Extracting Systemic Anticancer Therapy and Response Information From Clinical Notes Following the RECIST Definition.

PURPOSE: The RECIST guidelines provide a standardized approach for evaluating the response of cancer to treatment, allowing for consistent comparison of treatment efficacy across different therapies and patients. However, collecting such information from electronic health records manually can be extremely labor-intensive and time-consuming because of the complexity and volume of clinical notes. The aim of this study is to apply natural language processing (NLP) techniques to automate this process, minimizing manual data collection efforts, and improving the consistency and reliability of the results. METHODS: We proposed a complex, hybrid NLP system that automates the process of extracting, linking, and summarizing anticancer therapy and associated RECIST-like responses from narrative clinical text. The system consists of multiple machine learning-/deep learning-based and rule-based modules for diverse NLP tasks such as named entity recognition, assertion classification, relation extraction, and text normalization, to address different challenges associated with anticancer therapy and response information extraction. We then evaluated the system performances on two independent test sets from different institutions to demonstrate its effectiveness and generalizability. RESULTS: The system used domain-specific language models, BioBERT and BioClinicalBERT, for high-performance therapy mentions identification and RECIST responses extraction and categorization. The best-performing model achieved a 0.66 score in linking therapy and RECIST response mentions, with end-to-end performance peaking at 0.74 after relation normalization, indicating substantial efficacy with room for improvement. CONCLUSION: We developed, implemented, and tested an information extraction system from clinical notes for cancer treatment and efficacy assessment information. We expect this system will support future cancer research, particularly oncologic studies that focus on efficiently assessing the effectiveness and reliability of cancer therapeutics.

Traditional Chinese medicine for acute myelocytic leukemia therapy: exploiting epigenetic targets.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy with historically high mortality rates. The treatment strategies for AML is still internationally based on anthracyclines and cytarabine, which remained unchanged for decades. With the rapid advance on sequencing technology, molecular targets of leukemogenesis and disease progression related to epigenetics are constantly being discovered, which are important for the prognosis and treatment of AML. Traditional Chinese medicine (TCM) is characterized by novel pharmacological mechanisms, low toxicity and limited side effects. Several biologically active ingredients of TCM are effective against AML. This review focuses on bioactive compounds in TCM targeting epigenetic mechanisms to address the complexities and heterogeneity of AML.

Exploring the Impact of Adequate Energy Supply on Nutrition, Immunity, and Inflammation in Elderly Patients with Chronic Obstructive Pulmonary Disease.

Background: Chronic Obstructive Pulmonary Disease (COPD) progression in the elderly is notably influenced by nutritional, immune, and inflammatory status. This study aimed to investigate the impact of adequate energy supply on these indicators in COPD patients. Methods: COPD patients meeting specific criteria were recruited and categorized into energy-adequate and energy-deficient groups based on their energy supply. Comparable demographic factors such as age, gender, smoking and drinking history, COPD duration, inhaled drug classification, and home oxygen therapy application were observed. Notable differences were found in BMI and inhaled drug use between the two groups. Results: The energy-adequate group exhibited significant improvements in various health indicators, including lymphocyte count, hemoglobin, CRP, total cholesterol, prealbumin, albumin, PNI, SII, SIRI, CAR, and CONUT scores in the secondary auxiliary examination. These positive changes suggest a notable enhancement in nutritional, immune, and inflammatory status. Conclusion: This research highlights the substantial benefits of adequate energy supply in elderly COPD patients. The observed improvements in nutritional, immune, and inflammatory markers underscore the importance of addressing energy needs to positively influence disease-related outcomes in this population. These findings have implications for developing targeted interventions to optimize the well-being of elderly individuals with COPD.

Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene.

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

Efferocytosis and Respiratory Disease.

Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is called efferocytosis. If the process fails, this may cause different types of diseases. More and more evidence suggests that a faulty efferocytosis process is closely related to the pathological processes of respiratory diseases. In this review, we will first introduce the process and the related mechanisms of efferocytosis of the macrophage. Secondly, we will propose some methods that can regulate the function of efferocytosis at different stages of the process. Next, we will discuss the role of efferocytosis in different lung diseases and the related treatment approaches. Finally, we will summarize the drugs that have been applied in clinical practice that can act upon efferocytosis, in order to provide new ideas for the treatment of lung diseases.

PLGA-Based Micro/Nanoparticles: An Overview of Their Applications in Respiratory Diseases.

Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are critical areas of medical research, as millions of people are affected worldwide. In fact, more than 9 million deaths worldwide were associated with respiratory diseases in 2016, equivalent to 15% of global deaths, and the prevalence is increasing every year as the population ages. Due to inadequate treatment options, the treatments for many respiratory diseases are limited to relieving symptoms rather than curing the disease. Therefore, new therapeutic strategies for respiratory diseases are urgently needed. Poly (lactic-co-glycolic acid) micro/nanoparticles (PLGA M/NPs) have good biocompatibility, biodegradability and unique physical and chemical properties, making them one of the most popular and effective drug delivery polymers. In this review, we summarized the synthesis and modification methods of PLGA M/NPs and their applications in the treatment of respiratory diseases (asthma, COPD, cystic fibrosis (CF), etc.) and also discussed the research progress and current research status of PLGA M/NPs in respiratory diseases. It was concluded that PLGA M/NPs are the promising drug delivery vehicles for the treatment of respiratory diseases due to their advantages of low toxicity, high bioavailability, high drug loading capacity, plasticity and modifiability. And at the end, we presented an outlook on future research directions, aiming to provide some new ideas for future research directions and hopefully to promote their widespread application in clinical treatment.

Chronic exposure to low-level lipopolysaccharide dampens influenza-mediated inflammatory response via A20 and PPAR network.

Influenza A virus (IAV) infection leads to severe inflammation, and while epithelial-driven inflammatory responses occur via activation of NF-κB, the factors that modulate inflammation, particularly the negative regulators are less well-defined. In this study we show that A20 is a crucial molecular switch that dampens IAV-induced inflammatory responses. Chronic exposure to low-dose LPS environment can restrict this excessive inflammation. The mechanisms that this environment provides to suppress inflammation remain elusive. Here, our evidences show that chronic exposure to low-dose LPS suppressed IAV infection or LPS stimulation-induced inflammation in vitro and in vivo. Chronic low-dose LPS environment increases A20 expression, which in turn positively regulates PPAR-α and -γ, thus dampens the NF-κB signaling pathway and NLRP3 inflammasome activation. Knockout of A20 abolished the inhibitory effect on inflammation. Thus, A20 and its induced PPAR-α and -γ play a key role in suppressing excessive inflammatory responses in the chronic low-dose LPS environment.

A Systematic Review of Antiaging Effects of 23 Traditional Chinese Medicines.

BACKGROUND: Aging is an inevitable stage of body development. At the same time, aging is a major cause of cancer, cardiovascular disease, and neurodegenerative diseases. Chinese herbal medicine is a natural substance that can effectively delay aging and is expected to be developed as antiaging drugs in the future. Aim of the review. This paper reviews the antiaging effects of 23 traditional Chinese herbal medicines or their active components. Materials and methods. We reviewed the literature published in the last five years on Chinese herbal medicines or their active ingredients and their antiaging role obtained through the following databases: PubMed, EMBASE, Scopus, and Web of Science. RESULTS: A total of 2485 papers were found, and 212 papers were screened after removing the duplicates and reading the titles. Twenty-three studies met the requirements of this review and were included. Among these studies, 13 articles used Caenorhabditis elegans as the animal model, and 10 articles used other animal models or cell lines. CONCLUSION: Chinese herbal medicines or their active components play an antiaging role by regulating genes related to aging through a variety of signaling pathways. Chinese herbal medicines are expected to be developed as antiaging drugs or used in the medical cosmetology industry.

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization.

BACKGROUND: Severe, steroid-resistant asthma (SSRA) is a serious clinical problem in asthma management. Affected patients have severe clinical symptoms, worsened quality of life, and do not respond to steroid, a mainstay steroid treatment of asthma. Thus, effective therapies are urgently needed. Exosomes derived from mesenchymal stem cell (MSC-Exo) has become attractive candidates for the lung inflammatory diseases through its immunomodulatory effects. In this study, we explored the therapeutic effects of MSC-Exo in SSRA and identified the therapeutic mechanism of MSC-Exo. METHOD: Exosomes from human umbilical cord mesenchymal stem cell (hUCMSC) were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis and flow cytometry analysis. Effects of MSC-Exo on airway hyper responsiveness (AHR), inflammation, histopathology, and macrophage polarization in SSRA in mice were evaluated. Systematic depletion of macrophages determined the role of macrophages in the therapeutic effect of SSRA in mice. LPS-stimulated RAW 264.7 cell model was constructed to determine the underlying mechanism of MSC-Exo on macrophage polarization. qRT-PCR, Western blotting, immunofluorescence, and flow cytometry were performed to evaluate the expression of M1 or M2 markers. Tandem mass tags (TMT)-labeled quantitative proteomics were applied to explore the central protein during the regulation effect of MSC-Exo on macrophage polarization. Knockdown and overexpression of TRAF1 were used to further clarify the role of the central protein on macrophage polarization. RESULT: We successfully isolated and characterized exosomes from hUCMSCs. We verified that the intratracheal administration of MSC-Exo reversed AHR, histopathology changes, and inflammation in SSRA mice. Systematic depletion of macrophages weakened the therapeutic effect of MSC-Exo. We found that MSC-Exo treatment inhibited M1 polarization and promoted M2 polarization in LPS-stimulated RAW 264.7 cells. Subsequently, tumor necrosis factor receptor-associated factor 1 (TRAF1) was determined as the central protein which may be closely related to the regulation of macrophage polarization from TMT-labeled quantitative proteomics analysis. Knockdown and overexpression of TRAF1 demonstrated that the effect of MSC-Exo treatment on macrophage polarization, NF-κB and PI3K/AKT signaling was dependent on TRAF1. CONCLUSION: MSC-Exo can ameliorate SSRA by moderating inflammation, which is achieved by reshaping macrophage polarization via inhibition of TRAF1.

Cost-Effectiveness Analysis of PEG-rhG-CSF as Primary Prophylaxis to Chemotherapy-Induced Neutropenia in Women With Breast Cancer in China: Results Based on Real-World Data.

Background: Pegylated recombinant human granulocyte colony-stimulating factors (PEG-rhG-CSFs) are more commonly and widely used than recombinant human granulocyte colony-stimulating factors (rhG-CSFs) in preventing chemotherapy-induced neutropenia in patients with stage II-IV breast cancer. To reduce the financial burden on these patients, the corresponding medical insurance directory needs to be revised. Objectives: To evaluate the cost-effectiveness of PEG-rhG-CSF versus rhG-CSF in patients with stage II-IV breast cancer in central China. Methods: Two Markov models, a chemotherapy model and a post-chemotherapy model, were developed to study the effects and costs, with a time horizon of 12 weeks and 35 years, respectively. Cost and probability input data were primarily obtained from a retrospective real-world study conducted in five tertiary hospitals. Propensity score matching was adopted to overcome retrospective bias. Other parameters were extracted from literature as well as advice from clinical experts. Univariate and probabilistic sensitivity analyses were conducted. Results: In the first chemotherapy model, PEG-rhG-CSF was associated with fewer episodes of febrile neutropenia (FN) (N = 19 per 1000 patients treated), infections (N = 24 per 1000 patients treated) and deaths (N = 2 per 1000 patients treated), but higher costs (¥36 more per patient treated). The post-chemotherapy model indicated that PEG-rhG-CSF led to higher gains in quality-adjusted life years (QALYs) (11.695 versus 11.516) in comparison to rhG-CSF. Sensitivity analysis showed that the cost of PEG-rhG-CSF had the greatest impact on the incremental costs, and incremental QALYs were very sensitive to the risk of RDI <85%. The probability of PEG-rhG-CSF being cost-effective compared to rhG-CSF was 66% at the willingness to pay (WTP) thresholds of ¥72,371 per QALY gained. Conclusion: According to this economic evaluation based on real-world data, PEG-rhG-CSF may be considered as a more cost-effective strategy relative to rhG-CSF for stage II-IV breast cancer patients in central China. However, to reflect a national perspective, further evidence is needed using data from larger-scale studies.

A Systematic Review of the Anti-Inflammatory and Immunomodulatory Properties of 16 Essential Oils of Herbs.

BACKGROUND: Inflammation is a host defense mechanism in the body after it is infected and damaged. If inflammation is not treated in time, then it may cause a variety of diseases, such as cancer and autoimmune diseases. Herbal essential oils are natural extracts that can suppress inflammation effectively and are expected to be used in therapeutic drugs for anti-inflammatory diseases in the future. Aim of the review. We review the anti-inflammatory and immunomodulatory effects of essential oils derived from 16 herbs. Materials and methods. We searched the literature of the fields of anti-inflammatory and immunomodulatory herbal essential oil activity published in English within the past five years via databases (PubMed, EMBASE, Scopus, and The Web of Science). RESULTS: A total of 1932 papers were found by searching, and 132 papers were screened after removing duplicates and reading article titles. Fifteen articles met the requirements to be included in this review. Among those selected, 11 articles reported in vivo research results, and 10 articles showed research results. CONCLUSION: Essential oils extracted from herbs can reduce inflammation by regulating the release of inflammatory cytokines involved in multiple signalling pathways. Herbal essential oils are expected to be developed as anti-inflammatory drugs.

Liver cirrhosis contributes to the disorder of gut microbiota in patients with hepatocellular carcinoma.

BACKGROUND: Gut microbiota (GM) of patients with liver cancer is disordered, and syet no study reported the GM distribution of liver cirrhosis-induced HCC (LC-HCC) and nonliver cirrhosis-induced HCC (NLC-HCC). In this study, we aimed to characterize gut dysbiosis of LC-HCC and NLC-HCC to elucidate the role of GM in the pathogenesis of HCC. METHODS: A consecutive series of fecal samples of patients with hepatitis (24 patients), liver cirrhosis (24 patients), HCC (75 patients: 35 infected by HBV, 25 infected by HCV, and 15 with alcoholic liver disease), and healthy controls (20 patients) were obtained and sequenced on the Illumina Hiseq platform. The HCC group contains 52 LC-HCC and 23 NLC-HCC. Bioinformatic analysis of the intestinal microbiota was performed with QIIME and MicrobiomeAnalyst. RESULTS: Alpha-diversity analysis showed that fecal microbial diversity was significantly decreased in the LC group, and there were significant differences in 3 phyla and 27 genera in the LC group vs the other groups (the healthy, hepatitis, and HCC groups). Beta-diversity analysis showed that there were large differences between LC and the others. Gut microbial diversity was significantly increased from LC to HCC. Characterizing the fecal microbiota of LC-HCC and NLC-HCC, we found that microbial diversity was increased from LC to LC-HCC rather than NLC-HCC. Thirteen genera were discovered to be associated with the tumor size of HCC. Three biomarkers (Enterococcus, Limnobacter, and Phyllobacterium) could be used for precision diagnosis. We also found that HBV infection, HCV infection, or ALD (alcoholic liver disease) was not associated with intestinal microbial dysbiosis in HCC. CONCLUSION: Our results suggest that GM disorders are more common in patients with LC-HCC. The butyrate-producing genera were decreased, while genera producing-lipopolysaccharide (LPS) were increased in LC-HCC patients. Further studies of GM disorders may achieve early diagnosis and new therapeutic approaches for HCC patients.

An Updated Overview of Metabolomic Profile Changes in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), a common and heterogeneous respiratory disease, is characterized by persistent and incompletely reversible airflow limitation. Metabolomics is applied to analyze the difference of metabolic profile based on the low-molecular-weight metabolites (<1 kDa). Emerging metabolomic analysis may provide insights into the pathogenesis and diagnosis of COPD. This review aims to summarize the alteration of metabolites in blood/serum/plasma, urine, exhaled breath condensate, lung tissue samples, etc. from COPD individuals, thereby uncovering the potential pathogenesis of COPD according to the perturbed metabolic pathways. Metabolomic researches have indicated that the dysfunctions of amino acid metabolism, lipid metabolism, energy production pathways, and the imbalance of oxidations and antioxidations might lead to local and systematic inflammation by activating the Nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway and releasing inflammatory cytokines, like interleutin-6 (IL-6), tumor necrosis factor-α, and IL-8. In addition, they might cause protein malnutrition and oxidative stress and contribute to the development and exacerbation of COPD.

Identification of lncRNA-miRNA-mRNA regulatory network associated with epithelial ovarian cancer cisplatin-resistant.

To construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) regulatory network related to epithelial ovarian cancer (EOC) cisplatin-resistant, differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed miRNAs (DEMs) between MDAH and TOV-112D cells lines were identified. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to analyze the biological functions of DEGs. Downstream mRNAs or upstream lncRNAs for miRNAs were analyzed at miRTarBase 7.0 or DIANA-LncBase V2, respectively. A total of 485 significant DEGs, 85 DELs, and 5 DEMs were identified. Protein-protein interaction (PPI) network of DEGs contrains 81 nodes and 141 edges was constructed, and 25 hub genes related to EOC cisplatin-resistant were identified. Subsequently, a lncRNA-miRNA-mRNA regulatory network contains 4 lncRNAs, 4 miRNAs, and 35 mRNAs was established. Taken together, our study provided evidence concerning the alteration genes involved in EOC cisplatin-resistant, which will help to unravel the mechanisms underlying drug resistant.

Columbianadin Suppresses Lipopolysaccharide (LPS)-Induced Inflammation and Apoptosis through the NOD1 Pathway.

Columbianadin (CBN) is one of the main bioactive constituents isolated from the root of Angelica pubescens. Although the anti-inflammatory activity of CBN has been reported, the underpinning mechanism of this remains unclear. In this study, we investigated the anti-inflammatory effect of CBN on lipopolysaccharide (LPS)-stimulated THP-1 cells and explored the possible underlying molecular mechanisms. The results showed that CBN suppressed LPS-mediated inflammatory response mainly through the inactivation of the NOD1 and NF- κ B p65 signaling pathways. Knockdown of NOD1 reduced the degree to which inflammatory cytokines decreased following CBN treatment, whereas forced expression of NOD1 and CBN treatment reduced NF- κ B p65 activation and the secretion of inflammatory cytokines. Furthermore, CBN significantly reduced cellular apoptosis by inhibiting the NOD1 pathway. Collectively, our results indicate that CBN suppressed the LPS-mediated inflammatory response by inhibiting NOD1/NF- κ B activation. Further investigations are required to determine the mechanisms of action of CBN in the inhibition of NOD signaling: However, CBN may be employed as a therapeutic agent for multiple inflammatory diseases.

[Application of broad easy immediate surgery in percutaneous transforaminal endoscopic technology for lumbar lateral recess stenosis in the elderly].

OBJECTIVE: To explore the safety and effectiveness of percutaneous transforaminal endoscopic BEIS technology for lumbar lateral recess stenosis in the elderly. METHODS: From February 2014 to May 2016, 21 patients with lumbar lateral recess stenosis in elderly were treated with percutaneous endoscopic BEIS. There were 13 males and 8 females, aged from 70 to 85 years old with an average of 74.3 years. Preoperative, 1 and 12 months postoperative visual analogue scale(VAS) scores and Oswestry Disability Index(ODI) were statistically analyzed. MacNab was used to assess the clinical effects. RESULTS: All the operations were successful. The time ranged from 90 to 130 min with an average of 110 min. All the patients were followed up for 12 to 38 months with an average of 18 months. Preoperative, 1 and 12 months postoperative VAS scores were 8.47±1.23, 1.78±0.72, 0.68±0.32, and ODI scores were 32.48±10.03, 19.53±3.55, and 5.15±1.02, respectively. Postoperative scores of VAS and ODI were obviously improved(P<0.05). According to modified MacNab standard to evaluate the clinical effects, 14 cases obtained excellent results, 5 good, 2 fair. Lower limb paresthesia occurred in 1 case, and the condition was restored at 3 months postoperatively with conservative treatment. One patient was complicated with emphysema before operation secondary to pulmonary infection, and was effectively controlled with regulate antibiotic therapy. No infection of vertebral body or intervertebral space, no injuries of blood vessels or nerve root, no tear of dura, or the leakage of cerebrospinal fluid were found. CONCLUSIONS: Percutaneous transforaminal endoscopic BEIS is a safe and effective method for lumbar lateral recess stenosis in the elderly.

Sub-anesthesia Dose of Isoflurane in 60% Oxygen Reduces Inflammatory Responses in Experimental Sepsis Models.

BACKGROUND: Sepsis is a major cause of mortality in Intensive Care Units. Anesthetic dose isoflurane and 100% oxygen were proved to be beneficial in sepsis; however, their application in septic patients is limited because long-term hyperoxia may induce oxygen toxicity and anesthetic dose isoflurane has potential adverse consequences. This study was scheduled to find the optimal combination of isoflurane and oxygen in protecting experimental sepsis and its mechanisms. METHODS: The effects of combined therapy with isoflurane and oxygen on lung injury and sepsis were determined in animal models of sepsis induced by cecal ligation and puncture (CLP) or intraperitoneal injection of lipopolysaccharide (LPS) or zymosan. Mouse RAW264.7 cells or human peripheral blood mononuclear cells (PBMCs) were treated by LPS to probe mechanisms. The nuclear factor kappa B (NF-κB) signaling molecules were examined by Western blot and cellular immunohistochemistry. RESULTS: The 0.5 minimum alveolar concentration (MAC) isoflurane in 60% oxygen was the best combination of oxygen and isoflurane for reducing mortality in experimental sepsis induced by CLP, intraperitoneal injection of LPS, or zymosan. The 0.5 MAC isoflurane in 60% oxygen inhibited proinflammatory cytokines in peritoneal lavage fluids (tumor necrosis factor-alpha [TNF-ß]: 149.3 vs. 229.7 pg/ml, interleukin [IL]-1ß: 12.5 vs. 20.6 pg/ml, IL-6: 86.1 vs. 116.1 pg/ml, and high-mobility group protein 1 [HMGB1]: 323.7 vs. 449.3 ng/ml; all P< 0.05) and serum (TNF-ß: 302.7 vs. 450.7 pg/ml, IL-1ß: 51.7 vs. 96.7 pg/ml, IL-6: 390.4 vs. 722.5 pg/ml, and HMGB1: 592.2 vs. 985.4 ng/ml; all P< 0.05) in septic animals. In vitro experiments showed that the 0.5 MAC isoflurane in 60% oxygen reduced inflammatory responses in mouse RAW264.7 cells, after LPS stimulation (all P< 0.05). Suppressed activation of NF-κB pathway was also observed in mouse RAW264.7 macrophages and human PBMCs after LPS stimulation or plasma from septic patients. The 0.5 MAC isoflurane in 60% oxygen also prevented the increases of phospho-IKKß/ß, phospho-IκBß, and phospho-p65 expressions in RAW264.7 macrophages after LPS stimulation (all P< 0.05). CONCLUSION: Combined administration of a sedative dose of isoflurane with 60% oxygen improves survival of septic animals through reducing inflammatory responses.

Downregulation of miR-199b promotes the acute spinal cord injury through IKKß-NF-κB signaling pathway activating microglial cells.

Inflammatory response played an important role in the progression of spinal cord injury (SCI). Several miRNAs were associated with the pathology of SCI. However, the molecular mechanism of miRNA involving in inflammatory response in acute SCI (ASCI) was poorly understood. Sprague-Dawley (SD) rats were divided into 2 groups: control group (n=6) and acute SCI (ASCI) group (n=6). The expression of miR-199b and IκB kinase ß-nuclear factor-kappa B (IKKß-NF-κB) signaling pathway were evaluated by quantitative reverse transcription-PCR (qRT-PCR) in rats with ASCI and in primary microglia activated by lipopolysaccharide (LPS). We found that downregulation of miR-199b and activation of IKKß/NF-κB were observed in rats after ASCI and in activated microglia. miR-199b negatively regulated IKKß by targeting its 3'- untranslated regions (UTR) through using luciferase reporter assay. Overexpression of miR-199b reversed the up-regulation of IKKß, p-p65, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in LPS-treated BV2 cells assessed by western blotting analysis. In addition, BMS-345541 reversed the up-regulation effects of miR-199b inhibitor on the expression of TNF-α and IL-1ß. In the SCI rats, overexpression of miR-199b attenuated ASCI and decreased the expression of IKKß-NF-κB signaling pathway and TNF-α and IL-1ß. These results indicated that miR-199b attenuated ASCI at least partly through IKKß-NF-κB signaling pathway and affecting the function of microglia. Our findings suggest that miR-199b may be employed as therapeutic for spinal cord injury.

Isomeric folate-conjugated polymeric micelles bind to folate receptors and display anticancer effects.

The present study aimed to prepare and evaluate polymeric micelles conjugated with folic acid through α- or γ-carboxyl groups for antitumor efficacy. The isomeric block copolymers, α- and γ-folate-polyethyleneglycol- distearoyl phosphatidylethanolamine (α- and γ-Fol-PEG-DSPE), were produced by solid phase peptide synthesis. Three types of doxorubicin (DOX)-loaded polymeric micelles (MPEG-DSPE-DOX and α- / γ-Fol-PEG-DSPE- DOX micelles) were prepared via the film formation method. Compared with MPEG-DSPE-DOX micelles, the α- / γ-Fol-PEG-DSPE-DOX micelles presented a higher cellular uptake behavior in the live cell study. Cell viability percentages were 81.8%, 57.3%, 56.6% at 2 hours for MPEG-DSPE-DOX, α- and γ-Fol-PEG-DSPE- DOX micelles, respectively (p<0.05). Using the KB xenograft tumor model, both α- and γ-folate-conjugated micelles were found to have better antitumor effects with lower toxicity in comparison with MPEG-DSPE-DOX micelles. No difference in in vivo antitumor efficacy was found between α-and γ-Fol-PEG-DSPE-DOX micelles. The folate-conjugated micelles might be a potentially useful strategy for tumor targeting of therapeutic agents, whether grafting with folic acid through α- or γ-carboxyl groups.

Down-regulation of ether-a-go-go-related gene potassium channel protein through sustained stimulation of AT1 receptor by angiotensin II.

We investigated the effects of AT1 receptor stimulation by angiotensin II (Ang II) on human ether-a-go-go-related gene (hERG) potassium channel protein in a heterogeneous expression system with the human embryonic kidney (HEK) 293 cells which stably expressed hERG channel protein and were transiently transfected with the human AT1 receptors (HEK293/hERG). Western-blot analysis showed that Ang II significantly decreased the expression of mature hERG channel protein (155-kDa band) in a time- and dose-dependent manner without affecting the level of immature hERG channel protein (135-kDa band). The relative intensity of 155-kDa band was 64.7±6.8% of control (P<0.01) after treatment of Ang II at 100nM for 24h. To investigate the effect of Ang II on the degradation of mature hERG channel protein, we blocked forward trafficking from ER to Golgi with a Golgi transit inhibitor brefeldin A (10µM). Ang II significantly enhanced the time-dependent reduction of mature hERG channel protein. In addition, the proteasomal inhibitor lactacystin (5µM) inhibited Ang II-mediated the reduction of mature hERG channel protein, but the lysosomal inhibitor bafilomycin A1 (1µM) had no effect on the protein. The protein kinase C (PKC) inhibitor bisindolylmaleimide 1 (1µM) antagonized the reduction of mature hERG channel protein induced by Ang II. The results indicate that sustained stimulation of AT1 receptors by Ang II reduces the mature hERG channel protein via accelerating channel proteasomal degradation involving the PKC pathway.