The RPA-RNF20-SNF2H cascade promotes proper chromosome segregation and homologous recombination repair.

The human tumor suppressor Ring finger protein 20 (RNF20)-mediated histone H2B monoubiquitination (H2Bub) is essential for proper chromosome segregation and DNA repair. However, what is the precise function and mechanism of RNF20-H2Bub in chromosome segregation and how this pathway is activated to preserve genome stability remain unknown. Here, we show that the single-strand DNA-binding factor Replication protein A (RPA) interacts with RNF20 mainly in the S and G2/M phases and recruits RNF20 to mitotic centromeres in a centromeric R-loop-dependent manner. In parallel, RPA recruits RNF20 to chromosomal breaks upon DNA damage. Disruption of the RPA-RNF20 interaction or depletion of RNF20 increases mitotic lagging chromosomes and chromosome bridges and impairs BRCA1 and RAD51 loading and homologous recombination repair, leading to elevated chromosome breaks, genome instability, and sensitivities to DNA-damaging agents. Mechanistically, the RPA-RNF20 pathway promotes local H2Bub, H3K4 dimethylation, and subsequent SNF2H recruitment, ensuring proper Aurora B kinase activation at centromeres and efficient loading of repair proteins at DNA breaks. Thus, the RPA-RNF20-SNF2H cascade plays a broad role in preserving genome stability by coupling H2Bub to chromosome segregation and DNA repair.

The relationship between air pollutants and preterm birth and blood routine changes in typical river valley city.

OBJECTIVE: To collect maternal maternity information on preterm births in two tertiary hospitals in the urban area of Baota District, Yan'an City, from January 2018 to December 2020, to explore the long-term and short-term effects of air pollutants (PM2.5, PM10, SO2, NO2, CO and O3) and preterm births, and to explore changes in blood cell counts due to air pollutants. METHODS: Daily average mass concentration data of six air pollutants in the urban area of Yan'an City from January 1, 2017 to December 31, 2020 were collected from the monitoring station in Baota District, Yan'an City. Meteorological information was obtained from the Meteorological Bureau of Yan'an City, including temperature,relative humidity and wind speed for the time period. The mass concentration of air pollutants in each exposure window of pregnant women was assessed by the nearest monitoring station method, and conditional logistic regression was used to analyze the relationship between air pollutants and preterm births, as well as the lagged and cumulative effects of air pollutants. Multiple linear regression was used to explore the relationship between air pollutants and blood tests after stepwise linear regression was used to determine confounders for each blood test. RESULTS: The long-term effects of pollutants showed that PM2.5, PM10, SO2, NO2and CO were risk factors for preterm birth. In the two-pollutant model, PM2.5, PM10, SO2 and NO2 mixed with other pollutants were associated with preterm birth. The lagged effect showed that PM2.5, PM10, SO2, NO, and CO were associated with preterm birth; the cumulative effect showed that other air pollutants except O3 were associated with preterm birth. The correlation study between air pollutants and blood indicators showed that air pollutants were correlated with leukocytes, monocytes, basophils, erythrocytes, hs-CRPand not with CRP. CONCLUSION: Exposure to air pollutants is a risk factor for preterm birth. Exposure to air pollutants was associated with changes in leukocytes, monocytes, basophils and erythrocytes and hs-CRP.

MTAP deficiency contributes to immune landscape remodelling and tumour evasion.

Methylthioadenosine phosphorylase (MTAP) deficiency occurs in various malignancies and is associated with poor survival in cancer patients. However, the mechanisms underlying tumour progression due to MTAP loss are yet to be elucidated. Utilizing integrated analyses of the transcriptome, proteome and secretome, we demonstrated that MTAP deficiency alters tumour-intrinsic, immune-related pathways and reprograms cytokine profiles towards a tumour-favourable environment. Additionally, MTAP-knockout cells exhibited a marked increase in the immune checkpoint protein PD-L1. Upon co-culturing primary T cells with cancer cells, MTAP loss-mediated PD-L1 upregulation inhibited T cell-mediated killing activity and induced several T cell exhaustion markers. In two xenograft tumour models, we showed a modest increase in average volume of tumours derived from MTAP-deficient cells than that of MTAP-proficient tumours. Surprisingly, a remarkable increase in tumour size was observed in humanized mice bearing MTAP-deficient tumours, as compared to their MTAP-expressing counterparts. Following immunophenotypic characterization of tumour-infiltrating leukocytes by mass cytometry analysis, MTAP-deficient tumours were found to display decreased immune infiltrates with lower proportions of both T lymphocytes and natural killer cells and higher proportions of immunosuppressive cells as compared to MTAP-expressing tumour xenografts. Taken together, our results suggest that MTAP deficiency restructures the tumour immune microenvironment, promoting tumour progression and immune evasion.

Inositol possesses antifibrotic activity and mitigates pulmonary fibrosis.

BACKGROUND: Myo-inositol (or inositol) and its derivatives not only function as important metabolites for multiple cellular processes but also act as co-factors and second messengers in signaling pathways. Although inositol supplementation has been widely studied in various clinical trials, little is known about its effect on idiopathic pulmonary fibrosis (IPF). Recent studies have demonstrated that IPF lung fibroblasts display arginine dependency due to loss of argininosuccinate synthase 1 (ASS1). However, the metabolic mechanisms underlying ASS1 deficiency and its functional consequence in fibrogenic processes are yet to be elucidated. METHODS: Metabolites extracted from primary lung fibroblasts with different ASS1 status were subjected to untargeted metabolomics analysis. An association of ASS1 deficiency with inositol and its signaling in lung fibroblasts was assessed using molecular biology assays. The therapeutic potential of inositol supplementation in fibroblast phenotypes and lung fibrosis was evaluated in cell-based studies and a bleomycin animal model, respectively. RESULTS: Our metabolomics studies showed that ASS1-deficient lung fibroblasts derived from IPF patients had significantly altered inositol phosphate metabolism. We observed that decreased inositol-4-monophosphate abundance and increased inositol abundance were associated with ASS1 expression in fibroblasts. Furthermore, genetic knockdown of ASS1 expression in primary normal lung fibroblasts led to the activation of inositol-mediated signalosomes, including EGFR and PKC signaling. Treatment with inositol significantly downregulated ASS1 deficiency-mediated signaling pathways and reduced cell invasiveness in IPF lung fibroblasts. Notably, inositol supplementation also mitigated bleomycin-induced fibrotic lesions and collagen deposition in mice. CONCLUSION: These findings taken together demonstrate a novel function of inositol in fibrometabolism and pulmonary fibrosis. Our study provides new evidence for the antifibrotic activity of this metabolite and suggests that inositol supplementation may be a promising therapeutic strategy for IPF.

Intensified antiplatelet therapy in patients after percutaneous coronary intervention with high on-treatment platelet reactivity: the OPTImal Management of Antithrombotic Agents (OPTIMA)-2 Trial.

High on-treatment platelet reactivity (HOPR) is associated with increased risk of cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We randomised post-PCI patients with HOPR after 5 days of standard dual antiplatelet therapy (DAPT) to intensified therapy with aspirin 100 mg once daily in combination with either clopidogrel 150 mg once daily, clopidogrel 75 mg once daily plus cilostazol 100 mg twice daily, ticagrelor 90 mg twice daily, or standard therapy with clopidogrel 75 mg once daily (STD) for 1 month, after which all patients were switched to standard DAPT for a further 11 months. The primary outcome was residual HOPR rate at 1 month. We screened 1724 patients with light transmission aggregation studies and randomised 434 with HOPR. At 1 month the proportion of patients with persistent HOPR was significantly lower in the intensified therapy groups compared with STD group. Compared to the group receiving STD therapy, those receiving intensified therapy had significantly lower rate of major adverse cardiovascular events (MACE) at both 1 month and 12 months with no significant increase in bleeding. In patients with post-PCI HOPR, 1 month of intensified antiplatelet therapy provides greater platelet inhibition and improves outcomes without increasing bleeding. Clinical Trial Registration URL: http://www.clinicaltrials.gov; Unique Identifier: NCT01955200.

Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis.

Argininosuccinate synthase 1 (ASS1) serves as a critical enzyme in arginine biosynthesis; however, its role in interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unknown. This study aims at characterization and targeting of ASS1 deficiency in pulmonary fibrosis. We find that ASS1 was significantly decreased and inversely correlated with fibrotic status. Transcriptional downregulation of ASS1 was noted in fibroblastic foci of primary lung fibroblasts isolated from IPF patients. Genetic manipulations of ASS1 studies confirm that ASS1 expression inhibited fibroblast cell proliferation, migration, and invasion. We further show that the hepatocyte growth factor receptor (Met) receptor was activated and acted upstream of the Src-STAT3 axis signaling in ASS1-knockdown fibroblasts. Interestingly, both arginine-free conditions and arginine deiminase treatment were demonstrated to kill fibrotic fibroblasts, attenuated bleomycin-induced pulmonary fibrosis in mice, as well as synergistically increased nintedanib efficacy. Our data suggest ASS1 deficiency as a druggable target and also provide a unique therapeutic strategy against pulmonary fibrosis.

Flow field characterization between vertical plate electrodes in a bench-scale cell of electrochemical water softening.

To analyze the effect of flow characteristics on electrochemical water softening, characteristics of flow fields in the vicinity of vertical plate electrodes in a bench-scale electrolysis cell for electrochemical water softening were visualized using particle image velocimetry technology, and the hardness drop values under different process conditions were measured. Properly increasing the current density or reducing the electrode spacing can increase the average flow velocity in the electrode gap. Excessive current density will cause bubble accumulation, form a bubble vortex, interfere with the orderly flow of surrounding liquid and reduce mass transfer efficiency. When the electrode spacing is 120 mm, the highest water softening efficiency measured at the current density of 60 A/m2 is 16.56%. When the current density is 50 A/m2, the highest average speed measured at the electrode spacing of 60 mm is 0.00169 m/s, but the highest water softening efficiency measured at the electrode spacing of 90 mm is 23.3%.The circulation efficiency in the electrode gap of a semi-closed structure is lower than that of a free convection structure. The behavior of bubbles is the key to flow and mass transfer. It is important to consider its influence on bubble behavior when optimizing electrochemical parameters.

Targeting the AXL Receptor in Combating Smoking-related Pulmonary Fibrosis.

Tobacco smoking is a well-known risk factor for both fibrogenesis and fibrotic progression; however, the mechanisms behind these processes remain enigmatic. RTKs (receptor tyrosine kinases) have recently been reported to drive profibrotic phenotypes in fibroblasts during pulmonary fibrosis (PF). Using a phospho-RTK array screen, we identified the RTK AXL as a top upregulated RTK in response to smoke. Both expression and signaling activity of AXL were indeed elevated in lung fibroblasts exposed to tobacco smoke, whereas no significant change to the levels of a canonical AXL ligand, Gas6 (growth arrest-specific 6), was seen upon smoke treatment. Notably, we found that smoke-exposed human lung fibroblasts exhibited highly proliferative and invasive activities and were capable of inducing fibrotic lung lesions in mice. Conversely, genetic suppression of AXL in smoke-exposed fibroblasts cells led to suppression of AXL downstream pathways and aggressive phenotypes. We further demonstrated that AXL interacted with MARCKS (myristoylated alanine-rich C kinase substrate) and cooperated with MARCKS in regulating downstream signaling activity and fibroblast invasiveness. Pharmacological inhibition of AXL with AXL-specific inhibitor R428 showed selectivity for smoke-exposed fibroblasts. In all, our data suggest that AXL is a potential marker for smoke-associated PF and that targeting of the AXL pathway is a potential therapeutic strategy in treating tobacco smoking-related PF.

Research on performance optimization and mechanism of electrochemical water softening applied by pulse power supply.

In order to promote the application of electrochemical water softening technology in industrial circulating cooling water systems, electric field type, cathode structure and solution residence time are selected for optimization analysis of an electrochemical water softening device. The experimental results show that the water softening performance per unit area of mesh cathode is better than that of a plate cathode. In addition, the softening amount per unit area of the mesh cathode can be further increased when the high-frequency (HF) power supply is applied. When the HF power supply is applied, the softening amount per unit area is 158.58 g/m2·h-1 more than when the direct current power supply is applied. In order to explore the growth mechanism of calcium carbonate, micro-analysis technology and high-speed bubble photography technology are used. The results show that the bubbles escape along the longitudinal direction of the electrode plate, and the main growth direction of calcium carbonate growth is consistent with the escape direction of the bubble; that is, the bubbles grow along the longitudinal direction of the electrode plate. The special structure of the diamond-shaped mesh cathode facilitates the growth of calcium carbonate crystals.

Regulation of ATP-binding cassette subfamily B member 1 by Snail contributes to chemoresistance in colorectal cancer.

Although accumulating evidence has indicated the intimate association between epithelial-mesenchymal transition (EMT) and acquired resistance to chemotherapy for colorectal cancer (CRC), the underlying mechanisms remain elusive. Herein, we reported that Snail, a crucial EMT controller, was upregulated in CRC tissues. Colorectal cancer cells overexpressing Snail were found to be more resistant to 5-fluorouracil (5-Fu). Mechanistic studies reveal that Snail could increase the expression of ATP-binding cassette subfamily B member 1 (ABCB1) rather than the other 23 chemoresistance-related genes. Additionally, knockdown of ABCB1 significantly attenuated Snail-induced 5-Fu resistance in CRC cells. Oxaliplatin increased Snail and ABCB1 expression in CRC cells. Snail and ABCB1 were upregulated in 5-Fu-resistant HCT-8 (HCT-8/5-Fu) cells and inhibition of Snail decreased ABCB1 in HCT-8/5-Fu cells. These results confirm the vital role played by ABCB1 in Snail-induced chemoresistance. Further investigation into the relevant molecular mechanism revealed Snail-mediated ABCB1 upregulation was independent of ß-catenin, STAT3, PXR, CAR and Foxo3a, which are commonly involved in modulating ABCB1 transcription. Instead, Snail upregulated ABCB1 transcription by directly binding to its promoter. Clinical analysis confirms that increased Snail expression correlated significantly with tumor size (P = .018), lymph node metastasis (P = .033), distant metastasis (P = .025), clinical stage grade (P = .024), and poor prognosis (P = .045) of CRC patients. Moreover, coexpression of Snail and ABCB1 was observed in CRC patients. Our study revealed that direct regulation of ABCB1 by Snail was critical for conferring chemoresistance in CRC cells. These findings unraveled the mechanisms underlying the association between EMT and chemoresistance, and provided potential targets for CRC clinical treatment.

Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease.

BACKGROUND: Cardiovascular outcomes in clinical trials with type 2 diabetes mellitus (T2DM) patients have shown that glucagon-like peptide-1 receptor agonist can have a beneficial effect on the kidney. This trial aimed to assess the effects of exenatide on renal outcomes in patients with T2DM and diabetic kidney disease (DKD). METHODS: We performed a randomized parallel study encompassing 4 general hospitals. T2DM patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and macroalbuminuria, defined as 24-h urinary albumin excretion rate (UAER) >0.3 g/24 h were randomized 1:1 to receive exenatide twice daily plus insulin glargine (intervention group) or insulin lispro plus glargine (control group) for 24 weeks. The primary outcome was the UAER percentage change from the baseline after 24 weeks of intervention. The rates of hypoglycemia, adverse events (AEs), and change in eGFR during the follow-up were measured as safety outcomes. RESULTS: Between March 2016 and April 2019, 92 patients were randomized and took at least 1 dose of the study drug. The mean age of the participants was 56 years. At baseline, the median UAER was 1,512.0 mg/24 h and mean eGFR was 70.4 mL/min/1.73 m2. After 24 weeks of treatment, the UAER percentage change was significantly lower in the intervention group than in the control group (p = 0.0255). Moreover, the body weight declined by 1.3 kg in the intervention group (the difference between the 2 groups was 2.7 kg, p = 0.0001). Compared to the control group, a lower frequency of hypoglycemia and more gastrointestinal AEs were observed in the intervention group. CONCLUSION: Exenatide plus insulin glargine treatment for 24 weeks resulted in a reduction of albuminuria in T2DM patients with DKD.

Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression.

Targeting activated fibroblasts, including myofibroblast differentiation, has emerged as a key therapeutic strategy in patients with idiopathic pulmonary fibrosis (IPF). However, there is no available therapy capable of selectively eradicating myofibroblasts or limiting their genesis. Through an integrative analysis of the regulator genes that are responsible for the activation of IPF fibroblasts, we noticed the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding protein, myristoylated alanine-rich C-kinase substrate (MARCKS), as a potential target molecule for IPF. Herein, we have employed a 25-mer novel peptide, MARCKS phosphorylation site domain sequence (MPS), to determine if MARCKS inhibition reduces pulmonary fibrosis through the inactivation of PI3K/protein kinase B (AKT) signaling in fibroblast cells. We first observed that higher levels of MARCKS phosphorylation and the myofibroblast marker α-smooth muscle actin (α-SMA) were notably overexpressed in all tested IPF lung tissues and fibroblast cells. Treatment with the MPS peptide suppressed levels of MARCKS phosphorylation in primary IPF fibroblasts. A kinetic assay confirmed that this peptide binds to phospholipids, particularly PIP2, with a dissociation constant of 17.64 nM. As expected, a decrease of phosphatidylinositol (3,4,5)-trisphosphate pools and AKT activity occurred in MPS-treated IPF fibroblast cells. MPS peptide was demonstrated to impair cell proliferation, invasion, and migration in multiple IPF fibroblast cells in vitro as well as to reduce pulmonary fibrosis in bleomycin-treated mice in vivo. Surprisingly, we found that MPS peptide decreases α-SMA expression and synergistically interacts with nintedanib treatment in IPF fibroblasts. Our data suggest MARCKS as a druggable target in pulmonary fibrosis and also provide a promising antifibrotic agent that may lead to effective IPF treatments.-Yang, D. C., Li, J.-M., Xu, J., Oldham, J., Phan, S. H., Last, J. A., Wu, R., Chen, C.-H. Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression.

Reelin Promotes Cisplatin Resistance by Induction of Epithelial-Mesenchymal Transition via p38/GSK3ß/Snail Signaling in Non-Small Cell Lung Cancer.

BACKGROUND Emerging evidence suggests the involvement of Reelin in chemoresistance in various cancers. However, its function in cisplatin (DDP) sensitivity of non-small cell lung cancer (NSCLC) needs to be investigated. MATERIAL AND METHODS Reelin expression in cisplatin-sensitive A549 cells and cisplatin-resistant NSCLC (A549/DDP) cells was analyzed by western blot analysis. qRT-PCR, western blotting, immunofluorescence, CCK-8 assays, Annexin V/propidium iodide apoptosis assay, and Transwell migration assays were carried out to determine the function of Reelin on DDP resistance. RESULTS Reelin was markedly increased in A549/DDP cells relative to A549 cells. Knockdown of Reelin enhanced DDP chemosensitivity of A549/DDP cells, whereas overexpression of Reelin enhanced DDP resistance of A549, H1299, and H460 cells. Reelin induced DDP resistance in NSCLC cells via facilitating epithelial-mesenchymal transition (EMT). Furthermore, Reelin modulated p38/GSK3ß signal transduction and promoted Snail (EMT-associated transcription factor) expression. Suppression of p38/Snail reversed Reelin-induced EMT and resistance of NSCLC cells to DDP. CONCLUSIONS These data indicated that Reelin induces DDP resistance of NSCLC by regulation of the p38/GSK3ß/Snail/EMT signaling pathway and provide evidence that Reelin suppression can be an effective strategy to suppress DDP resistance in NSCLC.

MiR-4756 promotes albumin-induced renal tubular epithelial cell epithelial-to-mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2.

Accumulating evidence indicates that proteinuria promotes the progression of diabetic kidney disease (DKD) and induces renal epithelial tubular cell epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress, but the mechanism remains unclear. In our previous research, we found that miR-4756 levels were increased in the urinary extracellular vesicles of type 2 diabetes mellitus patients with macroalbuminuria. In a preliminary study, we found that miR-4756 may be derived from renal tubular epithelial cells, but its role has not been elucidated. Albumin stimulation significantly increased miR-4756 levels in HK-2 cells. In addition, an miR-4756 mimic accelerated albumin-stimulated HK-2 cell EMT and ER stress, and an miR-4756 inhibitor suppressed these events. We then found that miR-4756 targeted the 3'-untranslated region (UTR) of Sestrin2 and directly suppressed Sestrin2 expression. Furthermore, the induction of EMT and ER stress by the overexpression of miR-4756 was abolished by Sestrin2 overexpression. Moreover, the overexpression of miR-4756 increased ERK1/2 activation and decreased 5' monophosphate-activated protein kinase activation. Thus, our study provides evidence that miR-4756 accelerates the process of DKD through Sestrin2, suggesting that targeting miR-4756 may be a novel strategy for DKD treatment.

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion.

BACKGROUND: Reversal of antiplatelet therapy is desirable in patients presenting with life-threatening bleeding or requiring urgent surgery. This study aimed to examine ticagrelor reversal using donor platelets and to explore the effects of residual ticagrelor on donor platelets. STUDY DESIGN AND METHODS: In Cohort 1, 16 healthy subjects were treated with ticagrelor 90 mg twice daily alone or in combination with aspirin 100 mg once daily for 7 days followed by single blood sampling for preparation of platelet-rich plasma. An additional 16 healthy subjects served as controls. In Cohort 2, 16 healthy subjects were treated with ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 7 days followed by serial blood samplings for preparation of platelet-poor plasma (PPP). An additional 16 healthy subjects served as controls. RESULTS: In Cohort 1, inhibition of adenosine diphosphate-induced platelet aggregation (PLADP ) by ticagrelor could not be fully reversed by mixing with up to 90% control platelets, whereas inhibition of arachidonic acid-induced platelet aggregation by aspirin was fully reversed with the addition of 60% control platelets. In Cohort 2, 10% PPP obtained from ticagrelor-treated subjects reduced PLADP from 74% to 40% at 2 hours, 72% to 58% at 6 hours, and 73% to 59% at 10 hours, while 10% or 20% PPP obtained from clopidogrel-treated subjects did not inhibit PLADP . CONCLUSION: The antiplatelet effect of ticagrelor cannot be fully reversed by donor platelets, which could be explained by the presence of active drug. The effect of residual drug on donor platelets appears to be evident for at least 10 hours after ticagrelor ingestion.

Woven-like change following intracoronary thrombosis recanalization: a case report.

BACKGROUND: A woven coronary artery is a rare congenital coronary anomaly and incidentally found in coronary angiogram. Coronary angiography is the major diagnostic modality, which shows the main trunk of coronary divides into several channels which later reconnect with normal blood flow (J Int Cardiol 113:121-123 2006). However, some cases and reviews inferred that this characteristic might be mimicked by recanalized coronary thrombus, which occurs following thrombotic occlusion. In some case, the multiple intraluminal channels have a 'Swiss cheese', a 'Spider web-like', a 'Honeycomb' or a 'Lotus root' appearance and most of them appear in local segment (Int J Cardiol 186: 239-240, 2015). As these images are nonspecific findings, there is no angiographic uniform definition of intracoronary thrombus. More information about the characteristics and the development of this woven-like structure is needed. CASE PRESENTATION: A 67-year-old male patient was admitted to our hospital because of chest pain. Coronary artery angiogram revealed that the right coronary artery (RCA) divided into multiple thin channels from proximal to distal, which was similar to the so-called woven coronary artery. Compared with his prior coronary angiograms which showed a tiny hazy lesion in distal segment of RCA, we found the woven-like phenomena should be caused by a late-stage recanalized coronary thrombus. Percutaneous coronary intervention (PCI) was performed to restore the RCA flow, and the angina symptom was extremely improved during clinical follow-up. CONCLUSIONS: The diagnostic criteria of woven coronary artery was based on angiographic image. However, some cases and reviews inferred that thrombotic recanalization might also share the same characteristic. In this case, we collected the baseline angiograms and intracoronary images then successfully diagnosed the woven-like RCA as thrombotic recanalization. For this kind of woven-like coronary artery, PCI could be a better treatment strategy. Detailed history collection and intracoronary image techniques should be emphasized in future clinical practice in the differentiating and treatment of woven-like phenomena.

Proteomic investigating the cooperative lethal effect of EGFR and MDM2 inhibitors on ovarian carcinoma.

With the concept of precision medicine, combining multiple molecular-targeting therapies has brought new approaches to current cancer treatments. Malfunction of the tumor suppressor protein, p53 is a universal hallmark in human cancers. Under normal conditions, p53 is degraded through an ubiquitin-proteosome pathway regulated by its negative regulator, MDM2. In contrast, cellular stress such as DNA damage will activate p53 to carry out DNA repair, cell cycle arrest, and apoptosis. In this study, we focused on ovarian carcinoma with high EGFR and MDM2 overexpression rate. We assessed the effects of combined inhibition by MDM2 (JNJ-26854165) and EGFR (gefitinib) inhibitors on various ovarian cell lines to determine the importance of these two molecular targets on cell proliferation. We then used a proteomic strategy to investigate the relationship between MDM2 and EGFR inhibition to explore the underlying mechanisms of how their combined signaling blockades work together to exert cooperative inhibition. Our results demonstrated that all four cell lines were sensitive to both individual and combined, MDM2 and EGFR inhibition. The proteomic analysis also showed that gefitinib/JNJ-treated CAOV3 cells exhibited downregulation of proteins involved in nucleotide biosynthesis such as nucleoside diphosphate kinase B (NME2). In conclusion, our study showed that the combined treatment with JNJ and gefitinib exerted synergistic inhibition on cell proliferation, thereby suggesting the potential application of combining MDM2 inhibitors with EGFR inhibitors for enhancing efficacy in ovarian cancer treatment.

Bitter melon (Momordica charantia) attenuates atherosclerosis in apo-E knock-out mice possibly through reducing triglyceride and anti-inflammation.

BACKGROUND: Bitter melon (BM, Momordica charantia) has been accepted as an effective complementary treatment of metabolic disorders such as diabetes, hypertension, dyslipidemia and etc. However it is unclear whether BM can prevent the progression of atherosclerosis. To confirm the effects of BM on atherosclerosis and explore its underlying mechanisms, we design this study. METHODS: Twenty four male apolipoprotein E knock-out (ApoE-/-) mice aged 8 weeks were randomly divided into control group fed with high fat diet (HFD) only and BM group fed with HFD mixed with 1.2%w/w BM. After 16 weeks, body weight, food intake, blood glucose, serum lipids were measured and the atherosclerotic plaque area and its histological composition were analyzed. The expression of vascular cell adhesive molecules and inflammatory cytokines in the aortas were determined using quantitative polymerase chain reaction. RESULTS: Body weight gain and serum triglycerides (TG) significantly decreased in BM group. BM reduced not only the atherosclerotic plaque area and the contents of collagen fibers in atherosclerotic plaques but also the serum soluble vascular cell adhesion molecule (VCAM)-1 and P-selectin levels, as well as the expressions of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 in aortas. CONCLUSION: Our study indicates that dietary BM can attenuate the development of atherosclerosis in ApoeE-/- mice possibly through reducing triglyceride and anti-inflammation mechanism.

Proteomic Analysis of Various Rat Ocular Tissues after Ischemia-Reperfusion Injury and Possible Relevance to Acute Glaucoma.

Glaucoma is a group of eye diseases that can cause vision loss and optical nerve damage. To investigate the protein expression alterations in various intraocular tissues (i.e., the cornea, conjunctiva, uvea, retina, and sclera) during ischemia-reperfusion (IR) injury, this study performed a proteomic analysis to qualitatively investigate such alterations resulting from acute glaucoma. The IR injury model combined with the proteomic analysis approach of two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to monitor the protein expression alterations in two groups of specimens (an IR injury group and a control group). The analysis results revealed 221 unique differentially expressed proteins of a total of 1481 proteins in the cornea between the two groups. In addition, 97 of 1206 conjunctival proteins, 90 of 1354 uveal proteins, 61 of 1180 scleral proteins, and 37 of 1204 retinal proteins were differentially expressed. These findings imply that different ocular tissues have different tolerances against IR injury. To sum up, this study utilized the acute glaucoma model combined with 2D-DIGE and MALDI-TOF MS to investigate the IR injury affected protein expression on various ocular tissues, and based on the ratio of protein expression alterations, the alterations in the ocular tissues were in the following order: the cornea, conjunctiva, uvea, sclera, and retina.