Publications by authors named "Hailing Yang"

64 Publications

Main pulmonary artery enlargement predicts 90-day readmissions in Chinese COPD patients.

J Thorac Dis 2021 Oct;13(10):5731-5740

Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Numerous studies have shown pulmonary artery enlargement when measured by chest computed tomography (CT) could predict a worse outcome in chronic obstructive pulmonary disease (COPD) patients. Herein, we studied the prognostic implication of main pulmonary artery diameter (MPAD) in Chinese COPD patients.

Methods: This is an observational case-control study. Patients with 90-day readmissions are case group and those without 90-day readmission are control group. The study comprised of 417 COPD patients who underwent chest CT in their initial admission due to acute exacerbation of COPD (AECOPD). We analyzed their clinical characteristics such as MPAD, arterial blood gas (ABG) results, other chest CT findings and comorbidities to identify the cause of readmission within 90 days.

Results: Median age of our study population is 75 years old, and 79.6% of them are male. The median MPAD is 2.8 cm and 80.6% were also diagnosed with community acquired pneumonia (CAP) in their first admission. The median MPAD in patients with 90-day readmission was 3.1 cm while patients without 90-day readmission had median MPAD of 2.8 cm. Through multivariate logistic regression analysis CAP (P=0.019, OR: 3.105, 95% CI: 1.203-8.019) and MPAD (P<0.001, OR: 2.898, 95% CI: 1.824-4.605) were statistically significant. In the second stage of analysis, subgroup of patients diagnosed with CAP and AECOPD (pAECOPD) were analyzed, MPAD remained statistically significant (P<0.001, OR: 3.490, 95% CI: 1.929-6.316) and receiver operative characteristic (ROC) curve for pAECOPD patients; area under the curve (AUC) was 0.704 (95% CI: 0.631-0.778) with a MPAD cut off value of 2.9 cm (sensitivity 72%, specificity 53%).

Conclusions: Enlarged MPAD and pAECOPD in initial admission are independent risk factors for 90-day readmission. In our pAECOPD patient population, MPAD >2.9 cm are at increased risk of 90-day readmission.
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http://dx.doi.org/10.21037/jtd-21-344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575810PMC
October 2021

Comprehensive Hospitals Nurses' Cognition on Palliative Care in Shandong Province, China: A Cross-Sectional Study.

Iran J Public Health 2021 Jul;50(7):1343-1351

Outpatient Department, Qilu Hospital of Shandong University, Jinan 250012, P.R. China.

Background: Palliative care is an essential part of medical practice, however, it has developed slowly in China. We aimed to analyze the current situations of the cognition on palliative care among the nurses in Shandong Province, China.

Methods: This was a cross sectional study. Investigation of 1050 nurses came from 5 third-class hospitals and 5 second-class hospitals in Shandong Province, China from Jul to Oct in 2018. The questionnaire included 4 parts: general information of the subject, the questionnaire of palliative nursing knowledge, attitude, and the behavior. Data were collected by the APP. Overall, after eliminating the invalid questionnaires, 1026 questionnaires were included in the final analyses. The software Stata 14.2 was used for all statistical analyses.

Results: The score of knowledge and attitude was low, the practice was higher. Multivariate analysis results: the significant independent variables of univariate analysis were included in the multivariate non-conditional logistic regression model for analysis. Some departments had statistical significance in knowledge multivariate Logistic regression analysis. The multivariate logistic regression analysis of practice was significant for physical health and religious beliefs. The statistical variables of the total score of cognition were gender, age of care, health status and religious beliefs.

Conclusion: Nursing knowledge is lacking and attitude remains to be improved as soon as possible. It is vital to improve the cognition of palliative care of nurses in Shandong general hospitals by developing relevant rules and regulations, strengthening the supervision of relevant ant departments, and enhancing training for nurses.
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http://dx.doi.org/10.18502/ijph.v50i7.6623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426764PMC
July 2021

Elevated thyroid-stimulating hormone levels are associated with poor sleep: a cross-sectional and longitudinal study.

Endocrine 2022 Jan 25;75(1):194-201. Epub 2021 Aug 25.

Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, 610041, Chengdu, China.

Purpose: Poor sleep accompanied by elevated TSH (thyroid stimulating hormone) levels is not uncommon since TSH secretion is controlled by the circadian rhythm. However, the relationship between poor sleep and TSH elevation is unclear; hence, we aimed to elucidate this relationship by conducting a cross-sectional and longitudinal study.

Methods: Participants with isolated elevated (N = 168) and normal (N = 119) TSH concentrations were recruited, and the Pittsburgh Sleep Quality Index (PSQI) was used to assess the sleep status. Subjects with an isolated TSH elevation were followed up longitudinally. The serum TSH concentration was remeasured after sleep status improved.

Results: The proportions of poor sleep and occasional poor sleep in subjects with isolated TSH elevation were significantly higher than those with normal TSH levels (70.24% vs. 49.58%, p = 0.001; 9.52% vs. 1.68%, p = 0.006). Subjects with isolated TSH elevation had significantly higher PSQI scores in the subjective sleep quality, sleep latency, sleep duration, and habitual sleep efficiency dimensions than those with normal TSH levels (all p < 0.05). Poor sleep was significantly associated with isolated TSH elevation in the multiple logistic regression analysis [odds ratio (OR) = 2.396, p = 0.001]. Among subjects with an isolated TSH elevation at baseline, the percentage of TSH normalization was significantly higher in those who slept better than in those who still slept poorly (85.42% vs. 6.45%, p < 0.001).

Conclusions: This study revealed that isolated elevated TSH concentrations normalize when the sleep status is improved; hence, we recommend that clinicians thoroughly assess the sleep status of patients and remeasure TSH concentrations after sleep status improves.
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http://dx.doi.org/10.1007/s12020-021-02849-0DOI Listing
January 2022

Directed evolution of cyclic peptides for inhibition of autophagy.

Chem Sci 2021 Jan 13;12(10):3526-3543. Epub 2021 Jan 13.

Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center USA

In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Unfortunately, chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B-two essential components of the autophagosome maturation machinery-with mid-nanomolar affinities and disrupted protein-protein interactions (PPIs) between LC3 and its binding partners . The most promising LC3-binding SUPR peptide accessed the cytosol at low micromolar concentrations as measured by chloroalkane penetration assay (CAPA) and inhibited starvation-mediated GFP-LC3 puncta formation in a concentration-dependent manner. LC3-binding SUPR peptides re-sensitized platinum-resistant ovarian cancer cells to cisplatin treatment and triggered accumulation of the adapter protein p62 suggesting decreased autophagic flux through successful disruption of LC3 PPIs in cell culture. In mouse models of metastatic ovarian cancer, treatment with LC3-binding SUPR peptides and carboplatin resulted in almost complete inhibition of tumor growth after four weeks of treatment. These results indicate that SUPR peptide mRNA display can be used to develop cell-penetrating macrocyclic peptides that target and disrupt the autophagic machinery and .
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http://dx.doi.org/10.1039/d0sc03603jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179393PMC
January 2021

CpG oligodeoxynucleotides attenuate RORγt-mediated Th17 response by restoring histone deacetylase-2 in cigarette smoke-exposure asthma.

Cell Biosci 2021 May 20;11(1):92. Epub 2021 May 20.

Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-Sen University, Guangzhou, People's Republic of China.

Background: Cigarette smoke (CS) exposure increases corticosteroid insensitive asthma related to increased Th17 phenotype, and new treatment strategies are needed for CS-associated asthma. Histone deacetylase 2 (HDAC2), found in the airway epithelium, is critical for ameliorating glucocorticoids insensitivity. We recently demonstrated the anti-inflammatory effects of CpG oligodeoxynucleotides (CpG-ODNs) on CS-exposure asthma. However, the effects of CpG-ODNs on HDAC2 expression and enzymatic activity remain unclear. This study aimed to assess whether CpG-ODNs protect against excessive Th17 immune responses in CS-induced asthma through HDAC2-dependent mechanisms and compared their effects with those of corticosteroids.

Methods: The effects of CpG-ODNs alone and in combination with budesonide (BUD) on airway inflammation and Th2/Th17-related airway immune responses were determined using an in vivo model of CS-induced asthma and in cultured bronchial epithelial (HBE) cells administered ovalbumin (OVA) and/or cigarette smoke extract (CSE). HDAC2 and retinoid-related orphan nuclear receptor γt (RORγt) expression were also assessed in mouse lung specimens and HBE cells.

Results: CpG-ODNs and BUD synergistically attenuated CS exposure asthmatic responses in vivo by modulating the influx of eosinophils and neutrophils, airway remodeling, Th2/Th17 associated cytokine and chemokine production, and airway hyperresponsiveness and blocking RORγt-mediated Th17 inflammation through induced HDAC2 expression/activity. In vitro, CpG-ODNs synergized with BUD to inhibit Th17 cytokine production in OVA- and CSE-challenged HBE cells while suppressing RORγt and increasing epithelial HDAC2 expression/activity.

Conclusions: CpG-ODNs reversed CS-induced HDAC2 downregulation and enhanced the sensitivity of CS-exposed asthmatic mice and CSE-induced HBE cells to glucocorticoid treatment. This effect may be associated with HDAC2 restoration via RORγt/IL-17 pathway regulation, suggesting that CpG-ODNs are potential corticosteroid-sparing agents for use in CS-induced asthma with Th17-biased immune conditions.
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http://dx.doi.org/10.1186/s13578-021-00607-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139164PMC
May 2021

Clinical diagnostic value of combined detection of IMA, D-D and MCP-1 in acute myocardial infarction.

Exp Ther Med 2021 May 2;21(5):457. Epub 2021 Mar 2.

Department of Emergency, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.

The aim of the study was to analyze the clinical value of the combined detection of ischemia-modified albumin (IMA), D-dimer (D-D) and monocyte chemoattractant protein-1 (MCP-1) in the diagnosis of acute myocardial infarction (AMI). Altogether 87 patients with AMI from January 2017 to January 2018 were enrolled in the AMI group, and 82 patients without coronary artery disease were included in the control group. The serum levels of IMA, D-D, MCP-1, cardiac troponin (CTnT) and high-sensitivity C-reactive protein (hs-CRP) in the two groups were detected by ELISA. The blood lipids of the two groups and the levels of IMA, D-D, MCP-1 after treatment were detected. The association between IMA, D-D, MCP-1, CTnT, hs-CRP and blood lipid in patients with AMI was analyzed. The values of IMA, D-D, and MCP-1 alone and combined in the diagnosis of AMI were analyzed by ROC curve. The levels of IMA, D-D, MCP-1, CTnT and hs-CRP in the AMI group were significantly higher than those in the control group (P<0.05). The levels of IMA, D-D and MCP-1 in the patients with poor prognosis were significantly higher than those of the good prognosis group (P<0.05). The changes of IMA, D-D and MCP-1 levels were positively correlated with the levels of CTT and hs-CRP (P<0.05). The AUC, specificity and sensitivity of patients with AMI diagnosed with MCP-1 alone were 0.8084, 81.61 and 69.51%, respectively. Those of patients diagnosed by D-D were 0.7302, 59.77 and 81.71%, those of patients diagnosed by IMA alone were 0.7289, 58.62 and 80.49%, and those of patients detected by the combination of MCP-1, D-D and IMA were 0.9047, 58.62 and 93.90%. In conclusion, the levels of IMA, D-D and MCP-1 in AMI patients are higher than those in the control group. The levels of IMA, D-D and MCP-1 were positively correlated with CTnT and hs-CRP levels in AMI patients. Combined detection of IMA, D-D, and MCP-1 can improve the accuracy.
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http://dx.doi.org/10.3892/etm.2021.9888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967864PMC
May 2021

Severe acute respiratory syndrome coronavirus 2 for physicians: Molecular characteristics and host immunity (Review).

Mol Med Rep 2021 04 12;23(4). Epub 2021 Feb 12.

Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China.

Recently, severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS‑CoV‑2)‑causing CoV disease 2019 (COVID‑19) emerged in China and has become a global pandemic. SARS‑CoV‑2 is a novel CoV originating from β‑CoVs. Major distinctions in the gene sequences between SARS‑CoV and SARS‑CoV‑2 include the spike gene, open reading frame (ORF) 3b and ORF 8. SARS‑CoV‑2 infection is initiated when the virus interacts with angiotensin‑converting enzyme 2 (ACE2) receptors on host cells. Through this mechanism, the virus infects the alveolar, esophageal epithelial, ileum, colon and other cells on which ACE2 is highly expressed, causing damage to target organs. To date, host innate immunity may be the only identified direct factor associated with viral replication. However, increased ACE2 expression may upregulate the viral load indirectly by increasing the baseline level of infectious virus particles. The peak viral load of SARS‑CoV‑2 is estimated to occur ~10 days following fever onset, causing patients in the acute stage to be the primary infection source. However, patients in the recovery stage or with occult infections can also be contagious. The host immune response in patients with COVID‑19 remains to be elucidated. By studying other SARS and Middle East respiratory syndrome coronaviruses, it is hypothesized that patients with COVID‑19 may lack sufficient antiviral T‑cell responses, which consequently present with innate immune response disorders. This may to a certain degree explain why this type of CoV triggers severe inflammatory responses and immune damage and its associated complications.
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http://dx.doi.org/10.3892/mmr.2021.11901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893688PMC
April 2021

Overexpression of Promotes Growth and Causes Leaf Wrinkle and Branch Appearance in .

Int J Mol Sci 2021 Jan 28;22(3). Epub 2021 Jan 28.

College of Biological Sciences and Biotechnology, Beijing Forestry University, Beijing 100083, China.

D-type cyclin (cyclin D, CYCD), combined with cyclin-dependent kinases (CDKs), participates in the regulation of cell cycle G1/S transition and plays an important role in cell division and proliferation. CYCD could affect the growth and development of herbaceous plants, such as , by regulating the cell cycle process. However, its research in wood plants (e.g., poplar) is poor. Phylogenetic analysis showed that in , genes expanded to six members, namely . genes were amplified based on the CDS region of genes. showed the highest expression in the shoot tip, and the higher expression in young leaves among all members. Therefore, this gene was selected for further study. The overexpression of in plants demonstrated obvious morphological changes during the observation period. The leaves became enlarged and wrinkled, the stems thickened and elongated, and multiple branches were formed by the plants. Anatomical study showed that in addition to promoting the differentiation of cambium tissues and the expansion of stem vessel cells, facilitated the division of leaf adaxial epidermal cells and palisade tissue cells. Yeast two-hybrid experiment exhibited that 12 PtoCDK proteins could interact with PtoCYCD3;3, of which the strongest interaction strength was PtoCDKE;2, whereas the weakest was PtoCDKG;3. Molecular docking experiments further verified the force strength of PtoCDKE;2 and PtoCDKG;3 with PtoCYCD3;3. In summary, these results indicated that the overexpression of significantly promoted the vegetative growth of , and PtoCYCD3;3 may interact with different types of CDK proteins to regulate cell cycle processes.
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http://dx.doi.org/10.3390/ijms22031288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866192PMC
January 2021

A Novel Salt Inducible Kinase 2 Inhibitor, ARN-3261, Sensitizes Ovarian Cancer Cell Lines and Xenografts to Carboplatin.

Cancers (Basel) 2021 Jan 25;13(3). Epub 2021 Jan 25.

Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.

Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of class IIa HDACs, affecting gene expression. Previously, we found that inhibition of SIK2 enhanced sensitivity of ovarian cancer cells to paclitaxel. Carboplatin and paclitaxel constitute first-line therapy for most patients with ovarian carcinoma, producing a 70% clinical response rate, but curing <20% of patients with advanced disease. We have asked whether inhibition of SIK2 with ARN-3261 enhances sensitivity to carboplatin in ovarian cancer cell lines and xenograft models. ARN-3261-induced DNA damage and apoptosis were measured with γ-H2AX accumulation, comet assays, and annexin V. ARN-3261 inhibited growth of eight ovarian cancer cell lines at an IC50 of 0.8 to 3.5 µM. ARN-3261 significantly enhanced sensitivity to carboplatin in seven of eight ovarian cancer cell lines and a carboplatin-resistant cell line tested. Furthermore, ARN-3261 in combination with carboplatin produced greater inhibition of tumor growth than carboplatin alone in SKOv3 and OVCAR8 ovarian cancer xenograft models. ARN-3261 enhanced DNA damage and apoptosis by downregulating expression of survivin. Thus, a SIK2 kinase inhibitor enhanced carboplatin-induced therapy in preclinical models of ovarian cancer and deserves further evaluation in clinical trials.
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http://dx.doi.org/10.3390/cancers13030446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865895PMC
January 2021

A possible underlying mechanism behind the cardioprotective efficacy of tangeretin on isoproterenol triggered cardiotoxicity via modulating PI3K/Akt signaling pathway in a rat model.

J Food Biochem 2020 09 9;44(9):e13368. Epub 2020 Jul 9.

Department of Cardiology, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, Jilin Provincial Cardiovascular Research Institute, Changchun, China.

This study was aimed to examine the possible underlying cardioprotective efficacy of tangeretin (TAN) in rats exposed to isoproterenol (ISP). Forty male SD rats were separated into four equal groups as the control group, ISP (myocardial infarction; MI group) group rats which were injected intraperitoneally (ip) with 85 mg/kg of ISP. Treatment TAN groups (TAN 50 and TAN 100) rats were orally pretreated with TAN (50 or 100 mg/kg) for 28 days before ISP exposure. Pretreatment with TAN (50/100) significantly reduced (p < .05/0.01) the infarct size, levels of inflammatory markers, cardiac marker enzymes, apoptotic markers along with improved antioxidants. Histo-morphological results also well-supported the results of the above biochemical parameters by displaying normal myofibrillar arrangement in TAN pretreated rats. Moreover, the protein expressions of pPI3K and pAkt were considerably elevated in rats administered with TAN. Collectively, TAN pretreatment (especially TAN 100) display better cardioprotective activity against ISP-induced MI rats. PRACTICAL APPLICATIONS: Tangeretin (TAN) has been reported to exhibit an array of biological functions including cardioprotective, hepatoprotective, and renoprotective activities. However, the in-depth mechanism is still lacking, which results in this study. Our results indicate that TAN could effectively reduce cardiac infarct size, inflammatory markers, oxidative stress, apoptotic markers, by modulating (upregulating) the protein expressions of the PI3K/Akt signaling pathway. Thus, demonstrating that TAN could be a strong contender for developing a cardioprotective agent and can recommend along with conventional cardioprotective drugs for abolishing MI-related complications/symptoms. Nevertheless, further human studies are needed to confirm the above suggestion.
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http://dx.doi.org/10.1111/jfbc.13368DOI Listing
September 2020

A novel role of the miR-152-3p/ERRFI1/STAT3 pathway modulates the apoptosis and inflammatory response after acute kidney injury.

J Biochem Mol Toxicol 2020 Jun 25:e22540. Epub 2020 Jun 25.

Emergency Department, The Third Hospital of Jilin University, Changchun, Jilin, China.

Acute kidney injury (AKI) is one of the most common and serious complications in the development of sepsis. Many microRNAs are closely related to the occurrence, development, and prognosis of sepsis AKI (but the effect and mechanism of miR-152-3p in it is unclear). Meanwhile, the ERBB receptor feedback inhibitor 1 (ERRFI1) has a negative regulatory effect on signal transducer and activator of transcription 3 (STAT3) phosphorylation on uterine epithelial cells. But, the relationship between miR-152-3p and renal function, inflammatory factors, prognosis in AKI, and the mechanism is not clear. Analyzing sepsis-induced AKI rats and the cell model, our results revealed that miR-152-3p was upregulated in septic AKI patients and positively correlated with serum creatinine, urea nitrogen, interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). Downregulation of miR-152-3p with the inhibitor could dramatically attenuate caspase-3, bromodeoxyuridine and IL-1β, and TNF-α in the AKI rats' model. Furthermore, downregulation of miR-152-3p attenuated lipopolysaccharide-induced apoptosis and inflammatory response in HK-2 and HEK293 cells. To further explore the mechanisms, we found ERRFI1 was appreciably downregulated and STAT3 was upregulated in AKI, whereas ERRFI1 was radically upregulated and STAT3 was greatly downregulated after the addition of miR-152-3p inhibitor, no matter in vivo or in vitro. Summarily, our study confirmed that miR-152-3p could promote the expression of STAT3 by targeting ERRFI1, aggravate cell apoptosis and inflammatory response, and thereby aggravate kidney injury in sepsis AKI.
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http://dx.doi.org/10.1002/jbt.22540DOI Listing
June 2020

Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.

Cancer 2020 08 2;126(15):3579-3592. Epub 2020 Jun 2.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease.

Methods: By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2.

Results: Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling.

Conclusions: Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.
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http://dx.doi.org/10.1002/cncr.32985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384209PMC
August 2020

The multiple organs insult and compensation mechanism in mice exposed to hypobaric hypoxia.

Cell Stress Chaperones 2020 09 19;25(5):779-791. Epub 2020 May 19.

School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.

This study was first and systematically conducted to evaluate the hypoxia response of the brain, heart, lung, liver, and kidney of mice exposed to an animal hypobaric chamber. First, we examined the pathological damage of the above tissues by Hematoxylin & eosin (H&E) staining. Secondly, biochemical assays were used to detect oxidative stress indicators such as superoxide dismutase (SOD), malondialdehyde (MDA), reduced glutathione (GSH), and oxidized glutathione (GSSG). Finally, the hypoxia compensation mechanism of tissues was evaluated by expression levels of hypoxia-inducible factor 1 alpha (HIF-1α), erythropoietin (EPO), and vascular endothelial growth factor (VEGF). During the experiment, the mice lost weight gradually on the first 3 days, and then, the weight loss tended to remain stable, and feed consumption showed the inverse trend. H&E staining results showed that there were sparse and atrophic neurons and dissolved chromatin in the hypoxia group. And hyperemia occurred in the myocardium, lung, liver, and kidney. Meanwhile, hypoxia stimulated the enlargement of myocardial space, the infiltration of inflammatory cells in lung tissue, the swelling of epithelial cells in hepatic lobules and renal tubules, and the separation of basal cells. Moreover, hypoxia markedly inhibited the activity of SOD and GSH and exacerbated the levels of MDA and GSSG in the serum and five organs. In addition, hypoxia induced the expression of HIF-1α, EPO, and VEGF in five organs. These results suggest hypoxia leads to oxidative damage and compensation mechanism of the brain, heart, lung, liver, and kidney in varying degrees of mice.
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http://dx.doi.org/10.1007/s12192-020-01117-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479670PMC
September 2020

LNCRNA OIP5-AS1 regulates oxidative low-density lipoprotein-mediated endothelial cell injury via miR-320a/LOX1 axis.

Mol Cell Biochem 2020 Apr 18;467(1-2):15-25. Epub 2020 Feb 18.

Intensive Care Unit of Emergency Department, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, Jilin, China.

An increasing amount of research showed that endothelial cells (ECs) play crucial role in vascular disorders such as atherosclerosis (AS). LncRNA OIP5-AS1 and microRNA-320a (miR-320a) were reported to exert function in ECs. The purpose of this research was to investigate the functional mechanism of OIP5-AS1 and miR-320a in ox-LDL-treated HUVECs. The RNA levels of OIP5-AS1, miR-320a, and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of LOX1 and cell apoptosis-related genes were determined by Western blot assay. In addition, Cell Counting Kit-8 (CCK-8) and flow cytometry analysis were used to assess cell viability and apoptosis, respectively. Lactate dehydrogenase (LDH) activity was measured using LDH release assay. Besides, the interaction between miR-320a and OIP5-AS1 or LOX1 was predicted by starbase and verified by the dual-luciferase reporter assay. OIP5-AS1 expression was increased and miR-320a expression was decreased in oxidative low-density lipoprotein (ox-LDL)-treated HUVECs. OIP5-AS1 knockdown upregulated ox-LDL-treated HUVECs viability and suppressed apoptosis as well as LDH release. Interestingly, OIP5-AS1 elevated LOX1 level through downregulating miR-320a expression. As expected, miR-320a modulated LOX1 expression to mediate ox-LDL-treated HUVECs progression. Furthermore, OIP5-AS1 knockdown modulated cell progression via regulating miR-320a/LOX1 axis in ox-LDL-treated HUVECs. Our results demonstrated that the depletion of OIP5-AS1 enhanced cell viability and repressed apoptosis as well as LDH release in ox-LDL-treated HUVECs, providing potential target for the treatment of AS.
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http://dx.doi.org/10.1007/s11010-020-03688-9DOI Listing
April 2020

Brassica rapa Polysaccharides Ameliorate CCl -Induced Acute Liver Injury in Mice through Inhibiting Inflammatory Apoptotic Response and Oxidative Stress.

Chem Biodivers 2020 Jan 20;17(1):e1900534. Epub 2019 Dec 20.

School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China.

Brassica rapa L., also called NIUMA, is used empirically in Tibetan medicine for its antioxidant, anti-inflammatory and antiradiation activities. This study explored the hepatoprotective effects of B. rapa polysaccharides (BRPs) on acute liver injury induced by carbon tetrachloride (CCl ) in mice and the underlying mechanisms. Mice were treated with CCl after the oral administration of BRPs (55, 110 and 220 mg/kg) or bifendate (100 mg/kg) for 7 days. Blood and liver samples of mice were collected for analysis after 24 h. The ALP, ALT and AST levels and the biological activities of SOD, MDA and GSH-Px were measured. Histopathological changes in the liver were determined through hematoxylin and eosin staining. Moreover, TNF-α, IL-1β and IL-6 expression levels were detected by commercial reagent kits. Finally, Western blot analysis was used to check the relative expression levels of caspase-3, p-JAK2 and p-STAT3. The BRP pre-treatment significantly decreased the enzymatic activities of ALT, ALP and AST in the serum, markedly increased the activities of SOD and GSH-Px in the liver and reduced the MDA concentration in the liver. BRPs alleviated hepatocyte injury and markedly inhibited the expression of TNF-α, IL-1β and IL-6, also downregulating the CCl -induced hepatic tissue expression of caspase-3. Furthermore, BRPs inhibited the JAK2/STAT3 signaling pathway in a dose-dependent manner in the liver. This study demonstrated that BRPs exert hepatoprotective effect against the CCl -induced liver injury via modulating the apoptotic and inflammatory responses and downregulating the JAK2/STAT3 signaling pathway. Therefore, B. rapa could be considered a hepatoprotective medicine.
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http://dx.doi.org/10.1002/cbdv.201900534DOI Listing
January 2020

Fast Prediction of Deterioration and Death Risk in Patients With Acute Exacerbation of Chronic Obstructive Pulmonary Disease Using Vital Signs and Admission History: Retrospective Cohort Study.

JMIR Med Inform 2019 Oct 21;7(4):e13085. Epub 2019 Oct 21.

Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Chronic obstructive pulmonary disease (COPD) has 2 courses with different options for medical treatment: the acute exacerbation phase and the stable phase. Stable patients can use the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to guide treatment strategies. However, GOLD could not classify and guide the treatment of acute exacerbation as acute exacerbation of COPD (AECOPD) is a complex process.

Objective: This paper aimed to propose a fast severity assessment and risk prediction approach in order to strengthen monitoring and medical interventions in advance.

Methods: The proposed method uses a classification and regression tree (CART) and had been validated using the AECOPD inpatient's medical history and first measured vital signs at admission that can be collected within minutes. We identified 552 inpatients with AECOPD from February 2011 to June 2018 retrospectively and used the classifier to predict the outcome and prognosis of this hospitalization.

Results: The overall accuracy of the proposed CART classifier was 76.2% (83/109 participants) with 95% CI 0.67-0.84. The precision, recall, and F-measure for the mild AECOPD were 76% (50/65 participants), 82% (50/61 participants), and 0.79, respectively, and those with severe AECOPD were 75% (33/44 participants), 68% (33/48 participants), and 0.72, respectively.

Conclusions: This fast prediction CART classifier for early exacerbation detection could trigger the initiation of timely treatment, thereby potentially reducing exacerbation severity and recovery time and improving the patients' health.
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http://dx.doi.org/10.2196/13085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913742PMC
October 2019

Tracking and analysis of DBP precursors' properties by fluorescence spectrometry of dissolved organic matter.

Chemosphere 2020 Jan 6;239:124790. Epub 2019 Sep 6.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, China. Electronic address:

Disinfection by-products (DBPs) play a significant role in human health. Identification of the precursor of DBPs, which constitutes dissolved organic matter (DOM), can help optimize the processes in a drinking water treatment plant (DWTP). This is very important for obtaining more safe water. In this context, a one-year study was performed in a DWTP. Fluorescence spectra of DOM were quantified for determining DOM composition and properties, and the corresponding DBPs formation was analyzed. Hydrophobic neutral and acidic compounds were found to be the two predominant substances forming DBPs, which also were dominant in the DOM. Coagulation and sedimentation were not effective in DOM elimination. Besides, sand filtration caused organic compounds to increase by 14.8% on average, especially 28.59% for aromatic protein II and 18.7% for soluble microbial product-like compounds, which was due to metabolism by microorganisms present in the filter. Carbonaceous DBPs were elevated from 34.8 μg/L in source water to 42.5 μg/L in effluent, along with organic compounds increasing in filtration, and nitrogenous DBPs were under detection in winter. All DBPs appeared at a high level in summer. Accordingly, enhanced coagulation process and measures that can avoid the release of organic compounds during filtration have been suggested. As the source water was rarely affected by human activities in the study area and owing to the wide use of traditional treatment process, the data of this research can be regarded as environmental background values and the results are considered as a significant reference.
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http://dx.doi.org/10.1016/j.chemosphere.2019.124790DOI Listing
January 2020

6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers.

Clin Cancer Res 2019 09 7;25(18):5702-5716. Epub 2019 Aug 7.

Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas.

Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 () depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of on tumor cell growth .

Results: Knockdown of inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type (wt). Silencing significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of si increased the glycolysis rate, but decreased the flow of intermediates through the pentose-phosphate pathway in cancer cells with wt, decreasing NADPH. ROS accumulated after knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma.

Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wt.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744996PMC
September 2019

Hyaluronic acid-functionalized bilosomes for targeted delivery of tripterine to inflamed area with enhancive therapy on arthritis.

Drug Deliv 2019 Dec;26(1):820-830

a School of Pharmacy, Chengdu University of Traditional Chinese Medicine , Chengdu , China.

Arthritis treatment has been challenging because of low drug exposure to the articular cavity. This study was intended to develop hyaluronic acid (HA)-functionalized bilosomes for targeted delivery of tripterine (Tri), an antiphlogistic phytomedicine, to the inflamed joint via ligand-receptor interaction. Tri-loaded bilosomes (Tri-BLs) with cationic lipid (DOTAP) were prepared by a thin film hydration method followed by HA coating to form [email protected] [email protected] were then characterized by particle size (), entrapment efficiency (), and structural morphology. The drug release, hemocompatibility test and cellular uptake were performed to examine the formulation performances of [email protected] The pharmacokinetics and antiarthritic efficacy were evaluated in arthritic models, respectively. The obtained [email protected] possessed a of 118.5 nm around with an of 99.56%. [email protected] exhibited excellent cellular uptake and targeted delivery efficiency for Tri, which resulted in elongation of circulatory residence time and enhancement of intra-arthritic bioavailability (799.9% relative to Tri solution). The antiarthritic efficacy of [email protected] was also significantly superior to uncoated Tri-BLs that gave rise to obvious inflammation resolution. Our findings suggest that HA-functionalized bilosomes are a promising vehicle for articular delivery of antiphlogistic drugs to potentiate their efficacy.
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http://dx.doi.org/10.1080/10717544.2019.1636423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713218PMC
December 2019

miRNA‑mRNA regulatory network analysis of mesenchymal stem cell treatment in cisplatin‑induced acute kidney injury identifies roles for miR‑210/Serpine1 and miR‑378/Fos in regulating inflammation.

Mol Med Rep 2019 Aug 13;20(2):1509-1522. Epub 2019 Jun 13.

Emergency Department, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130031, P.R. China.

The present study aimed to identify microRNAs (miRNAs) that may be crucial for the mechanism of mesenchymal stem cell (MSC) treatment in cisplatin‑induced acute kidney injury (AKI) and to investigate other potential drugs that may have a similar function. Transcriptomics (GSE85957) and miRNA expression (GSE66761) datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified using the linear models for microarray data method and mRNA targets of DEMs were predicted using the miRWalk2.0 database. The crucial DEGs were screened by constructing a protein‑protein interaction (PPI) network and module analysis. Functions of target genes were analyzed using the database for annotation, visualization and integrated discovery. Small molecule drugs were predicted using the connectivity map database. As a result, 5 DEMs were identified to be shared and oppositely expressed in comparisons between AKI model and control groups, and between MSC treatment and AKI model groups. The 103 DEGs were overlapped with the target genes of 5 common DEMs, and the resulting list was used for constructing the miRNA‑mRNA regulatory network, including rno‑miR‑210/Serpine1 and rno‑miR‑378/Fos. Serpine1 (degree=17) and Fos (degree=42) were predicted to be hub genes according to the topological characteristic of degree in the PPI network. Function analysis indicated Serpine1 and Fos may be inflammation‑related. Furthermore, gliclazide was suggested to be a potential drug for the treatment of AKI because the enrichment score was the closest to ‑1 (‑0.9). In conclusion, it can be speculated that gliclazide may have a similar mechanism to MSC as a potential therapeutic agent for cisplatin‑induced AKI, by regulating miR‑210/Serpine1 and miR‑378‑/Fos‑mediated inflammation and cell apoptosis.
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http://dx.doi.org/10.3892/mmr.2019.10383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625446PMC
August 2019

MiRNA-204-5p and oxaliplatin-loaded silica nanoparticles for enhanced tumor suppression effect in CD44-overexpressed colon adenocarcinoma.

Int J Pharm 2019 Jul 7;566:585-593. Epub 2019 Jun 7.

Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China. Electronic address:

Main purpose of present study was to enhance the therapeutic efficacy in the treatment of colon adenocarcinoma by combining the benefits of chemotherapy and gene therapy. In this study, we have successfully formulated oxaliplatin (OXL) and miRNA-204-5p loaded polyethyleneimine (PEI)/hyaluronic acid (HA)-assembled mesoporous silica nanoparticles (OXmi-HSMN). Our study, for the first time, proved that miRNA-204-5p can generate a synergistic anticancer effect with OXL with HMSN, and thus improve the effects of therapeutic efficacy in colon cancers. In vitro targeting studies showed that OXmi-HSMN exhibited higher uptake efficiency in CD44 receptor over-expressed HT-29 cells via CD44 receptor-mediated endocytosis. OXmi-HMSN exhibited a higher cell cytotoxicity compared to any other formulations indicating that internalization via CD44 receptor-mediated endocytosis increased the anticancer effect. The OXmi-HMSN showed significantly higher pre-apoptotic cells (43.9%) with significant apoptosis fractions (upper right quadrant - 20%) indicating the superior anticancer efficacy in terms of apoptosis inducing potentials. Importantly, OXmi-HMSN caused conspicuous inhibition of tumor growth and was significantly greater than that of either OXL or OXL-MSN (p < 0.0001). OXmi-HMSN showed 30% of TUNEL positive cells compared to 8% TUNEL positive cells for free OXL and 6% for free miRNA-204-5p treated group indicating the wide spread apoptosis of cells throughout the tissue section. Current study provides a delivery platform for dual therapeutics for enhanced therapeutic efficacy in the management of colon cancer.
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http://dx.doi.org/10.1016/j.ijpharm.2019.06.020DOI Listing
July 2019

Key Genes and Signaling Pathways Contribute to the Pathogensis of Diabetic Nephropathy.

Iran J Kidney Dis 2019 03;13(2):87-97

Department of Nephrology, China-Japan Union Hospital of Jilin University, No.126 Xiantai Street, Changchun, China.

Introduction: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus involving damage to the capillaries in the glomerulus. This study aimed to explore key genes and signaling pathways participate in the progression of DN.

Methods: Two gene expression profile datasets GSE1009 and GSE30528 downloaded from Gene Expression Omnibus (GEO) were used to analyze the differentially expressed genes (DEGs) between DN samples and controls. Coupled two-way clustering (CTWC) and correspondence analysis were performed to explore the potential functions of DEGs. Then, Gene Ontology (GO) terms and pathways associated with DEGs were identified, followed by constructing of the co-expressed gene network and module. Ultimately, the regulatory network based on the DEGs, miRNAs and transcription factors (TFs) was established.

Results: Total 283 common DEGs were identified from the two datasets, including 219 down-regulated ones (bone morphogenetic protein 7 (BMP7), decay accelerating factor (CD55) and coagulation Factor V (F5) etc.) and 64 up-regulated ones (inhibin beta c subunit (INHBC) and colony stimulating factor 1 receptor (CSF1R) etc.). The miRNA-TF regulatory network was established with three miRNAs, 8 TFs and 58 DEGs. Besides, three significant pathways including cytokine-cytokine receptor interaction, complement and coagulation cascades and TGF-beta signaling pathways were identified.

Conclusion: BMP7, CD55, CSF1R, INHBC and F5 are likely to take crucial roles in the pathogenesis of DN.
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March 2019

(3R)‑5,6,7‑trihydroxy‑3‑isopropyl‑3‑methylisochroman‑1‑one attenuates cardiac dysfunction via the apelin/APJ signaling pathway.

Mol Med Rep 2019 Jun 3;19(6):5007-5014. Epub 2019 Apr 3.

Department of Emergency, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.

Myocardial infarction (MI) is associated with a high risk of mortality and is a major global health concern. The present study aimed to investigate the protective effects of (3R)‑5,6,7‑trihydroxy‑3‑isopropyl‑3‑methylisochroman‑1‑one (TIM) against MI induced by isoproterenol (ISO) in a rat model and the underlying mechanisms. Wistar rats were assigned to 4 groups (n=10): The control group received saline treatment; the ISO group received an intraperitoneal injection of ISO (100 mg/kg); and the TIM (low) and TIM (high) groups received an intraperitoneal injection of ISO, plus a 1 and 2 mg/kg dose of TIM orally, respectively. TIM rats were treated with TIM daily for 12 days and received ISO injections on the final 2 days to induce MI. Cardiac function, apoptosis index and protein expression were subsequently determined. The levels of oxidative stress markers were determined by ELISAs, whereas DNA damage was detected using a Cell Death Detection ELISA kit. Gene and protein expression were determined via reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. Following treatment with ISO, the maximum left ventricular contraction/relaxation velocity and left ventricular systolic pressure were significantly decreased, whereas the left ventricular end‑diastolic pressure was increased; however, treatment with TIM significantly ameliorated ISO‑induced cardiac dysfunction. Additionally, TIM treatment significantly decreased oxidative stress and inhibited the apoptosis of cardiomyocytes, as determined by a decrease in caspase activities, increased expression of B‑cell lymphoma 2 (Bcl‑2) and reduced expression of cleaved caspase‑3, cleaved caspase‑9 and Bcl‑2‑associated X. Furthermore, treatment with TIM upregulated the levels of apelin in the plasma and myocardium of ISO‑treated rats. The results indicated that TIM protected cardiomyocytes against ISO‑induced MI, potentially via the apelin/apelin receptor signaling pathway. The results of the present study suggested that TIM may be a potential novel therapy for the treatment of MI.
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http://dx.doi.org/10.3892/mmr.2019.10122DOI Listing
June 2019

The role of vascular endothelial growth factor, interleukin 8, and insulinlike growth factor in sustaining autophagic DIRAS3-induced dormant ovarian cancer xenografts.

Cancer 2019 04 8;125(8):1267-1280. Epub 2019 Jan 8.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Re-expression of the imprinted tumor suppressor gene DIRAS family GTPase 3 (DIRAS3) (aplysia ras homology member I [ARHI]) induces autophagy and tumor dormancy in ovarian cancer xenografts, but drives autophagic cancer cell death in cell culture. The current study explored the tumor and host factors required to prevent autophagic cancer cell death in xenografts and the use of antibodies against those factors or their receptors to eliminate dormant autophagic ovarian cancer cells.

Methods: Survival factors (insulinlike growth factor 1 [IGF-1], vascular endothelial growth factor [VEGF], and interleukin 8 [IL-8]) were detected with growth factor arrays and measured using enzyme-linked immunoadsorbent assay analysis. Phosphorylation of protein kinase B (AKT), phosphorylation of extracellular signal-regulated kinase (ERK), nuclear localization of translocation factor EB (TFEB) or forkhead box O3a (FOXo3a), and expression of microtubule-associated proteins 1A/1B light chain 3B (MAPLC3B; LC3B) were examined using Western blot analysis. The effect of treatment with antibodies against survival factors or their receptors was studied using DIRAS3-induced dormant xenograft models.

Results: Ovarian cancer cells grown subcutaneously in nude mice exhibited higher levels of phosphorylated ERK/AKT activity and lower levels of nuclear TFEB/FOXo3a, MAPLC3B, and autophagy compared with cells grown in culture. Induction of autophagy and dormancy with DIRAS3 was associated with decreased ERK/AKT signaling. The addition of VEGF, IGF-1, and IL-8 weakened the inhibitory effect of DIRAS3 on ERK/AKT activity and reduced DIRAS3-mediated TFEB or FOXo3a nuclear localization and MAPLC3B expression in ovarian cancer cells. Treatment with antibodies against VEGF, IL-8, and IGF receptor inhibited the growth of dormant xenografts, thereby prolonging survival from 99 to >220 days (P < .05) and curing a percentage of mice.

Conclusions: Treatment with a combination of anti-VEGF, anti-IL-8, and anti-IGF receptor antibodies prevented the outgrowth of dormant cells and prolonged survival in a preclinical model.
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http://dx.doi.org/10.1002/cncr.31935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538072PMC
April 2019

Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT.

Bioconjug Chem 2018 09 31;29(9):3180-3195. Epub 2018 Aug 31.

School of Biomedical Informatics , The University of Texas Health Science Center at Houston , Houston , Texas 77030 , United States.

Quantitative imaging of apoptosis in vivo could enable real-time monitoring of acute cell death pathologies such as traumatic brain injury, as well as the efficacy and safety of cancer therapy. Here, we describe the development and validation of F-18-labeled caspase-3 substrates for PET/CT imaging of apoptosis. Preliminary studies identified the O-benzylthreonine-containing substrate 2MP-TbD-AFC as a highly caspase 3-selective and cell-permeable fluorescent reporter. This lead compound was converted into the radiotracer [F]-TBD, which was obtained at 10% decay-corrected yields with molar activities up to 149 GBq/μmol on an automated radiosynthesis platform. [F]-TBD accumulated in ovarian cancer cells in a caspase- and cisplatin-dependent fashion. PET imaging of a Jo2-induced hepatotoxicity model showed a significant increase in [F]-TBD signal in the livers of Jo2-treated mice compared to controls, driven through a reduction in hepatobiliary clearance. A chemical control tracer that could not be cleaved by caspase 3 showed no change in liver accumulation after induction of hepatocyte apoptosis. Our data demonstrate that [F]-TBD provides an immediate pharmacodynamic readout of liver apoptosis in mice by dynamic PET/CT and suggest that [F]-TBD could be used to interrogate apoptosis in other disease states.
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http://dx.doi.org/10.1021/acs.bioconjchem.8b00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467260PMC
September 2018

Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability.

Clin Cancer Res 2018 10 3;24(20):5072-5084. Epub 2018 Jul 3.

Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.

Most patients with ovarian cancer receive paclitaxel chemotherapy, but less than half respond. Pre-treatment microtubule stability correlates with paclitaxel response in ovarian cancer cell lines. Microtubule stability can be increased by depletion of individual kinases. As microtubule stability can be regulated by phosphorylation of microtubule-associated proteins (MAPs), we reasoned that depletion of pairs of kinases that regulate phosphorylation of MAPs could induce microtubule stabilization and paclitaxel sensitization. Fourteen kinases known to regulate paclitaxel sensitivity were depleted individually in 12 well-characterized ovarian cancer cell lines before measuring proliferation in the presence or absence of paclitaxel. Similar studies were performed by depleting all possible pairs of kinases in six ovarian cancer cell lines. Pairs that enhanced paclitaxel sensitivity across multiple cell lines were studied in depth in cell culture and in two xenograft models. Transfection of siRNA against 10 of the 14 kinases enhanced paclitaxel sensitivity in at least six of 12 cell lines. Dual knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity more than silencing single kinases. Sequential knockdown was superior to concurrent knockdown. Dual silencing of IKBKB/STK39 or EDN2/TBK1 stabilized microtubules by inhibiting phosphorylation of p38 and MAP4, inducing apoptosis and blocking cell cycle more effectively than silencing individual kinases. Knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity in two ovarian xenograft models. Sequential knockdown of dual kinases increased microtubule stability by decreasing p38-mediated phosphorylation of MAP4 and enhanced response to paclitaxel in ovarian cancer cell lines and xenografts, suggesting a strategy to improve primary therapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191368PMC
October 2018

Identification of Potential Molecular Mechanisms and Candidate Genes Involved in The Acute Phase of Myocardial Infarction.

Cell J 2018 Oct 15;20(3):435-442. Epub 2018 May 15.

Department of Emergency, China-Japan Union Hospital, Jilin University, Changchun, China.

Objective: This study used bioinformatics to determine genetic factors involved in progression of acute myocardial infarction (MI).

Materials And Methods: In this prospective study, gene expression profile GSE59867 was downloaded from the Gene Expression Omnibus database, which contained 46 normal samples obtained from stable coronary artery disease patients (n=46) who were without history of MI (control) and 390 samples from patients (n=111) who had evolving ST-segment elevation myocardial infarction (STEMI) as the MI group. These samples were divided into 4 groups based on time points. After identification of differentially expressed genes (DEGs), we conducted hierarchical clustering and functional enrichment analysis. Protein interaction and transcriptional regulation among DEGs were analysed.

Results: We observed 8 clusters of DEGs that had a peak or a minimum at the t=1 time point according to gene expression levels. Upregulated DEGs showed significant enrichment in the biological process, single-organism cellular process, response to stimulus and stress, and osteoclast differentiation and lysosome. Downregulated DEGs enriched in the T-cell receptor signalling pathway and natural killer cell mediated cytotoxicity. We identified multiple genes, including signal transducer and activator of transcription 3 (STAT3); LCK proto-oncogene, Src family tyrosine kinase (LCK); and FYN proto-oncogene, Src family tyrosine kinase (FYN) from the protein-protein interaction (PPI) network and/or the transcriptional regulatory network.

Conclusion: Cytokine-mediated inflammation, lysosome and osteoclast differentiation, and metabolism processes, as well as STAT3 may be involved in the acute phase of MI.
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http://dx.doi.org/10.22074/cellj.2018.5213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005004PMC
October 2018

Investigation of mechanisms of mesenchymal stem cells for treatment of diabetic nephropathy via construction of a miRNA-TF-mRNA network.

Ren Fail 2018 Nov 13;40(1):136-145. Epub 2018 Mar 13.

c Department of Nephrology , China-Japan Union Hospital of Jilin University , Changchun , China.

Background: Recent studies have reported that mesenchymal stem cells (MSCs) exert therapeutic effects on the treatment of diabetic nephropathy (DN), but the underlying mechanisms remain unclear.

Methods: A dataset GSE65561 was obtained from Gene Expression Omnibus (GEO) database, which contained four healthy control samples (group 1), four healthy controls samples co-cultured with MSCs (group 2), five DN samples (group 3) and five DN samples co-cultured with MSCs (group 4). The differentially expressed genes (DEGs) between group 3 vs. group 1 and group 4 vs. group 2 were constructed using Linear Models for Microarray (LIMMA) package package. Then, DAVID was used to analyze the functional enrichment of DEGs. Based on STRING database the protein-protein interaction (PPI) network was visualized by the Cytoscape plug-in CytoNCA. Besides, the hub miRNAs and transcription factors (TFs) regulating DEGs were predicted using Webgestalt.

Results: Totally, 303 up-regulated and 88 down-regulated DEGs were shared in group 3 vs. group 1 and group 4 vs. group 2. Besides, the up-regulated DEGs were mainly enriched in 'translation' and 'translational elongation', while the down-regulated genes were only enriched in 'protein kinase activity'. RPS27A and RPLP0 had a higher degree in the PPI network and they were regulated by EIF3M. In addition, ETF1 was predicted to be an important gene, which was regulated by miR-150, miR-134 and EIF2S1.

Conclusions: RPS27A, RPLP0 and ETF1 may be potential targets for MSCs on the treatment of DN. Highlights RPS27A and RPLP0 may be important genes in the treatment of MSCs for DN. TF EIF3M may play a key role in the treatment of MSCs for DN. MiR-150 and miR-134 may be essential microRNAs in the treatment of MSCs for DN.
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http://dx.doi.org/10.1080/0886022X.2017.1421556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014302PMC
November 2018

RAS-related GTPases DIRAS1 and DIRAS2 induce autophagic cancer cell death and are required for autophagy in murine ovarian cancer cells.

Autophagy 2018 21;14(4):637-653. Epub 2018 Mar 21.

a Department of Experimental Therapeutics , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.

Among the 3 GTPases in the DIRAS family, DIRAS3/ARHI is the best characterized. DIRAS3 is an imprinted tumor suppressor gene that encodes a 26-kDa GTPase that shares 60% homology to RAS and RAP. DIRAS3 is downregulated in many tumor types, including ovarian cancer, where re-expression inhibits cancer cell growth, reduces motility, promotes tumor dormancy and induces macroautophagy/autophagy. Previously, we demonstrated that DIRAS3 is required for autophagy in human cells. Diras3 has been lost from the mouse genome during evolutionary re-arrangement, but murine cells can still undergo autophagy. We have tested whether DIRAS1 and DIRAS2, which are homologs found in both human and murine cells, could serve as surrogates to DIRAS3 in the murine genome affecting autophagy and cancer cell growth. Similar to DIRAS3, these 2 GTPases share 40-50% homology to RAS and RAP, but differ from DIRAS3 primarily in the lengths of their N-terminal extensions. We found that DIRAS1 and DIRAS2 are downregulated in ovarian cancer and are associated with decreased disease-free and overall survival. Re-expression of these genes suppressed growth of human and murine ovarian cancer cells by inducing autophagy-mediated cell death. Mechanistically, DIRAS1 and DIRAS2 induce and regulate autophagy by inhibition of the AKT1-MTOR and RAS-MAPK signaling pathways and modulating nuclear localization of the autophagy-related transcription factors FOXO3/FOXO3A and TFEB. Taken together, these data suggest that DIRAS1 and DIRAS2 likely serve as surrogates in the murine genome for DIRAS3, and may function as a backup system to fine-tune autophagy in humans.
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http://dx.doi.org/10.1080/15548627.2018.1427022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959337PMC
March 2019
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