Metabolomics of human umbilical vein endothelial cell-based analysis of the relationship between hyperuricemia and dyslipidemia.

BACKGROUND AND AIMS: Hyperuricemia frequently accompanies dyslipidemia, yet the precise mechanism remains elusive. Leveraging cellular metabolomics analyses, this research probes the potential mechanisms wherein hyperuricemia provokes endothelial cell abnormalities, inducing disordered bile metabolism and resultant lipid anomalies. METHODS AND RESULTS: We aimed to identify the differential metabolite associated with lipid metabolism through adopting metabolomics approach, and thereafter adequately validating its protective function on HUVECs by using diverse assays to measure cellular viability, reactive oxygen species, migration potential, apoptosis and gene and protein levels of inflammatory factors. Taurochenodeoxycholic acid (TCDCA) (the differential metabolite of HUVECs) and the TCDCA-involved primary bile acid synthesis pathway were found to be negatively correlated with high UA levels based on the results of metabolomics analysis. It was noted that compared to the outcomes observed in UA-treated HUVECs, TCDCA could protect against UA-induced cellular damage and oxidative stress, increase proliferation as well as migration, and decreases apoptosis. In addition, it was observed that TCDCA might protect HUVECs by inhibiting UA-induced p38 mitogen-activated protein kinase/nuclear factor kappa-B p65 (p38MAPK/NF-κB p65) pathway gene and protein levels, as well as the levels of downstream inflammatory factors. CONCLUSION: The pathogenesis of hyperuricemia accompanying dyslipidemia may involve high uric acid levels eliciting inflammatory reactions and cellular damage in human umbilical vein endothelial cells (HUVECs), mediated through the p38MAPK/NF-κB signaling pathway, subsequently impinging on cellular bile acid synthesis and reducing bile acid production.

Effect of continuous nursing combined with respiratory exercise nursing on pulmonary function of postoperative patients with lung cancer.

BACKGROUND: Lung cancer is a malignant tumor with high morbidity and mortality among cancers. Surgery is currently one of the primary methods of treating lung cancer. Although it can slow down the progression of the disease by removing the lesion, this invasive surgery inevitably damages the integrity of the patient's chest. Moreover, the patient's pulmonary function may have a low compensatory capacity after surgery, causing various respiratory diseases such as atelectasis, respiratory function decline, and even serious cardiovascular disease. All of these have great negative impacts on the surgical effect and the prognosis of patients. With the continuous exploration and development of nursing, continuous nursing and respiratory exercise nursing have been gradually applied in the nursing of patients after lung cancer surgery, and have achieved good nursing results. AIM: To investigate the effect of continuous nursing combined with respiratory exercise nursing on the pulmonary function of postoperative patients with lung cancer. METHODS: A total of 80 patients with lung cancer who underwent surgery in our hospital from January 2021 to December 2021 were selected as the study subjects. All subjects were randomly divided into the control group (n = 40 cases) and the experimental group (n = 40 cases). Patients with lung cancer in the control group were given conventional nursing after surgery, while the experimental group was given continuous nursing combined with respiratory exercise nursing based on conventional nursing. The recovery of pulmonary function and respiratory symptoms was observed before and after 3 mo of intervention in both groups. The pulmonary function parameters, blood gas analysis, MD Anderson Symptom Inventory-lung cancer module (MDASI-LC) scores, incidence of pulmonary complications, and Morisky compliance scores were compared between the two groups before and after 3 mo of intervention. RESULTS: There was no significant difference in pulmonary function and blood gas analysis between the two groups before intervention (P > 0.05). 3 mo after the intervention, the pulmonary function parameters in the experimental group (SpO2, VC, MVV, FEV1, FEV1% pred, and FEV1/FVC) were higher than those in the control group, and the differences were statistically significant (P < 0.05). There was no significant difference in blood gas analysis between the two groups before intervention (P > 0.05). PaO2 in the experimental group was significantly higher than that in the control group, and PaCO2 was significantly lower than that in the control group 3 mo after the intervention. The difference had statistical significance (P < 0.05). 3 mo after the intervention, the MDASI score of respiratory symptoms in the experimental group was significantly lower than that in the control group (P < 0.05), and the incidence of pulmonary complications was lower than that in the control group (P < 0.05). In addition, the treatment compliance and nursing satisfaction of patients in the experimental group were higher than those in the control group, and the differences were statistically significant (P < 0.05). CONCLUSION: Continuous nursing combined with respiratory exercise nursing can significantly accelerate the recovery of respiratory function in postoperative lung cancer patients, reduce the incidence of postoperative complications of lung cancer as well as improve the treatment compliance of patients.

First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors.

PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1-60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.

Nomogram Incorporating Contrast-Enhanced Ultrasonography Predicting Time to the Development of Castration-Resistant Prostate Cancer.

BACKGROUND: It is valuable to predict the time to the development of castration-resistant prostate cancer (CRPC) in patients with advanced prostate cancer (PCa). This study aimed to build and validate a nomogram incorporating the clinicopathologic characteristics and the parameters of contrast-enhanced ultrasonography (CEUS) to predict the time to CRPC after androgen deprivation therapy (ADT). METHODS: Patients with PCa were divided into the training (n = 183) and validation cohorts (n = 37) for nomogram construction and validation. The clinicopathologic characteristics and CEUS parameters were analyzed to determine the independent prognosis factors and serve as the basis of the nomogram to estimate the risk of 1-, 2-, and 3-year progress to CRPC. RESULTS: T stage, distant metastasis, Gleason score, area under the curve (AUC), prostate-specific antigen (PSA) nadir, and time to PSA nadir were the independent predictors of CRPC (all P < 0.05). Three nomograms were built to predict the time to CRPC. Owing to the inclusion of CEUS parameter, the discrimination of the established nomogram (C-index: 0.825 and 0.797 for training and validation datasets) was improved compared with the traditional prediction model (C-index: 0.825 and 0.797), and when it excluded posttreatment PSA, it still obtained an acceptable discrimination (C-index: 0.825 and 0.797). CONCLUSIONS: The established nomogram including regular prognostic indicators and CEUS obtained an improved accuracy for the prediction of the time to CRPC. It was also applicable for early prediction of CRPC when it excluded posttreatment PSA, which might be helpful for individualized diagnosis and treatment.

The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy.

BACKGROUND: A disintegrin and metalloproteinase 17 (ADAM17) is a transmembrane protein that is widely expressed in various tissues; it mediates the shedding of many membrane-bound molecules, involving cell-cell and cell-matrix interactions. We investigated the role of ADAM17 within mouse cardiac fibroblasts (mCFs) in heart fibrosis. METHODS: mCFs were isolated from the hearts of neonatal mice. Effects of ADAM17 on the differentiation of mCFs towards myofibroblasts and their fibrotic behaviors following induction with TGF-ß1 were examined. The expression levels of fibrotic proteins, such as collagen I and α-SMA, were assessed by qRT-PCR analysis and western blotting. Cell proliferation and migration were measured using the CCK-8 and wound healing assay. To identify the target gene for ADAM17, the protein levels of the components of endoplasmic reticulum (ER) stress and the PINK1/Parkin pathway were assessed following ADAM17 silencing. The effects of ADAM17 silencing or treatment with thapsigargin, a key stimulator of acute ER stress, on mCFs proliferation, migration, and collagen secretion were also examined. In vivo, we used a mouse model of cardiac fibrosis established by left anterior descending artery ligation; the mice were administered oral gavage with a selective ADAM17 inhibitor (TMI-005) for 4 weeks after the operation. RESULTS: We found that the ADAM17 expression levels were higher in fibrosis heart tissues and TGF-ß1-treated mCFs. The ADAM17-specific siRNAs decreased TGF-ß1-induced increase in the collagen secretion, proliferation, and migration of mCFs. Knockdown of ADAM17 reduces the activation of mCFs by inhibiting the ATF6 branch of ER stress and further activating mitophagy. Moreover, decreased ADAM17 expression also ameliorated cardiac fibrosis and improved heart function. CONCLUSIONS: This study highlights that mCF ADAM17 expression plays a key role in cardiac fibrosis by regulating ER stress and mitophagy, thereby limiting fibrosis and improving heart function. Therefore, ADAM17 downregulation, within the physiological range, could exert protective effects against cardiac fibrosis.

Ultrasound-visualized, site-specific vascular embolization using magnetic protein microcapsules.

Imaging-guided vascular embolization is frequently performed on patients with advanced hepatocellular carcinoma (HCC) to alleviate symptoms and extend their survival time. Current operation procedures are not only painful for patients, but are also inaccurate in tumor targeting after the release of embolic agents from the catheter, leading to injury to healthy tissues simultaneously. In this study, we developed an ultrasound-visualized, site-specific vascular embolization strategy with magnetic protein microcapsules (MPMs). MPMs were fabricated using a rapid emulsification method, giving it a smooth surface and a core-shell structure. Their diameters could be controlled within 10 µm, allowing them to pass through capillaries. The core-shell structure and loading of magnetic Fe3O4 endowed MPMs with good contrast under ultrasound imaging and magnetically inducible targeting properties, as well as aggregation response even under flowing conditions. In vitro cytotoxicity and hemolysis evaluation demonstrated good biocompatibility of the MPMs. Furthermore, mock embolization showed that cell death could be induced by aggregation of the MPMs. Such a combination of real-time monitoring using ultrasound and control on targeted vascular embolization might be a breakthrough in the treatment of advanced HCC.

The "Sweet Spot" Revisited: Optimal Recall Rates for Cancer Detection With 2D and 3D Digital Screening Mammography in the Metro Chicago Breast Cancer Registry.

OBJECTIVE. One central question pertaining to mammography quality relates to discerning the optimal recall rate to maximize cancer detection while minimizing unnecessary downstream diagnostic imaging and breast biopsies. We examined the trade-offs for higher recall rates in terms of biopsy recommendations and cancer detection in a single large health care organization. MATERIALS AND METHODS. We included 2D analog, 2D digital, and 3D digital (tomosynthesis) screening mammography examinations among women 40-79 years old performed between January 1, 2005, and December 31, 2017, with cancer follow-up through 2018. There were 36, 67, and 38 radiologists who read at least 1000 2D analog examinations, 2D digital examinations, and 3D tomosynthesis examinations, respectively, who were included in these analyses. Using logistic regression with marginal standardization, we estimated radiologist-specific mean recall (abnormal interpretations/1000 mammograms), biopsy recommendation, cancer detection (screening-detected in situ and invasive cancers/1000 mammograms), and minimally invasive cancer detection rates while adjusting for differences in patient characteristics. RESULTS. Among 1,060,655 screening mammograms, the mean recall rate was 10.7%, the cancer detection rate was 4.0/1000 mammograms, and the biopsy recommendation rate was 1.60%. Recall rates between 7% and 9% appeared to maximize cancer detection while minimizing unnecessary biopsies. CONCLUSION. The results of this investigation are in contrast to those of a recent study suggesting appropriateness of higher recall rates. The "sweet spot" for optimal cancer detection appears to be in the recall rate range of 7-9% for both 2D digital mammography and 3D tomosynthesis. Too many women are being called back for diagnostic imaging, and new benchmarks could be set to reduce this burden.

Left atrial appendage perforation with Watchman device implantation: Strategies for surgical repair.

Percutaneous occlusion of the left atrial appendage is increasingly being used as an alternative for stroke prevention in patients with non-valvular atrial fibrillation at high risk of complications from long term anticoagulation. We describe a case of left atrial appendage perforation during Watchman device implantation requiring emergency repair of the left atrium using sternotomy and cardiopulmonary bypass. Technical considerations for surgical decision making are discussed; in hemodynamically unstable patients as well as those at high risk for embolization.

The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway.

BACKGROUND AND AIMS: We examined whether the inflammation resolution mediator lipoxin A4 (LXA4) inhibits foam cell formation and oxidized low-density lipoprotein (oxLDL)-induced apoptotic signaling in macrophages and the role of circulating/local LXA4 biosynthesis in atherogenesis. METHODS: LXA4 levels were measured by enzyme-linked immunosorbent assay. Dil-oxLDL and Dil-acLDL binding to and uptake by macrophages were evaluated by flow cytometry. Apoptosis was evaluated by TUNEL and Annexin V/PI assays. RESULTS: Circulating LXA4 levels in patients with coronary artery disease were much higher than those in respective controls. Local LXA4 levels were much lower in rabbit atherosclerotic vessel walls. Interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) were elevated in atherosclerotic vessels. After the inflammatory stimulus (IFN-γ, TNF-α, and C-reactive protein), LXA4 synthesis decreased significantly in foam cells. LXA4 dose-dependently suppressed the expression of the cholesterol uptake genes CD36 and SR-A in macrophages, which was blocked by the LXA4 receptor antagonist BOC-2. LXA4 also inhibited oxLDL-induced CD36 upregulation, Dil-oxLDL uptake, and foam cell formation. Furthermore, LXA4 inhibited the oxLDL-activated c-Jun N-terminal kinase pathway and reduced oxLDL-induced macrophage apoptosis by inhibiting caspase-3 activation and restoring the mitochondrial membrane potential. CONCLUSIONS: We found that LXA4 inhibited foam cell formation, oxLDL-induced inflammation, and apoptotic signaling in macrophages. Insufficient levels of the anti-inflammatory pro-resolution molecule LXA4 were found in rabbit atherosclerotic arteries, which might contribute to preventing inflammation resolution during atherogenesis.

MicroRNA-143 Targets ATG2B to Inhibit Autophagy and Increase Inflammatory Responses in Crohn's Disease.

Background: Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including Crohn's disease (CD). Genetic analyses have found that microRNA (miRNA) levels are altered in the intestinal tissues of CD patients. Methods: The Sequencing Alternative Poly-Adenylation Sites (SAPAS) method was used to compare the 3' end of the total mRNA sequence of 3 surgical specimens of CD patients (including inflamed tissues and corresponding noninflamed tissues in each case). The levels of autophagy-related 2B (ATG2B), LC3, and miR-143 were compared between inflamed tissues and noninflamed tissues using immunoblot and quantitative reverse transcription polymerase chain reaction. Luciferase assays were used to verify the interactions between miR-143 and ATG2B. Autophagy was measured by immunoblot analyses of LC3 and transmission electron microscopy. Inflammatory cytokines and IκBα were analyzed to evaluate the effect of miR-143 on inflammatory response. Results: The tandem repeat 3'-UTR of ATG2B was longer in inflamed tissues than in corresponding noninflamed tissues and contained an miR-143 target site. miR-143 expression was elevated, whereas ATG2B and LC3-II were downregulated in inflamed tissues. The direct interaction between miR-143 and ATG2B was verified by a 3'-UTR dual-luciferase reporter assay. Constitutive expression of miR-143 or depletion of ATG2B in cultured intestinal epithelial cells inhibited autophagy, reduced IκBα levels, and increased inflammatory responses. Conclusions: miR-143 may induce bowel inflammation by regulating ATG2B and autophagy, suggesting that miR-143 might play a critical role in the development of CD. Therefore, miR-143 could be a promising novel target for gene therapy in CD patients.

Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway.

Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions, which is widely used for the treatment of various diseases, such as pancreatitis and sepsis. Although the therapeutic effects of UTI are reported to be associated with a variety of mechanisms, the signaling pathways mediating the anti-inflammatory action of UTI remain to be elucidated. In the present study we carried out a systematic study on the anti-inflammatory and anti-oxidative mechanisms of UTI and their relationships in LPS-treated RAW264.7 cells. Pretreatment with UTI (1000 and 5000 U/mL) dose-dependently decreased the mRNA levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, iNOS) and upregulated anti-inflammatory cytokines (IL-10 and TGF-ß1) in LPS-treated RAW264.7 cells. UTI pretreatment significantly inhibited the nuclear translocation of NF-κB by preventing the degradation of IκB-α. UTI pretreatment only markedly inhibited the phosphorylation of JNK at Thr183, but it did not affect the phosphorylation of JNK at Tyr185, ERK-1/2 and p38 MAPK; JNK was found to function upstream of the IκB-α/NF-κB signaling pathway. Furthermore, UTI pretreatment significantly suppressed LPS-induced ROS production by activating PI3K/Akt pathways and the nuclear translocation of Nrf2 via promotion of p62-associated Keap1 degradation. However, JNK was not involved in mediating the anti-oxidative stress effects of UTI. In summary, this study shows that UTI exerts both anti-inflammatory and anti-oxidative effects by targeting the JNK/NF-κB and PI3K/Akt/Nrf2 pathways.

The CD44s splice isoform is a central mediator for invadopodia activity.

The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh)RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis.

Tachycardia pacing induces myocardial neovascularization and mobilizes circulating endothelial progenitor cells partly via SDF-1 pathway in canines.

Neovascularization plays pivotal role in ischemic heart failure; however, it is unclear in non-ischemic heart failure. Non-ischemic heart failure was induced by chronic rapid right ventricular pacing at 200 beats/min, respectively, for 3 and 6 weeks in 12 dogs. Sham-operation was performed in another 6 dogs as control. Three-week tachycardia pacing could induce mild/moderate heart failure and 6-week pacing could induce severe heart failure. Pan-microvessel density (MVD) was assessed by CD31 and neovascularization density was assessed by CD105. Mean CD31-MVD and CD105-MVD were significantly increased after 3-week pacing. However, CD105-MVD was significantly decreased by 80 % in 6-week pacing group compared with 3-week pacing group, whereas CD31-MVD was only decreased slightly (15 %; P < 0.05). Myocardial proangiogenic factor stromal cell-derived factor 1 (SDF-1), hypoxia-inducible factors 1α (HIF-1α, a transcription factor which could regulate SDF-1 expression), serum SDF-1 levels and circulating EPC mobilization were greatly elevated after 3-week pacing but nearly returned to baseline level after 6-week pacing, which were in accordance with the changes of neovascularization levels assessed by CD105. Angiogenesis and migrating ability of EPCs were enhanced after stimulation of SDF-1, which could be abolished by pretreatment with SDF-1 receptor antagonist AMD3100. In addition, angiogenesis and migrating functions of EPCs were significantly enhanced by the serum from 3-week pacing dogs, but had much weaker response to the serum from 6-week pacing dogs. In conclusion, tachycardia pacing-induced non-ischemic heart failure, promoted myocardial neovascularization and mobilized circulating EPCs, which might be mediated partly through SDF-1 pathway.

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism.

Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear whether signaling pathways triggered by hypoxia contribute to radiation resistance. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1α), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1α in regulating tumor response to radiation, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1α. Deletion of HIF-1α sensitized primary sarcomas to radiation exposure in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1α, or in which HIF-1α was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1α can promote radiation resistance in a cell autonomous manner. In HIF-1α-intact and -deleted sarcoma cells, radiation-induced reactive oxygen species, DNA damage repair and activation of autophagy were similar. However, sarcoma cells lacking HIF-1α had impaired mitochondrial biogenesis and metabolic response after irradiation, which might contribute to radiation resistance. These results show that HIF-1α promotes radiation resistance in a cell autonomous manner.

The microRNA-23b/27b/24 cluster promotes breast cancer lung metastasis by targeting metastasis-suppressive gene prosaposin.

MicroRNAs (miRNAs) have been shown to function as key regulators of tumor progression and metastasis. Recent studies have indicated that the miRNAs comprising the miR-23b/27b/24 cluster might influence tumor metastasis, although the precise nature of this regulation remains unclear. Here, expression of the miR-23b/27b/24 cluster is found to correlate with metastatic potential in mouse and human breast cancer cell lines and is elevated in metastatic lung lesions in human breast cancer patients. Ectopic expression of the miRNAs in the weakly metastatic mouse 4TO7 mammary tumor cell line had no effect on proliferation or morphology of tumor cells in vitro but was found to increase lung metastasis in a mouse model of breast cancer metastasis. Furthermore, gene expression profiling analysis of miRNA overexpressing 4TO7 cells revealed the direct targeting of prosaposin (PSAP), which encodes a secreted protein found to be inversely correlated with metastatic progression in human breast cancer patients. Importantly, ectopic expression of PSAP was able to suppress the metastatic phenotype in highly metastatic 4T1 and MDA-MB-231 SCP28 cells, as well as in cells ectopically expressing miR-23b/27b/24. These findings support a metastasis-promoting function of the miR-23b/27b/24 cluster of miRNAs, which functions in part through the direct inhibition of PSAP.

Angiotensin II-derived reactive oxygen species promote angiogenesis in human late endothelial progenitor cells through heme oxygenase-1 via ERK1/2 and AKT/PI3K pathways.

Angiotensin II (Ang II), the main component of renin-angiotensin system, could mediate pathogenic angiogenesis in cardiovascular disorders. Late endothelial progenitor cells (EPCs) possess potent self-renewal and angiogenic potency superior to early EPCs, but few study focused on the cross-talk between Ang II and late EPCs. We observed that Ang II could increase reactive oxygen species (ROS) and promote capillary formation in late EPCs. Ang II-derived ROS could also upregulate heme oxygenase-1 (HO-1) expression, and treating late EPCs with HO-1 small interfering RNA or heme oxygenase inhibitor (HO inhibitor) could inhibit Ang II-induced tube formation and increase ROS level and apoptosis rate. In addition, PD98059 and LY294002 pretreatment attenuated Ang II-induced HO-1 expression. Accordingly, Ang II-derived ROS could promote angiogenesis in late EPCs by inducing HO-1 expression via ERK1/2 and AKT/PI3K pathways, and we believe HO-1 might be a promising intervention target in EPCs due to its potent proangiogenic, antioxidant, and antiapoptosis potentials.

Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.

UNLABELLED: Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. SIGNIFICANCE: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2.

[Composition analysis of volatile oil of Asarum heterotropoides var. mandshuricum extracted by three different methods].

OBJECTIVE: To study the differences of the constituents of the volatile oil from Asarum heterotropoides var. mandshuricum with three different extracted methods. METHODS: Volatile oil from Asarum heterotropoides var. mandshuricum was extracted by steam distillation, supercritical carbon dioxide extraction and supercritical carbon dioxide extraction followed by concentration under pressure to remove volatile components, respectivily. GC-MS was utilized to analyze the components of volatile oil. RESULTS: The volatile oil from Asarum heterotropoides var. mandshuricum extracted by steam distillation and supercritical carbon dioxide extraction method contained 36 ingredients, 16 of which were the same, but different in amount. 11 kinds of non-volatile components of the volatile oil from Asarum heterotropoides var. mandshuricum were identified as the main components with supercrtical carbon dioxide extraction followed by concentration under reduced pressure, which were mainly fats and oils. CONCLUSION: The common components and their relative contents of the volatile oil from Asarum heterotropoides var. mandshuricum are obtained and compared with different extraction methods. It's the first time to extract the volatile components in the volatile oil from Asarum heterotropoides var. mandshuricum by supercritical carbon dioxide extraction, which provides the basis for Chinese herbal medicinal ingredients and quality control of the Asarum to some extent.

An HMGA2-IGF2BP2 axis regulates myoblast proliferation and myogenesis.

A group of genes that are highly and specifically expressed in proliferating skeletal myoblasts during myogenesis was identified. Expression of one of these genes, Hmga2, increases coincident with satellite cell activation, and later its expression significantly declines correlating with fusion of myoblasts into myotubes. Hmga2 knockout mice exhibit impaired muscle development and reduced myoblast proliferation, while overexpression of HMGA2 promotes myoblast growth. This perturbation in proliferation can be explained by the finding that HMGA2 directly regulates the RNA-binding protein IGF2BP2. Add-back of IGF2BP2 rescues the phenotype. IGF2BP2 in turn binds to and controls the translation of a set of mRNAs, including c-myc, Sp1, and Igf1r. These data demonstrate that the HMGA2-IGF2BP2 axis functions as a key regulator of satellite cell activation and therefore skeletal muscle development.

[Significance of serum golgi protein 73 (GP73), alpha-fetoprotein (AFP) and lectin-reactive alpha-fetoprotein (AFP-L3) expresssion in primary hepatic carcinoma].

OBJECTIVE: To explore the alone and joint diagnostic value of serum golgi protein 73 (GP73), alpha-fetoprotein (AFP) and the percentage of lectin-reactive aipha-fetoprotein (AFP-L3) of primary hepatic carcinoma (PHC), and provide a novel method for diagnosis for PHC and screening for high-risk population. METHODS: ELISA was used to detect the serum level of GP73, AFP and AFP-L3% in 81 cases of PHC,176 cases chronic hepatitis and liver cirrhosis, 30 cases other tumber cancer and 40 cases of health people. RESULTS: The sensitivity of GP73, AFP and AFP-L3% in PHC is 77.78%, 62.69% and 51.85%, and the specificity is 84.55%, 86.99% and 96.34%, respectively. Joint detection could increase the sensitivity up to 88.89%. CONCLUSION: GP73 was a high sensitivity mark for dignosis of PHC, while AFP-L3% was a high specificity mark for dignosis of PHC. The joint detection could improve PHC diagnostic performance.