A multifunctional sensor for detecting tetracycline, 4-nitrophenol, and pesticides.

In recent years, due to the abuse of antibiotics, nitro explosives and pesticides, which have caused great harm to the environment and human health, social concerns have prompted researchers to develop more sensitive detection platforms for these pollutants. In this paper, a novel two-dimensional Zn (II) coordination polymer, [Zn(L)0.5(1,2-bimb)]·DMF (1), [H4L=[1,1':4',1''-terphenyl]-2, 2'',4, 4'' -tetracarboxylic acid, 1,2-bimb = 1,2-bis(imidazol-1-ylmethyl)benzene] was synthesized using a hydro-solvothermal method. Among commonly used organic solvents, 1 exhibits significant stability. Fast and efficient fluorescence response can be achieved for tetracycline (TET), 4-nitrophenol (4-NP), fluazinam (FLU), and abamectin benzoate (AMB) with low detection limits. A binary intelligent logic gate device with FLU and AMB as chemical input signals is successfully constructed, which provides a new idea for biochemical detection. In addition, a portable visual test paper has been prepared, which has high sensitivity, good selectivity, and simple operation. It can be used for rapid detection of pollutants in daily life and has broad application prospects. Finally, a detailed discussion was conducted on the fluorescence sensing mechanism of 1 for detecting TET, 4-NP, AMB and FLU.

Regression of ovarian cancer xenografts by depleting or inhibiting RLIP.

Ovarian cancer (OC) is the most prevalent and deadly cancer of the female reproductive system. Women will continue to be impacted by OC-related morbidity and mortality. Despite the fact that chemotherapy with cisplatin is the main component as the first-line anticancer treatment for OC, chemoresistance and unfavorable side effects are important obstacles to effective treatment. Targets for effective cancer therapy are required for cancer cells but not for non-malignant cells because they are expressed differently in cancer cells compared to normal cells. Targets for cancer therapy should preferably be components that already exist in biochemical and signalling frameworks and that significantly contribute to the development of cancer or regulate the response to therapy. RLIP is an important mercapturic acid pathway transporter that is crucial for survival and therapy resistance in cancers, therefore, we examined the role of RLIP in regulating essential signalling proteins involved in relaying the inputs from upstream survival pathways and mechanisms contributing to chemo-radiotherapy resistance in OC. The findings of our research offer insight into a novel anticancer effect of RLIP depletion/inhibition on OC and might open up new therapeutic avenues for OC therapy.

A Scoring System to Select the Candidates for Adjuvant Chemotherapy Alone in High-Risk Early-Stage Cervical Cancer Patients With Pelvic Lymph Node Metastases After Surgery.

BACKGROUND: The aim was to build a risk scoring system to guide the adjuvant treatment for early-stage cervical cancer patients with pelvic lymph node (LN) metastases after surgery. METHODS: A cohort of 1213 early-stage cervical cancer patients with pelvic LN metastases (T1-2aN1M0) were selected from the NCI SEER database, of which 1040 patients received adjuvant external beam radiotherapy concurrent with chemotherapy (EBRT+Chemo) and 173 patients received adjuvant chemotherapy alone. The Cox regression analysis was applied to identify the risk factors associated with worse survival. The exp (ß) of each independent risk factors from multivariate analysis was assigned to develop the risk scoring system. The total cohort was divided into different risk subgroups accordingly and the efficacy of different adjuvant modalities in each risk subgroups was compared. RESULTS: The patients were divided into 3 risk subgroups (Low-risk: total score <7.20, Middle-risk:7.20≤ total score≤ 8.40, High-risk: total score<8.40) based on the scoring system incorporating 5 independent risk factors. The survival analysis suggested that low-risk (hazard ratio [HR]=1.046, 95% CI: 0.586-1.867; P= 0.879) and middle-risk patients (HR=0.709, 95% CI: 0.459-1.096; P =0.122) could not benefit more from EBRT+Chemo than Chemo alone. However, EBRT+Chemo remained the superiority to Chemo alone in the high-risk subgroup (HR=0.482, 95% CI: 0.294-0.791; P =0.003). CONCLUSION: A risk scoring system has been built to direct the adjuvant treatment for early-stage cervical cancer patients with pelvic LN metastases after surgery, where Chemo alone was totally enough for low-risk and middle-risk patients stratified by the model while EBRT+Chemo was still recommended for patients in the high-risk subgroup.

Postoperative Pain Management Outcomes at a Chinese Hospital: A Cross-Sectional Survey.

PURPOSE: Postoperative pain is one of the most common postoperative complications, and improper management not only adds to patient suffering but also affects patients' recovery. In this study, we measured patients' postoperative pain to understand the status of patients after surgery and to identify factors influencing postoperative pain. DESIGN: A descriptive and cross-sectional study METHODS: This survey was conducted at a large tertiary hospital in Chengdu, Sichuan Province. A total of 655 postoperative inpatients were included. The survey was conducted using the Chinese version of the Houston Pain Outcome Instrument. General patient data, pain management-related factors, and the pain management index were used to survey risk factors. We used t-tests and ANOVA for univariate analysis of each pain outcome category to explore the association with the predictor variables. Then, those variables with a significance level of 0.05 on univariate analysis were entered into multivariable regression analysis to identify parsimonious subsets of independent risk factors. FINDINGS: In this survey, 58.7% of patients experienced moderate to severe pain in the 24-hour postoperative period, and 33.6% of patients had moderate to severe average pain over the 24-hour postoperative period. The postoperative pain impact scores on patient mood, somatic function, patient satisfaction with postoperative pain management, and pain education were 3.5 ± 2.1, 4.3 ± 3.1, 8.9 ± 1.4 and 8.2 ± 1.8, respectively. The pain management index, surgery type, insurance, and pain assessment of nurse were influential factors of postoperative pain intensity. Age, ethnicity, insurance, surgery type, patents' knowledge of pain, and pain assessment of the nurse affected the patients' postoperative physiological function (F = 3.822, R2 = 0.065, P = .000). In addition, area of residence and physician attitudes affected the outcomes of patient satisfaction with pain management (F = 26.652, R2 = 0.259, P = .000). CONCLUSIONS: The incidence of moderate to severe pain in post-surgical patients remains high, and postoperative pain affects patients physically and psychologically. Special attention should be given to patients with lower income and literacy levels.

A population-based risk scoring system to individualize adjuvant treatment for stage IIIC endometrial cancer patients after surgery.

BACKGROUND: To develop a risk scoring system to tailor the adjuvant treatment for stage IIIC EC patients after surgery. METHODS: Data source was from the Surveillance, Epidemiology, and End Results (SEER) registry, where 3251 post-operative stage IIIC EC patients with different adjuvant treatment were included. Cox regression analysis was used to identify risk factors. The exp (ß) of each independent risk factors generating from the cox analysis was used to construct the risk scoring system, which was further utilized to divide the patients into different risk subgroups and the efficacy of different adjuvant modalities in each risk subgroups would be compared accordingly. RESULTS: Six independent risk factors were identified to develop the scoring system, which further divided the patients into three risk subgroups based on the total risk score (Low-risk≤8.46, 8.47 ≤ Middle-risk≤9.94, High-risk≥9.95). This study revealed that CRT was not superior to RT alone (HR:1.208, 95%CI: 0.852-1.741; P = 0.289) or CT alone (HR:1.260, 95%CI: 0.750-2.116; P = 0.382) in Low-risk subgroup. We also observed that CRT had a survival advantage over other treatment modalities in the Middle-risk subgroup (All P < 0.001), but CRT and CT alone to be superimposable in the High-risk subgroup (HR: 1.395, 95%CI: 0.878-2.216; P = 0.159). CONCLUSION: A risk scoring system has been developed to tailor the adjuvant treatment for stage IIIC EC patients after surgery, where RT or CT alone could be a substitute for CRT in Low-risk patients and CT alone was a potential alternative for High-risk patients while CRT remained to be the optimal choice for the Middle-risk patients.

Translation and validation of M.D. Anderson Symptom Inventory-Thyroid Cancer module in Chinese thyroid cancer patients: a cross-sectional and methodological study.

AIM: To translate and validate the Chinese version of the MDASI-THY among thyroid cancer patients. BACKGROUND: The M.D. Anderson Symptom Inventory-Thyroid Cancer module (MDASI-THY) is one of well-validated instruments for thyroid-specific symptom assessment. To date, the instrument has not been used in China. METHODS: After standard forward- and back-translation procedures, two instruments, the Chinese version of MDASI-THY and the European Organization for Research and Treatment of Cancer QLQ C30, were answered by 309 thyroid patients. The content, convergent discriminant validity and reliability of the MDASI-THY were evaluated. RESULTS: The scale of content validity index (S-CVI) and the item of content validity index (I-CVI) of the instrument were over 0.80. There were significant relationships between MDASI-THY and EORTC QLQ-C30 (r range, 0.139 ~ 0.766, -0.759 ~ -0.461, p < 0.001). Symptoms were severer for patients underwent surgical treatment (Z = -9.999, p < 0.001). The Cronbach's alpha was 0.966 (between 0.954 and 0.827 for subscales). Most symptom items had moderate to high interitem correlations (r range, 0.297 ~ 0.773). CONCLUSIONS: The Chinese version of MDASI-THY demonstrated favorable validity and reliability. It can be used in development of symptom management program in thyroid cancer patients in China. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers can apply this instrument to assess Chinese thyroid cancer patients to increase the understanding of their symptom experience, resulting in a better symptom management.

Ibrutinib ameliorates cerebral ischemia/reperfusion injury through autophagy activation and PI3K/Akt/mTOR signaling pathway in diabetic mice.

Bruton's tyrosine kinase (BTK) is involved in the diabetogenic process and cerebral ischemic injury. However, it remained unclear whether BTK inhibition has remedial effects on ischemia/reperfusion (I/R) injury complicated with diabetes. We aim to investigate the regulatory role and potential mechanism of ibrutinib, a selective inhibitor of BTK, in cerebral I/R injured diabetic mice. The cytotoxicity and cell vitality tests were performed to evaluate the toxic and protective effects of ibrutinib at different incubating concentrations on normal PC12 cells or which were exposed to high glucose for 24 h, followed by hypoxia and reoxygenation (H/R), respectively. Streptozotocin (STZ) stimulation-induced diabetic mice were subjected to 1 h ischemia and then reperfusion. Then the diabetic mice received different dosages of ibrutinib or vehicle immediately and 24 h after the middle cerebral artery occlusion (MCAO). The behavioral, histopathological, and molecular biological tests were then performed to demonstrate the neuroprotective effects and mechanism in I/R injured diabetic mice. Consequently, Ibrutinib improved the decreased cell viability and attenuated oxidative stress in the high glucose incubated PC12 cells which subjected to H/R injury. In the I/R injured diabetic mice, ibrutinib reduced the cerebral infarct volume, improved neurological deficits, ameliorated pathological changes, and improved autophagy in a slightly dose-dependent manner. Furthermore, the expression of PI3K/AKT/mTOR pathway-related proteins were significantly upregulated by ibrutinib treatment. In summary, our finding collectively demonstrated that Ibrutinib could effectively ameliorate cerebral ischemia/reperfusion injury via ameliorating inflammatory response, oxidative stress, and improving autophagy through PI3K/Akt/mTOR signaling pathway in diabetic mice.

Targeting CA-125 Transcription by Development of a Conditionally Replicative Adenovirus for Ovarian Cancer Treatment.

CA-125, encoded by the MUC16 gene, is highly expressed in most ovarian cancer cells and thus serves as a tumor marker for monitoring disease progression or treatment response in ovarian cancer patients. However, targeting MUC16/CA-125 for ovarian cancer treatment has not been successful to date. In the current study, we performed multiple steps of high-fidelity PCR and obtained a 5 kb DNA fragment upstream of the human MUC16 gene. Reporter assays indicate that this DNA fragment possesses transactivation activity in CA-125-high cancer cells, but not in CA-125-low cancer cells, indicating that the DNA fragment contains the transactivation region that controls specific expression of the MUC16 gene in ovarian cancer cells. We further refined the promoter and found a 1040 bp fragment with similar transcriptional activity and specificity. We used this refined MUC16 promoter to replace the E1A promoter in the adenovirus type 5 genome DNA, where E1A is an essential gene for adenovirus replication. We then generated a conditionally replicative oncolytic adenovirus (CRAd) that replicates in and lyses CA-125-high cancer cells, but not CA-125-low or -negative cancer cells. In vivo studies showed that intraperitoneal virus injection prolonged the survival of NSG mice inoculated intraperitoneally (ip) with selected ovarian cancer cell lines. Furthermore, the CRAd replicates in and lyses primary ovarian cancer cells, but not normal cells, collected from ovarian cancer patients. Collectively, these data indicate that targeting MUC16 transactivation utilizing CRAd is a feasible approach for ovarian cancer treatment that warrants further investigation.

Natural variation and evolutionary dynamics of transposable elements in Brassica oleracea based on next-generation sequencing data.

Brassica oleracea comprises various economically important vegetables and presents extremely diverse morphological variations. They provide a rich source of nutrition for human health and have been used as a model system for studying polyploidization. Transposable elements (TEs) account for nearly 40% of the B. oleracea genome and contribute greatly to genetic diversity and genome evolution. Although the proliferation of TEs has led to a large expansion of the B. oleracea genome, little is known about the population dynamics and evolutionary activity of TEs. A comprehensive mobilome profile of 45,737 TE loci was obtained from resequencing data from 121 diverse accessions across nine B. oleracea morphotypes. Approximately 70% (32,195) of the loci showed insertion polymorphisms between or within morphotypes. In particular, up to 1221 loci were differentially fixed among morphotypes. Further analysis revealed that the distribution of the population frequency of TE loci was highly variable across different TE superfamilies and families, implying a diverse expansion history during host genome evolution. These findings provide better insight into the evolutionary dynamics and genetic diversity of B. oleracea genomes and will potentially serve as a valuable resource for molecular markers and association studies between TE-based genomic variations and morphotype-specific phenotypic differentiation.

Repositioning Quinacrine Toward Treatment of Ovarian Cancer by Rational Combination With TRAIL.

Quinacrine has been identified as a potent DR5-inducing agent that sensitizes cancer cells to TRAIL-induced apoptosis. In the current study, we found that quinacrine increased DR5 mRNA levels significantly in ovarian cancer cell lines regardless of p53 status. Further study showed the half-life of DR5 in quinacrine-treated cells was significantly prolonged, indicating that DR5 protein degradation was inhibited by quinacrine. We tested if the combination of TRAIL and quinacrine could be effective in ovarian cancer treatment in vitro and in ovarian cancer xenograft mouse models. We found that quinacrine enhanced TRAIL sensitivity or reversed TRAIL resistance in all the ovarian cancer cell lines tested. Mice treated with quinacrine and TRAIL remained disease-free for up to 20 weeks, however, mice treated with TRAIL or quinacrine alone and in control group died within ~8 weeks after treatment. Intraperitoneal delivery of quinacrine and TRAIL is rational and practical with extraordinary synergistic anti-cancer effects in preclinical models of ovarian cancer. Clinical investigation of combining quinacrine with TRAIL for ovarian cancer treatment is warranted.

Anthocyanin Protects Cardiac Function and Cardiac Fibroblasts From High-Glucose Induced Inflammation and Myocardial Fibrosis by Inhibiting IL-17.

Diabetic cardiomyopathy (DCM) is one of the major causes of death in diabetic patients. Its pathogenesis involves inflammation and fibrosis that damages the heart tissue and impairs cardiac function. Interleukin (IL)-17, a pro-inflammatory cytokine that plays an important role in a variety of chronic inflammatory processes can serve as an attractive therapeutic target. Anthocyanin, a water-soluble natural pigment, possesses impressive anti-inflammatory activity. However, its role in DCM is unclear. Hence, we investigated the protective effect of anthocyanin on the cardiovascular complications of diabetes using a mouse type 1 diabetes mellitus model induced by streptozotocin. Cardiac function and structural alterations in diabetic mice were tested by echocardiography, hematoxylin and eosin staining, and Masson trichrome staining. Immunohistochemistry was performed to evaluate the distribution and deposition of IL-17 and collagen I and III from the left ventricular tissues of diabetic mice. Cell viability was measured using the methyl thiazolyl tetrazolium assay. Protein levels of IL-17, tumor necrosis factor α, IL-1ß, and IL-6 were determined using enzyme-linked immunosorbent assay. IL-17 and collagen I and III were detected by western blotting and immunofluorescence, and their mRNA levels were quantified using quantitative reverse transcription PCR. We observed that anthocyanin lowered blood glucose, improved cardiac function, and alleviated inflammation and fibrosis in the heart tissue of diabetic mice. Meanwhile, anthocyanin reduced the expression of IL-17 in high-glucose-treated cardiac fibroblasts and exhibited an anti-inflammatory effect. Deposition of collagen I and III was also decreased by anthocyanin, suggesting that anthocyanin contributes to alleviating myocardial fibrosis. In summary, anthocyanin could protect cardiac function and inhibit IL-17-related inflammation and fibrosis, which indicates its therapeutic potential in the treatment of diabetes mellitus-related complications.

PEP06 polypeptide 30 is a novel cluster-dissociating agent inhibiting α v integrin/FAK/Src signaling in oral squamous cell carcinoma cells.

Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies. In oral squamous cell carcinoma (OSCC), αv integrin is a crucial mediator of multicellular clustering and collective movement in vitro; however, its contribution to metastatic spread remains to be addressed. According to the emerging therapeutic concept, dissociation of tumor clusters into single cells could significantly suppress metastasis-seeding ability of carcinomas. This study aimed to investigate the anti-OSCC potential of novel endostatin-derived polypeptide PEP06 as a cluster-dissociating therapeutic agent in vitro. Firstly, we found marked enrichment of αv integrin in collectively invading multicellular clusters in human OSCCs. Our study revealed that metastatic progression of OSCC was associated with augmented immunostaining of αv integrin in cancerous lesions. Following PEP06 treatment, cell clustering on fibronectin, migration, multicellular aggregation, anchorage-independent survival and colony formation of OSCC were significantly inhibited. Moreover, PEP06 suppressed αv integrin/FAK/Src signaling in OSCC cells. PEP06-induced loss of active Src and E-cadherin from cell-cell contacts contributed to diminished collective migration of OSCC in vitro. Overall, these results suggest that PEP06 polypeptide 30 inhibiting αv integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions possesses anti-metastatic potential in OSCC by acting as a cluster-dissociating therapeutic agent.

Anthocyanidin attenuates myocardial ischemia induced injury via inhibition of ROS-JNK-Bcl-2 pathway: New mechanism of anthocyanidin action.

Despite treatment options available to date, myocardial ischemia (MI) remains the leading cause of death worldwide. Studies are focused on finding effective therapeutic strategies against MI injury. Growing interest has been developed in natural compounds possessing medicinal properties with scarcer side effects. Here, we have evaluated the cardioprotective potential of anthocyanidin against MI injury and explored its underlying protective mechanism. Left anterior descending coronary artery was ligated to induce MI in mice. Neonatal mice cardiomyocytes were treated with H2 O2 to induce oxidative stress (a major contributor to MI injury) in vitro. Anthocyanidin pretreatment significantly reduced the infarct size, preserved the cell viability, and protected against ischemia-induced cardiac injury in treatment groups compared with the H2 O2 -treated group in vitro. Measurement of reactive oxygen species (ROS) validated the strong antioxidant potential of anthocyanidin, as significant reduction in oxidative stress was observed in anthocyanidin-pretreated groups. Mechanistically, pretreatment with anthocyanidin significantly subdued the activation of JNK (to p-JNK) and elevated Bcl-2 levels. Both in vivo and in vitro findings suggest that anthocyanidin can induce a state of myocardial resistance against ischemic insult. We have provided the experimental evidence for inhibition of ROS/p-JNK/Bcl-2 pathway being the underlying mechanism of action of anthocyanidin. Our results support the use of anthocyanidin as therapeutic strategy against MI injury.

Polymorphisms in the APOBEC3G gene of Chinese rhesus macaques affect resistance to ubiquitination and degradation mediated by HIV-2 Vif.

Animal cells have multiple innate effector mechanisms that inhibit viral replication. For the pathogenic retrovirus human immunodeficiency virus 1 (HIV-1), there are widely expressed restriction factors, such as APOBEC3 proteins, tetherin/BST2, SAMHD1 and MX2, as well as TRIM5α. We previously found that the TRIM5α gene clearly affects SIVmac or HIV-2 replication, but the major determinant of the combinatorial effect caused by multiple host restriction factors is still not fully clear. APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G), a host restriction factor that restricts HIV replication by causing cytosine deamination, can be targeted and degraded by the SIV/HIV-1/HIV-2 accessory protein Vif. Although rhesus macaques are widely used in HIV/AIDS research, little is known regarding the impact of APOBEC3G gene polymorphisms on viral Vif-mediated ubiquitin degradation in Chinese-origin rhesus macaques. In this study, we therefore genotyped APOBEC3G in 35 Chinese rhesus macaques. We identified a novel transcript and 27 APOBEC3G polymorphisms, including 20 non-synonymous variants and 7 synonymous mutation sites, of which 10 were novel. According to the predicted structure of the A3G protein, we predicted that the E88K and G212D mutations, both on the surface of the A3G protein, would have a significant effect on Vif-induced A3G degradation. However, an in vitro overexpression assay showed that these mutations did not influence HIV-2-Vif-mediated degradation of APOBEC3G. Unexpectedly, another polymorphism L71R, conferred resistance to Vif-mediated ubiquitin degradation, strongly suggesting that L71R might play an important role in antiviral defense mechanisms.

Anthocyanin is involved in the activation of pyroptosis in oral squamous cell carcinoma.

BACKGROUND: The anti-carcinogenic effects of anthocyanin are well documented. Oral squamous cell carcinoma is one of the most common and lethal cancer types due to its high degree of malignancy and poor prognosis. The main purpose of the current study was to investigate the potential inhibitory effects of anthocyanin on oral squamous cell carcinoma and identify effective targets for therapy. METHODS: Cell viability was measured using cell counting kit-8 (CCK8). Cell migration and invasion abilities were determined using scratch-wound and Transwell invasion assays, respectively. mRNA and protein expression patterns of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3), caspase-1 and IL-1ß were detected using qRT-PCR, immunofluorescence and western blot. The gasdermin D (GSDMD) level was determined via confocal microscopy and western blot. RESULTS: Anthocyanin reduced the viability of oral squamous cell carcinoma cells and inhibited migration and invasion abilities. Simultaneously, activation of pyroptosis was associated with enhanced expression of NLRP3, caspase-1, and IL-1ß. Upon administration of caspase-1 inhibitors, anthocyanin-activated pyroptosis was suppressed and cell viability, migration, and invasion rates concomitantly enhanced. CONCLUSION: Anthocyanin promotes the death of oral squamous cell carcinoma cells through activation of pyroptosis and inhibits tumor progression.

Caspase-1 regulate AngII-induced cardiomyocyte hypertrophy via upregulation of IL-1ß.

Cardiac hypertrophy is a compensatory response to stress or stimuli, which results in arrhythmia and heart failure. Although multiple molecular mechanisms have been identified, cardiac hypertrophy is still difficult to treat. Pyroptosis is a caspase-1 dependent pro-inflammatory programmed cell death. Caspase-1 is involved in various types of diseases, including hepatic injury, cancers, and diabetes related complications. However, the exact role of caspase-1 in cardiac hypertrophy is yet to be discovered. The present study aimed to explore the possible role of caspase-1 in pathogenesis of cardiac hypertrophy. We established cardiac hypertrophy models both in vivo and in vitro to detect the expression of caspase-1 and IL-1ß. The results showed that caspase-1 and IL-1ß expression levels were significantly upregulated during cardiac hypertrophy. Subsequently, caspase-1 inhibitor was co-administered with angiotensin II (Ang II) in cardiomyocytes to observe whether it could attenuate cardiac hypertrophy. Results showed that caspase-1 attenuated the pro-hypertrophic effect of Ang II, which was related to the downregulation of caspase-1 and IL-1ß. In conclusion, our results provide a novel evidence that caspase-1 mediated pyroptosis is involved in cardiac hypertrophy, and the inhibition of caspase-1 will offer a therapeutic potential against cardiac hypertrophy.

Downregulation of Long Non-Coding RNA Kcnq1ot1: An Important Mechanism of Arsenic Trioxide-Induced Long QT Syndrome.

BACKGROUND/AIMS: Arsenic trioxide (ATO) is a known anti-acute promyelocytic leukemia (APL) reagent, whose clinical applications are limited by its serious cardiac toxicity and fatal adverse effects, such as sudden cardiac death resulting from long QT syndrome (LQTS). The mechanisms of cardiac arrhythmia due to ATO exposure still need to be elucidated. Long non-coding RNAs (lncRNAs) are emerging as major regulators of various pathophysiological processes. This study aimed to explore the involvement of lncRNAs in ATO-induced LQTS in vivo and in vitro. METHODS: For in vivo experiments, mice were administered ATO through the tail vein. For in vitro experiments, ATO was added to the culture medium of primary cultured neonatal mouse cardiomyocytes. To evaluate the effect of lncRNA Kcnq1ot1, siRNA and lentivirus-shRNA were synthesized to knockdown lncRNA Kcnq1ot1. RESULTS: After ATO treatment, the Kcnq1ot1 and Kcnq1 expression levels were down regulated. lncRNA Kcnq1ot1 knockdown prolonged the action potential duration (APD) in vitro and exerted LQTS in vivo. Correspondingly, Kcnq1 expression was decreased after silencing lncRNA Kcnq1ot1. However, the knockdown of Kcnq1 exerted no effect on lncRNA Kcnq1ot1 expression. CONCLUSIONS: To our knowledge, this report is the first to demonstrate that lncRNA Kcnq1ot1 downregulation is responsible for QT interval prolongation induced by ATO at least partially by repressing Kcnq1 expression. lncRNA Kcnq1ot1 has important pathophysiological functions in the heart and could become a novel antiarrhythmic target.

The Protective Effects of 18ß-Glycyrrhetinic Acid on Helicobacter pylori-Infected Gastric Mucosa in Mongolian Gerbils.

18ß-Glycyrrhetinic acid (GRA), a major component of Glycyrrhiza glabra, is widely used therapeutically in clinic. In this study, the effect of GRA on Helicobacter pylori- (H. pylori-) infected gastritis was investigated in Mongolian gerbils in vivo. The gerbils were randomly divided into groups: uninfected; H. pylori-infected; H. pylori + antibiotics (clarithromycin, amoxicillin, and esomeprazole); and H. pylori + GRA. The gastric intraluminal pH value, histopathological changes, and the expression levels of inflammation-related cytokines (IL-1ß, TNF-α, COX-2, and iNOS) were investigated. The results showed that, in the H. pylori + GRA group, the intraluminal gastric pH value was lower (2.14 ± 0.08 versus 3.17 ± 0.23, P < 0.05), erosion and hyperplasia were alleviated, the infiltration of neutrophils and mononuclear cells was attenuated (P < 0.05), and the expression levels of TNF-α, IL-1ß, COX-2, and iNOS were decreased (P < 0.05) compared with the H. pylori-infected group. There was no significant difference in results between the H. pylori + GRA group and the H. pylori + antibiotics group. This study indicated that GRA significantly attenuated H. pylori-infected gastritis in gerbils and has the potential to be developed as a new therapeutic drug.

Focal adhesion kinase activation is required for TNF-α-induced production of matrix metalloproteinase-2 and proinflammatory cytokines in cultured human periodontal ligament fibroblasts.

Since focal adhesion kinase (FAK) was proposed as a mediator of the inflammatory response, we have investigated the role of this molecule in the release of inflammatory cytokines by cultured human periodontal ligament fibroblasts (HPDLFs), cells that are thought to be important in the patient's response to periodontal infection. Human periodontal ligament fibroblasts were stimulated by tumor necrosis factor alpha (TNF-α) and its effects on interleukin (IL)-6 and IL-8 release were measured by ELISA. Expression of matrix metalloproteinase 2 (MMP-2) protein was analysed by western blotting. The levels of IL6, IL8, and MMP2 mRNA were evaluated by real-time PCR. Tumor necrosis factor alpha dose-dependently induced the phosphorylation of FAK, whereas small interfering FAK (siFAK) inhibited TNF-α-induced FAK phosphorylation. Tumor necrosis factor alpha also stimulated the production of IL-6, IL-8, and MMP-2 in a dose-dependent manner. Knockdown of FAK significantly suppressed TNF-α-induced expression of IL6 and IL8 mRNA and release of IL-6 and IL-8 protein in HPDLFs. Similarly, MMP-2 down-regulation was significantly prevented by siFAK. Our results strongly suggest that knockdown of FAK can decrease the production of TNF-α-induced IL-6, IL-8, and MMP-2 in HPDLFs. These effects may help in understanding the mechanisms that control expression of inflammatory cytokines in the pathogenesis of periodontitis.