38 colon carcinoma tumor models that show little response to PD-1 blockade alone. Intratumoral SD-101 substantially increased leukocyte infiltration and IFN-regulated gene expression, and its activity was dependent on CD8+ T cells and type I IFN signaling. Anti-PD-1 plus intratumoral SD-101 promoted infiltration of activated, proliferating CD8+ T cells and led to a synergistic increase in total and tumor antigen-specific CD8+ T cells expressing both IFN-γ and TNF-α. Additionally, PD-1 blockade could alter the CpG-mediated differentiation of tumor-specific CD8+ T cells into CD127lowKLRG1high short-lived effector cells, preferentially expanding the CD127highKLRG1low long-lived memory precursors. Tumor control and intratumoral T-cell proliferation in response to the combined treatment is independent of T-cell trafficking from secondary lymphoid organs. These findings suggest that a CpG oligonucleotide given intratumorally may increase the response of cancer patients to PD-1 blockade, increasing the quantity and the quality of tumor-specific CD8+ T cells.

Increased Hepatic Fatty Acids Uptake and Oxidation by LRPPRC-Driven Oxidative Phosphorylation Reduces Blood Lipid Levels.

Hyperlipidemia is one of the major risk factors of atherosclerosis and other cardiovascular diseases. This study aimed to investigate the impact of leucine rich pentatricopeptide repeat containing protein (LRPPRC)-driven hepatic oxidative phoshorylation on blood lipid levels. The hepatic LRPPRC level was modulated by liver-specific transgenic or adeno-associated virus 8 carried shRNA targeting Lrpprc (aav-shLrpprc). Mice were fed with a high fat diet to induce obesity. Gene expression was analyzed by quantitative real-time PCR and / or western blot. The hepatic ATP level, hepatic and serum lipids contents, and mitochondria oxidative phosphorylation (OxPhos) complex activities were measured using specific assay kits. The uptake and oxidation of fatty acid by hepatocytes were assessed using (14)C-palmitate. LRPPRC regulated the expression of genes encoded by mitochondrial genome but not those by nuclear genome involved in mitochondria biogenesis, OxPhos, and lipid metabolism. Increased OxPhos in liver mediated by LRPPRC resulted in the increase of hepatic ATP level. Lrpprc promoted palmitate uptake and oxidation by hypatocytes. The hepatic and serum triglyceride and total cholesterol levels were inversely associated with the hepatic LRPPRC level. These data demonstrated that LRPPRC-driven hepatic OxPhos could promote fatty acids uptake and oxidation by hepatocytes and reduce both hepatic and circulating triglyceride and cholesterol levels.

N-acetylcysteine negatively regulates Notch3 and its malignant signaling.

Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.

Efficacy and safety of solifenacin succinate tablets versus solifenacin succinate tablets with local estrogen for the treatment of overactive bladder in postmenopausal women--a multicenter, randomized, open-label, controlled comparison study.

OBJECTIVE: The aim of the study was to compare the effectiveness and safety of solifenacin succinate tablets alone or combined with local estrogen for overactive bladder treatment in postmenopausal women. METHODS: This multicenter, randomized, open, parallel-controlled clinical trial enrolled 104 women between January 2012 and August 2013. Participants meeting the inclusion criteria were randomized 1:1 to 12 weeks of treatment with group A (solifenacin 5 mg qd + promestriene vaginal capsules intravaginally) or group B (solifenacin 5 mg qd). Before and after 12 weeks of treatment, symptoms (urinary urgency, frequency, and urge incontinence) were analyzed. Our primary outcome was the change from baseline to the end of treatment in the mean number of voids in 24 hours. Quality of life (QoL) was assessed using International Prostate Symptom Score and Overactive Bladder Symptom Score questionnaires and safety according to the incidence of adverse events. The t test or the Mann-Whitney U test was used to compare continuous variables, and the χ(2) test or Fisher's exact test was used to compare categorical variables. RESULTS: The median decreases in the mean number of voids in 24 hours in groups A and B were 5.2. and 4.3, respectively, which were not significantly different. The median decreases in urgency episodes in groups A and B were 2.0 and 2.5, respectively. In addition, the QoL scores significantly changed in both groups (both P < 0.05). The most common adverse event was dry mouth (19.2% in both groups). CONCLUSIONS: Solifenacin with or without local estrogen was effective and safe for overactive bladder treatment in postmenopausal women. The addition of local estrogen improved subjective feelings and QoL.

Protective effect of heme oxygenase-1 on Wistar rats with heart failure through the inhibition of inflammation and amelioration of intestinal microcirculation.

BACKGROUND: Myocardial infarction (MI) has likely contributed to the increased prevalence of heart failure (HF). As a result of reduced cardiac function, splanchnic blood flow decreases, causing ischemia in villi and damage to the intestinal barrier. The induction of heme oxygenase-1 (HO-1) could prevent, or lessen the effects of stress and inflammation. Thus, the effect and mechanism thereof of HO-1 on the intestines of rats with HF was investigated. METHODS: Male Wistar rats with heart failure through ligation of the left coronary artery were identified with an left ventricular ejection fraction of < 45% through echocardiography and then divided into various experimental groups based on the type of peritoneal injection they received [MI: saline; MI + Cobalt protoporphyrin (CoPP): CoPP solution; and MI + Tin mesoporphyrin IX dichloride (SnMP): SnMP solution]. The control group was comprised of rats without coronary ligation. Echocardiography was performed before ligation for a baseline and eight weeks after ligation in order to evaluate the cardiac function of the rats. The bacterial translocation (BT) incidence, mesenteric microcirculation, amount of endotoxins in the vein serum, ileum levels of HO-1, carbon oxide (CO), nitric oxide (NO), interleukin (IL)-10, tumour necrosis factor-α (TNF-α), and the ileum morphology were determined eight weeks after the operation. RESULTS: The rats receiving MI + CoPP injections exhibited a recovery in cardiac function, an amelioration of mesenteric microcirculation and change in morphology, a lower BT incidence, a reduction in serum and ileac NO and TNF-α levels, and an elevation in ileac HO-1, CO, and interleukin-10 (IL-10) levels compared to the MI group (P < 0.05). The rats that received the MI + SnMP injections exhibited results inverse to the MI (P < 0.05) group. CONCLUSIONS: HO-1 exerted a protective effect on the intestines of rats with HF by inhibiting the inflammation and amelioration of microcirculation through the CO pathway. This protective effect could be independent from the recovery of cardiac function.

Antitumor Effects and Related Mechanisms of Penicitrinine A, a Novel Alkaloid with a Unique Spiro Skeleton from the Marine Fungus Penicillium citrinum.

Penicitrinine A, a novel alkaloid with a unique spiro skeleton, was isolated from a marine-derived fungus Penicillium citrinum. In this study, the isolation, structure and biosynthetic pathway elucidation of the new compound were described. This new compound showed anti-proliferative activity on multiple tumor types. Among them, the human malignant melanoma cell A-375 was confirmed to be the most sensitive. Morphologic evaluation, apoptosis rate analysis, Western blot and real-time quantitative PCR (RT-qPCR) results showed penicitrinine A could significantly induce A-375 cell apoptosis by decreasing the expression of Bcl-2 and increasing the expression of Bax. Moreover, we investigated the anti-metastatic effects of penicitrinine A in A-375 cells by wound healing assay, trans-well assay, Western blot and RT-qPCR. The results showed penicitrinine A significantly suppressed metastatic activity of A-375 cells by regulating the expression of MMP-9 and its specific inhibitor TIMP-1. These findings suggested that penicitrinine A might serve as a potential antitumor agent, which could inhibit the proliferation and metastasis of tumor cells.

[Gynecologic cancers in a hospital: a retrospective analysis of admission data over ten years].

OBJECTIVE: To investigate admission patterns of patients with gynecologic cancers over a ten year period, which will provide a basis for further epidemiological studies. METHODS: We reviewed medical records of patients with gynecologic cancers who were admitt d to the West China Second University Hospital of Sichuan University from 2003 to 2012. Their clinicopathological data were extracted and analysed. RESULTS: The number of admitted patients increased over the years, with cervical, uterine and ovary cancers as the top three gynaecological cancers. They accounted for 92.13% of total gynaecological cancers. The peak age of gynaecological cancers was 40-49 years, which accounted for 34.02% (3132/9207) of all patients, followed by 50-59 years (26.64%, 2453/9207). Most (72.46%, 3062/4226) cervical cancer patients aged 30-49 years, compared with 40-59 years for uterine cancers (69.77%, 1768/2534) and 40-59 years for ovarian cancers (58.30%, 1004/1722). Patients in their 20th account for 4.43% (408/9 207) of total cancers, with in which cervical and ovarian cancers as the most common pathological type. Patients under 20 years of age accounted for only 0.98% (90/9207) of total cancers, with ovarian cancers as the most common pathological type. Patients over 60 years accounted for 12.90% (1188/9207) of total cancers, with uterine and ovarian cancers as the most common pathological type. Most patients were at an early stage of cancers when they were admitted to the hospital. CONCLUSION: Hospitalized patients with gynecologic cancers increase over years. Cervical, uterine and ovary cancers remain to be a focus of treatment. Peak age of those cancers varies.