Cytosporin Derivatives from Arctic-Derived Fungus Eutypella sp. D-1 via the OSMAC Approach.

A chemical investigation of the Arctic-derived fungus Eutypella sp. D-1 based on the OSMAC (one strain many compounds) approach resulted in the isolation of five cytosporin polyketides (compounds 1-3 and 11-12) from rice medium and eight cytosporins (compounds 2 and 4-11) from solid defined medium. The structures of the seven new compounds, eutypelleudesmane A (1), cytosporin Y (2), cytosporin Z (3), cytosporin Y1 (4), cytosporin Y2 (5), cytosporin Y3 (6), and cytosporin E1 (7), were elucidated by analyzing their detailed spectroscopic data. Structurally, cytosporin Y1 (4) may be a key intermediate in the biosynthesis of the isolated cytosporins, rather than an end product. Compound 1 contained a unique skeleton formed by the ester linkage of two moieties, cytosporin F (12) and the eudesmane-type sesquiterpene dihydroalanto glycol. Additionally, the occurrence of cyclic carbonate moieties in compounds 6 and 7 was found to be rare in nature. The antibacterial, immunosuppressive, and cytotoxic activities of all compounds derived from Eutypella sp. D-1 were evaluated. Unfortunately, only compounds 3, 6, 8, and 10-11 displayed immunosuppressive activity, with inhibitory rates of 62.9%, 59.5%, 67.8%, 55.8%, and 68.7%, respectively, at a concentration of 5 µg/mL.

Bioactive Scalarane-Type Sesterterpenoids from Marine Sources.

Scalarane-type sesterterpenoids have received considerable attention in the scientific literature due to their diverse carbon skeletons and various biological activities and pharmacological properties. Among all these derivatives are commonly isolated from marine sponges and are occasionally derived from shell-less mollusks, such as nudibranchs. This review comprehensively discusses the marine-derived natural sources that give rise to these scalarane-type sesterterpenoids, providing the names, their chemical structures, biological properties, with emphasis on anticancer activity and literature references related to these metabolites. A critical summary of the 221 compounds generated from January 2010 up to December 2021 for their potential as anticancer agents is presented.

Bioactive metabolites from the Arctic fungus Nectria sp. B-13.

Two new cyclohexanone derivatives, nectriatones A-B (1-2), and one new natural product, nectriatone C (3), together with three known phenolic sesquiterpene derivatives (4-6), were isolated from the culture of Nectria sp. B-13 obtained from high-latitude soil of the Arctic. The structures of all compounds were unambiguously elucidated by extensive spectroscopic analysis, as well as by comparison with the literature. These compounds were evaluated in cytotoxic and antibacterial activities. Compounds 1-6 showed cytotoxicities against SW1990, HCT-116, MCF-7, and K562 cells, with IC50 values in the range of 0.43 to 42.64 µM. Only compound 4 exhibited antibacterial activity against Escherichisa coli, Bacillus subtilis, and Staphylococcus aureus (MIC 4.0, 2.0, and 4.0 µg/ml, respectively).

Nach Is a Novel Subgroup at an Early Evolutionary Stage of the CNC-bZIP Subfamily Transcription Factors from the Marine Bacteria to Humans.

Normal growth and development, as well as adaptive responses to various intracellular and environmental stresses, are tightly controlled by transcriptional networks. The evolutionarily conserved genomic sequences across species highlights the architecture of such certain regulatory elements. Among them, one of the most conserved transcription factors is the basic-region leucine zipper (bZIP) family. Herein, we have performed phylogenetic analysis of these bZIP proteins and found, to our surprise, that there exist a few homologous proteins of the family members Jun, Fos, ATF2, BATF, C/EBP and CNC (cap'n'collar) in either viruses or bacteria, albeit expansion and diversification of this bZIP superfamily have occurred in vertebrates from metazoan. Interestingly, a specific group of bZIP proteins is identified, designated Nach (Nrf and CNC homology), because of their strong conservation with all the known CNC and NF-E2 p45 subunit-related factors Nrf1 and Nrf2. Further experimental evidence has also been provided, revealing that Nach1 and Nach2 from the marine bacteria exert distinctive functions, when compared with human Nrf1 and Nrf2, in the transcriptional regulation of antioxidant response element (ARE)-battery genes. Collectively, further insights into these Nach/CNC-bZIP subfamily transcription factors provide a novel better understanding of distinct biological functions of these factors expressed in distinct species from the marine bacteria to humans.

Prospective phase II trial of nimotuzumab in combination with radiotherapy and concurrent capecitabine in locally advanced rectal cancer.

PURPOSE: The aim of the study was to evaluate the safety and efficacy of adding concurrent nimotuzumab to preoperative radiotherapy with concurrent capecitabine in locally advanced rectal cancer. METHODS AND MATERIALS: Patients with rectal cancer (clinical stage T3/4 or N+) were scheduled to receive weekly nimotuzumab (400 mg; days -6, 1, 8, 15, 22, and 29). Capecitabine (825 mg/m(2)) was delivered orally twice daily for the duration of radiotherapy. Radiotherapy was administered at 50.4 Gy (45 + 5.4 Gy). The main endpoint was the pathologic complete response (pCR) rate. RESULTS: Twenty-one patients with T3 or T4 disease were enrolled; 66.7 % were nodal-positive; the median distance from the anal verge was 5.5 cm. A pCR was achieved in four patients (19.0 %); 71.4 % patients obtained moderate or good tumor regression (Grade 2 and 3). Downstaging occurred in 15/21 (71.4 %) patients by T stage and 11/14 (78.6 %) by N stage. The actual dose intensities (median/mean, %) were nimotuzumab (100, 100) and capecitabine (100, 99.5). The most frequent Grade 1/2 toxicities were radiation dermatitis (57.1 %), nausea/vomiting (52.4 %), leukocytopenia (47.6 %), diarrhea (47.6 %), and proctitis (38.1 %). Grade 3 diarrhea was observed in 9.5 % of patients and Grade 3 leukocytopenia in 4.8 %. CONCLUSION: These preliminary results indicate that nimotuzumab can be safely combined with radiotherapy plus concurrent capecitabine. The efficacy of this regimen (pCR = 19.0 %) was significantly higher than that observed in previous phase II trials of preoperative radiotherapy with concurrent capecitabine and cetuximab in rectal cancer. Further investigation of concurrent nimotuzumab with radiotherapy plus capecitabine is warranted.

Establishment and value assessment of efficacy prediction model about transurethral prostatectomy.

OBJECTIVES: To establish and to evaluate discriminant models to predict the outcomes of transurethral prostatectomy. METHODS: Clinical data of patients treated with transurethral prostatectomy between January and December 2013 were collected, including medical history, symptoms, biochemical tests, ultrasonography and urodynamics. Surgical efficacy was evaluated at 6-month follow up. Predictive models were constructed by logistic regression. Receiver operating characteristic curve and diagnostic tests were used to test the accuracy of models before the predictive value between models was compared. RESULTS: A total of 182 patients were included, with 73.6% having an effective outcome. History of recurrent urinary tract infection (OR 1.33), score of storage phase (OR 2.58), maximum flow rate (OR 2.11) and detrusor overactivity (OR 3.13) were found to be risk factors. International Prostate Symptom Score (OR 0.13), transitional zone index (OR 0.58), resistive index of prostatic artery (OR 0.46), bladder wall thickness (OR 0.78), ultrasonic estimation of bladder weight (OR 0.28), bladder outlet obstruction index (OR 0.20) and bladder contractility index (OR 0.83) were found to be protective factors. The areas under the curve of models using factors from ultrasonography and urodynamics were 0.792 and 0.829 respectively, with no significant difference being found between them (P = 0.348). CONCLUSIONS: Surgical efficacy of transurethral prostatectomy is positively correlated to severe voiding phase symptoms, outlet obstruction and better detrusor contractility, and negative correlated with urinary infection, severe storage phase symptoms and excessive detrusor contractibility. Ultrasonography might replace urodynamics in selecting patients for whom transurethral prostatectomy is more likely to be beneficial.

Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

Astragalus polysaccharides suppress ICAM-1 and VCAM-1 expression in TNF-α-treated human vascular endothelial cells by blocking NF-κB activation.

AIM: To investigate the effects Astragalus polysaccharides (APS) on tumor necrosis factor (TNF)-α-induced inflammatory reactions in human umbilical vein endothelial cells (HUVECs) and to elucidate the underlying mechanisms. METHODS: HUVECs were treated with TNF-α for 24 h. The amounts of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined with Western blotting. HUVEC viability and apoptosis were detected using cell viability assay and Hoechst staining, respectively. Reactive oxygen species (ROS) production was measured by DHE staining. Monocyte and HUVEC adhesion assay was used to detect endothelial cell adhesive function. NF-κB activation was detected with immunofluorescence. RESULTS: TNF-α (1-80 ng/mL) caused dose- and time-dependent increases of ICAM-1 and VCAM-1 expression in HUVECs, accompanied by significant augmentation of IκB phosphorylation and NF-κB translocation into the nuclei. Pretreatment with APS (10 and 50 µg/mL) significantly attenuated TNFα-induced upregulation of ICAM-1 VCAM-1 and NF-κB translocation. Moreover, APS significantly reduced apoptosis, ROS generation and adhesion function damage in TNF-α-treated HUVECs. CONCLUSION: APS suppresses TNFα-induced adhesion molecule expression by blocking NF-κB signaling and inhibiting ROS generation in HUVECs. The results suggest that APS may be used to treat and prevent endothelial cell injury-related diseases.

Genomic insights into Aspergillus sydowii 29R-4-F02: unraveling adaptive mechanisms in subseafloor coal-bearing sediment environments.

Introduction: Aspergillussydowii is an important filamentous fungus that inhabits diverse environments. However, investigations on the biology and genetics of A. sydowii in subseafloor sediments remain limited. Methods: Here, we performed de novo sequencing and assembly of the A. sydowii 29R-4-F02 genome, an isolate obtained from approximately 2.4 km deep, 20-million-year-old coal-bearing sediments beneath the seafloor by employing the Nanopore sequencing platform. Results and Discussion: The generated genome was 37.19 Mb with GC content of 50.05%. The final assembly consisted of 11 contigs with N50 of 4.6 Mb, encoding 12,488 putative genes. Notably, the subseafloor strain 29R-4-F02 showed a higher number of carbohydrate-active enzymes (CAZymes) and distinct genes related to vesicular fusion and autophagy compared to the terrestrial strain CBS593.65. Furthermore, 257 positively selected genes, including those involved in DNA repair and CAZymes were identified in subseafloor strain 29R-4-F02. These findings suggest that A. sydowii possesses a unique genetic repertoire enabling its survival in the extreme subseafloor environments over tens of millions of years.

[Detection and clinical significance of apoptosis related protein in local advanced rectal cancer patients with preoperative neoadjuvant therapy].

OBJECTIVE: To discuss the mechanism of rectal cancer apoptosis induced by preoperative chemoradiotherapy and evaluate its effect by detection of apoptosis related proteins in locally advanced colorectal cancer patients who had received preoperative chemoradiation. METHODS: To detect Bcl-XL and Bax expression in rectal cancer before and after chemoradiotherapy by EnVision method, combined with patients clinical and pathological index, statistically analysis and evaluation their relationship and clinical significance. RESULTS: Patients with or without tumor shrinkage after preoperative chemoradiotherapy was 13 cases and 21 cases. While the positive rate of Bcl-XL in rectal cancer before and after chemoradiotherapy were 58.8% (20/34) and 52.9% (18/34), respectively. There were significant difference between Bcl-XL change before and after chemoradiation with tumor size, tumor cells shrinkage and operation pattern. The positive rate of Bax in rectal cancer before and after chemoradiotherapy were 32.4% (11/34) and 44.1% (15/34), respectively. There were no significant difference between Bax change before and after chemoradiotherapy with tumor cells shrinkage. There were statistically significant difference between Bax ratio (χ(2) = 9.607, P = 0.048) before and after chemoradiation while there were no significant difference between Bcl-XL/Bax ratio before and after chemoradiation with tumor shrinkage. According to layered analysis with preoperative therapy, there were statistically significant difference (χ(2) = 13.964, P = 0.007) between Bcl-XL change with operation pattern while the same of significant difference between Bax change with tumor infiltration and tumor shrinkage (χ(2) = 10.806 and 10.455, both P < 0.05). CONCLUSIONS: Preoperative chemoradiation can influence rectal cancer cell's apoptosis and treatment effect by changing Bcl-XL and Bax expression. Bcl-XL downregulation and Bax upregulation have shown important function in colorectal cancer cell apoptosis which induced by preoperative chemoradiation, it can also improve the effection of chemoradiation in rectal cancer.

Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase-Calmodulin Interaction.

Death-associated protein kinase 1 (DAPK1), as a calcium/calmodulin (CaM) regulated serine/threonine kinase, functions in apoptotic and autophagy pathways and represents an interesting drug target for inflammatory bowel disease and Alzheimer's disease. The crystal structure of the DAPK1 catalytic domain and the autoregulatory domain (ARD) in complex with CaM provides an understanding of CaM-dependent regulation of DAPK1 activity. However, the molecular basis of how distinct Trp305 (W305Y and W305D) mutations in the ARD modulate different DAPK1 activities remains unknown. Here, we performed multiple, µs-length molecular dynamics (MD) simulations of the DAPK1-CaM complex in three different (wild-type, W305Y, and W305D) states. MD simulations showed that the overall structural complex did not change significantly in the wild-type and W305Y systems, but underwent obvious conformational alteration in the W305D system. Dynamical cross-correlation and principal component analyses revealed that the W305D mutation enhanced the anti-correlated motions between the DAPK1 and CaM and sampled a broader distribution of conformational space relative to the wild-type and W305Y systems. Structural and energetical analyses further exhibited that CaM binding was unfavored in response to the W305D mutation, resulting in the decreased binding of CaM to the W305D mutant. Furthermore, the hydrogen bonds and salt bridges responsible for the loss of CaM binding on the interface of the DAPK1-CaM complex were identified in the W305D mutant. This result may provide insights into the key role of Trp305 in the regulation of CaM-mediated DAPK1 activity.

Vascular toxicity of multi-walled carbon nanotubes targeting vascular endothelial growth factor.

Multiwalled carbon nanotubes (MWCNTs) are currently widely used and are expected to be used as drug carriers and contrast agents in clinical practice. Previous studies mainly focused on their lung toxicity; therefore, their effects on the vascular endothelium are unclear. In this study, a human angiogenesis array was used to determine the effect of MWCNTs on the expression profile of angiogenic factors in endothelial cells and to clarify the role of vascular endothelial growth factor (VEGF) in MWCNT-induced endothelial cell injury at the cellular and animal levels. The results indicated that MWCNTs (20-30 nm and 30-50 nm) could enter endothelial cells and disrupt human umbilical vein endothelial cell (HUVECs) activity in a concentration-dependent manner. MWCNTs disrupted the tube formation ability and cell migration function of HUVECs. The results from a Matrigel Plug experiment in mice showed that angiogenesis in the MWCNT experimental group was significantly reduced. The results of a protein chip analysis indicated that VEGF expression in the MWCNT treatment group was decreased, a finding that was validated by ELISA results. The protein expression levels of AKT and eNOS in the MWCNT treatment group were significantly decreased; the administration of recombinant VEGF significantly alleviated the migration ability and tube formation ability of endothelial cells injured by MWCNTs, upregulated the protein expression of AKT and eNOS, and increased the number of neovascularization in mice in the MWCNT treatment group. This study demonstrated that MWCNTs affect angiogenesis via the VEGF-Akt-eNOS axis which can be rescued by VEGF endothelial treatment.

[Establishment of rat integrated discrete multiple organ cell culture (IdMOC) model].

OBJECTIVE: To establish the integrated discrete multiple organ cell culture (IdMOC) system. METHODS: Rat primary cell of hepatocyte, nephrocyte, cardiomyocytes, alveolar macrophage, dermal fibroblasts were isolated by collagenase digestion, separation of bronchial lavage, two-step digestion method and cultured respectively, with monolayer culture. To establish the integrated discrete multiple organ cell culture (IdMOC) system, glass slides of five different cells were used to the same dish with 10% FBS DMEM medium cultured 7d, using MTT comparison primary cells cultured alone and cocultured when growth. RESULTS: Established rat hepatocytes, renal cell, cardiomyocyte, alveolar macrophages, dermal fibroblasts separation method was stable, cell separation survival rate was about 90.0%. Hepatocytes separation survival rate 90.3% ,renal cell separation survival rate 91.9%, cardiomyocyte separation survival rate 93.0% and beating rate indifference curve among 3d-15d, alveolar macrophages cell separation survival rate 90.8%, dermal fibroblasts cell separation survival rate 92.7%. Five primary cells multiple organ cells coculture showed cocultured cell growth proliferation well, cultured alone and cocultured cells growth curve basic coincide. CONCLUSION: Established rat multiple organ cell co-culture is successful.

Glucose Starvation-Induced Rapid Death of Nrf1α-Deficient, but Not Nrf2-Deficient, Hepatoma Cells Results from Its Fatal Defects in the Redox Metabolism Reprogramming.

Metabolic reprogramming exists in a variety of cancer cells, with the most relevance to glucose as a source of energy and carbon for survival and proliferation. Of note, Nrf1 was shown to be essential for regulating glycolysis pathway, but it is unknown whether it plays a role in cancer metabolic reprogramming, particularly in response to glucose starvation. Herein, we discover that Nrf1α-/- hepatoma cells are sensitive to rapid death induced by glucose deprivation, such cell death appears to be rescued by Nrf2 interference, but HepG2 (wild-type, WT) or Nrf2-/- cells are roughly unaffected by glucose starvation. Further evidence revealed that Nrf1α-/- cell death is resulted from severe oxidative stress arising from aberrant redox metabolism. Strikingly, altered gluconeogenesis pathway was aggravated by glucose starvation of Nrf1α-/- cells, as also accompanied by weakened pentose phosphate pathway, dysfunction of serine-to-glutathione synthesis, and accumulation of reactive oxygen species (ROS) and damages, such that the intracellular GSH and NADPH were exhausted. These demonstrate that glucose starvation leads to acute death of Nrf1α-/- , rather than Nrf2-/- , cells resulting from its fatal defects in the redox metabolism reprogramming. This is owing to distinct requirements of Nrf1 and Nrf2 for regulating the constructive and inducible expression of key genes involved in redox metabolic reprogramming by glucose deprivation. Altogether, this work substantiates the preventive and therapeutic strategies against Nrf1α-deficient cancer by limiting its glucose and energy demands.

Circulating guanylyl cyclase C (GCC) mRNA is a reliable metastatic predictor and prognostic index of colorectal cancer.

BACKGROUND: Currently, few specific biomarkers or standard cutoff values are available for circulating tumor cells (CTCs) detection and survival prediction in patients with early stage colorectal cancer (CRC). Guanylyl cyclase C (GCC) presents as a specific expression in intestinal tumor cells and during their metastases, indicating its potential application as a metastatic predictor of CRC. METHODS: The circulating GCC mRNA of 160 colorectal cancer patients at stage I-III was detected via quantitative real-time (qRT)-PCR in our study, and the correlation of GCC mRNA level with tumor metastasis and long-term survival was explored. RESULTS: GCC mRNA was found to be positive in 43 out of 160 CRC patients and negative in ten healthy controls. It was found that GCC mRNA over the baseline (>100 copies/µL and 200 copies/µL) showed a significant correlation with disease-free survival (DFS) and overall survival (OS) in the stage II subgroup. It was further revealed that GCC mRNA over 300 copies/µL or higher than the median value of copy numbers was significantly correlated with reduced OS and DFS in CRC patients. A nomogram model based on variables including GCC mRNA copy number was established for predicting the OS of CRC patients (AUC =0.98). CONCLUSIONS: Circulating GCC mRNA over baseline is a reliable predictor for tumor metastasis and can be a prognostic index in CRC patients.

Extraperitoneal laparoscopic adenomectomy for benign prostatic hyperplasia.

OBJECTIVES: We assessed the feasibility of extraperitoneal laparoscopic prostatectomy in pilots in China. MATERIALS AND METHODS: Extraperitoneal laparoscopic retropubic prostatectomy has been performed in 45 patients with prostatic weight more than 60 g between May 2005 and May 2008. The laparoscopic approach was standard in all cases as follows: creation of a preperitoneal workspace, haemostatic control of lateral venous vesicoprostatic pedicles, transversal anterior incision of the prostate capsule, prostatic adenomectomy and retrieval of the specimen. RESULTS: The average prostate resected weight was 78.2 +/- 16.3 g. Mean operative time was 105.4 +/- 26.5 min. Conversion to open prostatectomy was not required. The transfusion was essential in three cases. During a 6 months follow-up period for 40 cases, the mean score of IPSS decreased from 25.5 +/- 2.4 to 6.2 +/- 2.1, Q(max) increased from 6.1 +/- 2.8 to 18.7 +/- 3.4 ml/s. None of the patients presented with urinary incontinence. CONCLUSIONS: In our experience, laparoscopic extraperitoneal adenomectomy (Millin's procedure) is feasible with minimal invasion and is a simple straightforward technique.

Unification of Opposites between Two Antioxidant Transcription Factors Nrf1 and Nrf2 in Mediating Distinct Cellular Responses to the Endoplasmic Reticulum Stressor Tunicamycin.

The water-soluble Nrf2 (nuclear factor, erythroid 2-like 2, also called Nfe2l2) is accepted as a master regulator of antioxidant responses to cellular stress, and it was also identified as a direct target of the endoplasmic reticulum (ER)-anchored PERK (protein kinase RNA-like endoplasmic reticulum kinase). However, the membrane-bound Nrf1 (nuclear factor, erythroid 2-like 1, also called Nfe2l1) response to ER stress remains elusive. Herein, we report a unity of opposites between these two antioxidant transcription factors, Nrf1 and Nrf2, in coordinating distinct cellular responses to the ER stressor tunicamycin (TU). The TU-inducible transcription of Nrf1 and Nrf2, as well as GCLM (glutamate cysteine ligase modifier subunit) and HO-1 (heme oxygenase 1), was accompanied by activation of ER stress signaling networks. Notably, the unfolded protein response (UPR) mediated by ATF6 (activating transcription factor 6), IRE1 (inositol requiring enzyme 1) and PERK was significantly suppressed by Nrf1-specific knockout, but hyper-expression of Nrf2 and its target genes GCLM and HO-1 has retained in Nrf1a-/- cells. By contrast, Nrf2-/-ΔTA cells with genomic deletion of its transactivation (TA) domain resulted in significant decreases of GCLM, HO-1 and Nrf1; this was accompanied by partial decreases of IRE1 and ATF6, rather than PERK, but with an increase of ATF4 (activating transcription factor 4). Interestingly, Nrf1 glycosylation and its trans-activity to mediate the transcriptional expression of the 26S proteasomal subunits, were repressed by TU. This inhibitory effect was enhanced by Nrf1a-/- and Nrf2-/-ΔTA, but not by a constitutive activator caNrf2ΔN (that increased abundances of the non-glycosylated and processed Nrf1). Furthermore, caNrf2ΔN also enhanced induction of PERK and IRE1 by TU, but reduced expression of ATF4 and HO-1. Thus, it is inferred that such distinct roles of Nrf1 and Nrf2 are unified to maintain cell homeostasis by a series of coordinated ER-to-nuclear signaling responses to TU. Nrf1 (i.e., a full-length form) acts in a cell-autonomous manner to determine the transcription of most of UPR-target genes, albeit Nrf2 is also partially involved in this process. Consistently, transactivation of ARE (antioxidant response element)-driven BIP (binding immunoglobulin protein)-, PERK- and XBP1 (X-box binding protein 1)-Luc reporter genes was mediated directly by Nrf1 and/or Nrf2. Interestingly, Nrf1 is more potent than Nrf2 at mediating the cytoprotective responses against the cytotoxicity of TU alone plus tBHQ (tert-butylhydroquinone). This is also further supported by the evidence that the intracellular reactive oxygen species (ROS) levels are increased in Nrf1a-/- cells, but rather are, to our surprise, decreased in Nrf2-/-ΔTA cells.

[Holmium laser urethrotomy for male urethral stricture].

OBJECTIVE: To evaluate transurethral holmium laser incision, its safety and effect in the treatment of male urethral stricture. METHODS: Thirty-eight males with urethral stricture were treated by 1045 W holmium laser urethrotomy, 18 with the stricture length shorter than 1.0 cm, 9 between 1.0 cm and 1.5 cm, 7 longer than 1.5 cm , 4 with occlusive stricture and 6 companies with bladder calculus. The average peak urinary flow rate (Q(max)) was (5.6 +/- 2.3) ml/s. RESULTS: Successful surgery was achieved in 36 of the cases, with no complications and the average Q(max) increased to (17.5 +/- 3.4) ml/s. Two cases were converted to open surgery. Thirty-two cases were followed up for 3-18 months, of whom 4 received urethral dilation and 2 underwent a second holmium laser urethrotomy. CONCLUSION: Holmium laser urethrotomy is a safe, effective and minimally invasive therapeutic modality for male urethral stricture.

[Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial].

OBJECTIVE: To our knowledge, there has been no clinical report of artesunate in the treatment of lung cancer. This study was designed to compare the efficacy and toxicity of artesunate combined with NP (a chemotherapy regimen of vinorelbine and cisplatin) and NP alone in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: One hundred and twenty cases of advanced NSCLC were randomly divided into simple chemotherapy group (control group, n=60) and combined artesunare with chemotherapy group (trial group, n=60). Patients in the control group were treated with NP regimen, including vinorelbine (25 mg/m(2), once-a-day intravenous injection, at the 1st and 8th day) and cisplatin (25 mg/m(2), once-a day intravenous drip, at the 2nd to 4th day). Patients in the trial group were treated with the basal therapy NP (in the same method and doses as control group) and artesunate (120 mg, once-a-day intravenous injection, from the 1st day to 8th day, for 8 days). At least two 21-day-cycles of treatment were performed. The short-term survival rate, disease controlled rate (DCR), time to progression (TTP), mean survival time (MST) and 1-year survival rate were analyzed as the primary end points, and the toxicity and safety were estimated. RESULTS: There were no significant differences in the short-term survival rate, MST and 1-year survival rate between the trial group and the control group, which were 45.1% and 34.5%, 44 weeks and 45 weeks, 45.1% and 32.7%, respectively (P>0.05). The DCR of the trial group (88.2%) was significantly higher than that of the control group (72.7%) (P<0.05), and the trial group's TTP (24 weeks) was significantly longer than that of the control group (20 weeks) (P<0.05). No significant difference was found in toxicity between the two groups, such as myelosuppression and digestion reaction (P>0.05). CONCLUSION: Artesunate can be used in the treatment of NSCLC. Artesunate combined with NP can elevate the short-term survival rate and prolong the TTP of patients with advanced NSCLC without extra side effects.

[Small interfering RNA inhibits the expression of connexin43 in the human corpus cavernosum penis smooth muscle cells].

OBJECTIVE: To inhibit the expression of connexin43 (Cx43) in the human corpus cavernosum penis smooth muscle cells by small interfering RNA (siRNA) and detect the gap junction intercellular communication (GJIC), and to investigate the application of siRNA technology in the gap junction of corpus cavernosum penis smooth muscle cells and its role in the penile erection process. METHODS: With the help of the software of Ambion Corporation, the specific recombinant plasmids with siRNA targeting human Cx43 gene were constructed. The recombinant plasmids having been stably transferred into human corpus cavernosum penis smooth muscle cells for 48 hours, semi-quantitive reverse transcription polymerase chain reaction (RT-PCR) and Western blotting techniques were used to examine the inhibitory effects of siRNA on the expressions of the Cx43 gene and protein, in comparison with the siRNA negative control and the blank control group, respectively. The GJIC was detected by scrape-loading and fluorescence dye transfer experiments through the fluorescence microscope. RESULTS: The results of enzyme digestion analysis and DNA sequencing showed that the recombinant plasmid pSilencer 1.0-U6-siRNA-Cx43 was successfully constructed. The relative levels of Cx43 mRNA and protein expression in the smooth muscle cells were (0.45 +/- 0.08)% and (0.56 +/- 0.06)% after successful transfer of the recombinant plasmid. However, the expression levels of mRNA and protein were (0.72 +/- 0.04)% and (0.80 +/- 0.08)% in the negative siRNA transfer group, and (0.74 +/- 0.09)% and (0.77 +/- 0.11)% in the blank control, respectively, with a significant difference (P < 0.05). The GJIC also decreased significantly. CONCLUSION: siRNA can significantly inhibit the expression of Cx43 and block the GJIC in the human corpus cavernosum penis smooth muscle cells. siRNA technology plays an important role in penile erection and flaccidity.