Objective To investigate if Shikonin(SKI)can induce ferroptosis via the ROS/JNK pathway to inhibit the malignant behavior of pancreatic cancer.Methods Human pancreatic cancer PANC-1 or BxPC-3 cells were selected.Drug efficacy experiments were established with a blank control group(Con group)and low,medium,and high dose SKI groups(2,4,8 μmol/L).JNK-related mechanism experiments were categorized into a blank control group(Con group),SKI group,and SKI+JNK inhibitor group(SKI+SP600125 group).ROS-related mechanism experiments were divided into a blank control group(Con group),SKI group,and SKI+ROS scavenger group(SKI+NAC group).Cell viability was assessed using the CCK-8 method to calculate IC50;Transwell experiments evaluated cell migration and invasion capabilities;the C11 BODIPY 581/591 probe was utilized for flow cytometry to detect lipid peroxidation levels,while the FerroOrange fluorescent probe measured ferrous ion levels;ROS levels were determined using a ROS detection kit;the Western blot method identified ferroptosis-related key proteins(SLC7A11,GPX4),apoptosis-related proteins(Caspase3,PARP),and JNK pathway proteins(JNK,p-JNK);an in vivo xenograft tumor model was employed to assess tumor proliferation.Results SKI treatment significantly and dose-dependently inhibited PANC-1 cell viability(IC50:6.04 μmol/L,P<0.0001)and BxPC-3 cell viability(IC50:12.27 μmol/L,P<0.0001),and significantly reduced migrating and invasive cell numbers(P<0.0001),with migration cell numbers dropping to about 30%of the control group at 8 μmol/L SKI treatment(P<0.0001).Mechanistically,SKI induced increased intracellular lipid peroxidation,Fe2+accumulation,and significant ROS production(P<0.0001),significantly downregulated SLC7A11 and GPX4 protein expression(GPX4 protein expression reduced to 40%of that in the control group,P<0.0001),and activated JNK phosphorylation(p-JNK/JNK ratio increased to 2.8-fold,P<0.0001).Pretreatment with the JNK-specific inhibitor SP600125 or ROS scavenger NAC effectively reversed SKI's inhibition of cell viability and downregulation of SLC7A11/GPX4 protein(all P<0.01).SKI also inhibited pancreatic cancer tumor cell proliferation in vivo(P<0.0001).Conclusion SKI induces ferroptosis by activating the ROS/JNK pathway,thereby inhibiting pancreatic cancer proliferation,migration,and invasion.

Normalizing inflamed soils including reactive oxygen species (ROS), nitric oxide (NO), cell-free DNA, and regulating inflammation-related seeds such as macrophages, neutrophils, fibroblasts, represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis (RA) treatment. Herein, ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o-phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/oPDA-PEG, NBOP NPs). The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation, but also decrease cytokines and chemokines to prevent immune cell recruitment. Specifically, NBOP NPs responded to high level ROS and NO, and disintegrated to release notopterol in inflamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic ones. The released notopterol could inhibit the JAK-STAT pathway of inflammatory cells to reduce the secretion of pro-inflammatory cytokines and chemokines. This strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation, achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat model. Taken together, our work offered a reference to adjust RA soils and seeds for enhanced RA treatment.

OBJECTIVE To investigate the effects of andrographolide （Andro） on angiogenesis in rats with diabetic foot and to explore its mechanism of action based on the Hippo-Yes-associated protein （YAP） signaling pathway. METHODS The rat model of type 2 diabetes was established by using low-dose streptozotocin combined with high-fat and high-glucose diet. On the basis of successful modeling， the rat model of diabetes foot was established by scalding. Model rats were randomly divided into 5 groups with 12 rats in each group： model group， Andro low-dose， medium-dose， and high-dose groups （1， 10， and 20 mg/kg）， as well as inhibitor group （20 mg/kg Andro+100 mg/kg of verteporfin， an specific inhibitor of Hippo-YAP signaling pathway）； other 12 healthy rats were included in the Control group. Rats in each group were intragastrically and intraperitoneally injected with solvents or corresponding drugs， once a day， for 2 consecutive weeks. The wound healing， fasting blood glucose （FBG） and fasting insulin （FINS） were detected in rats after medication. HE staining was performed to observe the tissue damage and capillary number of rat trauma； the number of endothelial progenitor cells （EPCs） in peripheral blood of rats was counted by using flow cytometry； the contents of serum total cholesterol （TC）， triglyceride （TG）， high-density lipoprotein cholesterol （HDL-C） and low-density lipoprotein cholesterol （LDL-C） in rats were determined by fully automatic biochemical analyzer； the expressions of hypoxia- inducible factor 1α （HIF-1α）， vascular endothelial growth factor （VEGF） and Hippo-YAP signaling pathway-related proteins in the traumatic tissues of rats in each group were detected by Western blot. RESULTS Compared with Control group， the wound healing rate， capillary number， the proportion of EPCs， HDL-C content， as well as the protein expression levels of HIF-1α and VEGF and the phosphorylation levels of mammalian Ste20-like kinase 1， large tumor suppressor gene 1 and YAP proteins were significantly reduced in the model group， while the FBG， FINS levels and TC， TG and LDL-C contents were significantly increased （P＜0.05）. Compared with model group， the above indexes were significantly reversed in Andro low-dose， medium-dose and high-dose group， in a dose-dependent manner （P＜ 0.05）； verteporfin attenuated the above reversal effect of Andro （P＜0.05）. CONCLUSIONS Andro has the effects of lowering blood glucose and blood lipids， promoting blood vessel formation and wound healing in rats with diabetic foot， and its mechanism of action may be related to the activation of Hippo-YAP signaling pathway.

This article summarizes and analyzes the reported synthetic routes of brivudine in patent and literature.2′-Deoxyuridine was employed as starting material, affording brivudine through iodization, heck coupling, hydrolysis, decarboxylation, bromination and recrystallization.After optimization of reaction conditions of each step, a synthetic route suitable for industrial production was achieved with simple synthetic process, high yield and excellent purity.

Objective:To explore the changes in somatosensory evoked potential (SEP) in rats with spinal cord injury (SCI) and the effects of relieving spinal cord compression at different times on recovery and the evoked potential.Methods:Seventy Sprague-Dawley rats were randomly divided into a control group of 10 and an experimental group of 60. The experimental group was further divided into a mild injury group of 10, a moderate injury group of 40 and a severe injury group of 10. Spinal cord injuries with different severities were established in the experimental group using a self-made percussion device. The rats′ SEPs were measured before the injury, and 5 minutes, 1 hour, 6 hours, 3 days and 7 days afterward. Some of the rats receiving decompression treatment.Results:The more seriously the spinal cord was injured, the longer was the latency and the smaller was the amplitude. Both differences were statistically significant. Rats with longer compression time had significantly longer incubation periods and greater decreases in the amplitude. After relieving the compression, rats from whom it had been relieved earlier had quicker amplitude recovery. For rats under compression for 30 minutes, their amplitude was the lowest seven days later.Conclusions:For spinal cord injury, longer compression time can lead to more significant changes in the latency and amplitude of SEP, with the change in the amplitude more significant than that in the latency.

Background and Objectives: Psoriasis is a chronic inflammatory skin disease, which the mechanisms behind its initiation and development are related to many factors. DMSCs (dermal mesenchymal stem cells) represent an important member of the skin microenvironment and play an important role in the surrounding environment and in neighbouring cells, but they are also affected by the microenvironment. We studied the glucose metabolism of DMSCs in psoriasis patients and a control group to reveal the relationship among glucose metabolism, cell proliferation activity，and VEC (vascular endothelial cell) differentiation in vitro, we demonstrated the biological activity and molecular mechanisms of DMSCs in psoriasis. Methods: and Results: We found that the OCR of DMSCs in psoriatic lesions was higher than that in the control group, and mRNA of GLUT1 and HK2 were up-regulated compared with the control group. The proliferative activity of DMSCs in psoriasis was reduced at an early stage, and mRNA involved in proliferation, JUNB and FOS were expressed at lower levels than those in the control group. The number of blood vessels in psoriatic lesions was significantly higher than that in the control group (p＜0.05), which the mRNA of VEC differentiation, CXCL12, CXCR7, HEYL and RGS5 tended to be increased in psoriatic lesions compared to the control group, in addition to Notch3. Conclusions We speculated that DMSCs affected local psoriatic blood vessels through glucose metabolism, and the differentiation of VECs, which resulted in the pathophysiological process of psoriasis.

Objective To investigate the influence of different prompt measures on the quality of cardiopulmonary resuscitation (CPR) chest compressions in the standardized training of residents in Chinese medicine hospitals. Methods There were 84 participants who were the first year standardized training residents recruited from Guangdong Provincial Hospital of Chinese medicine during July to August 2016, and eleven of them were excluded because of incomplete chest compression data collected from the feedback system. Finally, 73 participants being volunteers were enrolled. They were divided randomly into phone metronome group (n = 16), music metronome group (n = 15), depth display group (n = 22), and blank control group (n = 20). In phone metronome group, a mobile phone metronome was applied in the duration of CPR, with a frequency of 110 beats per minute, beat 2/4; in the music metronome group, it was accompanied by the music Staying Alive during the compression period, with frequency of 107 beats per minute, beat 4/4; in depth display group, a model electronic displayer was used in the duration of the compressions to feedback the real time compression depth and its rebound situation in CPR; there was no any intervention measure in blank control group. Each participant performed 5 cycles of CPR on a manikin. A chest compression feedback device was placed on the pressing point, on which the participants places the hand for CPR. The chest compression fraction 1 (CCF1), compression depth, compression rate, too slow frequency, too fast frequency, too shallow frequency, the total times of compressions, the correct times of compressions, correct rate, and the rate of compression retention were record as preliminary evaluation data by using the dual sensor and the pressure sensor built in the chest compression feedback device. At the same time, the correct compression ratio, correct ventilation ratio, the chest compression fraction 2 (CCF2) displayed on the human electronic displayer of the manikin were used as the review criteria. The quality of chest compression among the four groups of volunteers was compared. Results The compression rate and the too fast frequency in the depth display group were significantly higher than those in the music metronome group [compression rate (bpm): 140.59±17.90 vs. 124.27±21.43, the too fast frequency (times): 134.18±49.88 vs. 95.40±53.76, both P < 0.05], and the total compression times in depth display group were significantly higher than either in music metronome group or in blank control group (times: 152.73±27.05 vs. 135.60±10.38, 144.60±12.56, all P < 0.05), the rate of compression retention in depth display group was significantly higher than that in blank control group [37.50% (4.75%, 88.25%) vs. 12.00% (2.75%, 47.00%)]. Consistency detection of two sets of feedback systems for chest compression showed that the chest compression ratio in music metronome group evaluated by the chest compression feedback device was obviously lower than that assessed by the analog human electronic displayer [(53.60±9.87)% vs. (58.20±28.17)%], and it was suggested that the chest compression ratio in depth display group evaluated by the chest compression feedback device be markedly higher than that assessed by the analog human electronic displayer [(56.32±7.77)% vs. (43.86±27.63)%, P < 0.05], and it was shown that the correct rates of chest compression assessed by the chest compression feedback device were significantly lower than those evaluated by the analog human electronic displayer in metronome, music, depth and blank control groups [phone metronome group: 0.00% (0.00%, 60.75%) vs. 38.50% (24.25%, 92.00%), music metronome group: 0.00% (0.00%, 7.00%) vs. 60.00% (32.00%, 89.00%), depth display group: 0.00% (0.00%, 0.25%) vs. 34.00% (20.75%, 68.25%), blank control group: 0.00% (0.00%, 1.75%) vs. 61.50% (30.75%, 84.25%), all P < 0.05], suggesting that the consistency of this two feedback systems be poor and their degrees of reliability low. Conclusion The effects of intervention measures on the quality of chest compressions vary from person to person, and the quality of chest compressions can be really elevated only by systematic training and repeated practice.

BACKGROUND: Lung cancer is one of the most deadly cancers in the world for human. In recent years, the effect of targeted therapy has become increasingly significant. Apatinib is a multi-target anti-tumor drug that is currently under study. The purpose of this study is to investigate the effects of Apatinib on the biological characteristics of lung cancer cells and its possible mechanism. METHODS: Lung cancer cell lines H1299 and H3255 were cultured in vitro. The effects of Apatinib on proliferation, migration and invasion of H1299 and H3255 cells were detected by cell proliferation assays wound healing assays and Transwell assays. The protein expression related to cancer angiogenesis and invasion was detected by Western blot. RESULTS: Apatinib significantly inhibited the proliferation, migration and invasion of H1299 and H3255 in a concentration-dependent manner. Western blot showed that with the increasing of drug concentration, VEGF, VEGFR2, N-cadherin, MMP9, MMP2 and Vimentin were down-regulated, and E-cadherin were up-regulated. CONCLUSIONS Apatinib can inhibit the invasion and migration of lung adenocarcinoma cells H1299 and H3255. By regulation of epithelial-mesenchymal transition and the expression of matrix metalloproteinase-related proteins.
Antineoplastic Agents ; pharmacology ; Cell Line, Tumor ; Cell Movement ; drug effects ; Humans ; Lung Neoplasms ; pathology ; Neoplasm Invasiveness ; Pyridines ; pharmacology

BACKGROUND: Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells. METHODS: PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression. RESULTS: In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins. CONCLUSIONS The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.
Antineoplastic Agents ; pharmacology ; Cell Line, Tumor ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Drug Synergism ; Enhancer of Zeste Homolog 2 Protein ; antagonists & inhibitors ; ErbB Receptors ; antagonists & inhibitors ; Gefitinib ; pharmacology ; Humans ; Lung Neoplasms ; pathology ; Protein Kinase Inhibitors ; pharmacology

Objective To study the drug resistance situation of Mycobacterium tuberculosis strains isolated from the patients with HIV/AIDS complicating tuberculosis (TB).Methods One hundred and ninety-six inpatients with AIDS complicating TB in our hospital from January 2012 to December 2015 were collected.The drug resistance situation of Mycobacterium tuberculosis strains cultured from sputum/tissue fluid/fiber liquid and pathological tissue submitted samples in the patients with AIDS complicating active TB was analyzed.The BACTEC MGIT960 systems was adopted to perform the bacterial identification.The drug sensitivity test was conducted by using 960 culture testing system.Results One hundred and ninety-six strains of Mycobacterium tuberculosis were cultured,the total drug resistance rate of Mycobacterium tuberculosis was 26.02％.These cases were divided into the ＞100/μL and ≤100/μL groups according to different CD4+ T cells count.The drug resistance situation of Mycobacterium tuberculosis to 4 kinds of first line anti-TB drugs were compared between these two groups.The comparison results found that the resistance rate of Mycobacterium tuberculosis strains to the first line anti-TB drugs had no statistical difference between the two groups (P＞0.05).The resistance rates of first line anti-TB drugs from high to low were isoniazid,rifampicin,streptomycin and ethambutol.The drug resistance rate of Mycobacterium tuberculosis strains to 5 types of drug resistant TB had no statistical difference(P＞0.05).Conclusion The drug resistance rate in the initial patients with HIV complicating TB is consistent with the average initial drugresistance level of TB patients in our country.The TB drug resistance rate in the patients with HIV complicating TB has no correlation with CD4+ T cells count.