Schistosomicidal effects of histone acetyltransferase inhibitors against Schistosoma japonicum juveniles and adult worms in vitro.

BACKGROUND: Schistosomiasis is a relatively neglected parasitic disease that afflicts more than 250 million people worldwide, for which the control strategy relies mainly on mass treatment with the only available drug, praziquantel (PZQ). This approach is not sustainable and is a priority for developing novel drug candidates for the treatment and control of schistosomiasis. METHODOLOGYS/PRINCIPAL FINDINGS: In our previous study, we found that DW-3-15, a kind of PZQ derivative, could significantly downregulate the expression of the histone acetyltransferase of Schistosoma japonicum (SjHAT). In this study, several commercially available HAT inhibitors, A485, C646 and curcumin were screened in vitro to verify their antischistosomal activities against S. japonicum juveniles and adults. Parasitological studies and scanning electron microscopy were used to study the primary action characteristics of HAT inhibitors in vitro. Quantitative real-time PCR was employed to detect the mRNA level of SjHAT after treatment with different HAT inhibitors. Our results demonstrated that curcumin was the most effective inhibitor against both juveniles and adults of S. japonicum, and its schistosomicidal effects were time- and dose dependent. However, A485 and C646 had limited antischistosomal activity. Scanning electron microscopy demonstrated that in comparison with DW-3-15, curcumin caused similar tegumental changes in male adult worms. Furthermore, both curcumin and DW-3-15 significantly decreased the SjHAT mRNA level, and curcumin dose-dependently reduced the SjHAT expression level in female, male and juvenile worms. CONCLUSIONS: Among the three commercially available HATs, curcumin was the most potent against schistosomes. Both curcumin and our patent compound DW-3-15 markedly downregulated the expression of SjHAT, indicating that SjHAT may be a potential therapeutic target for developing novel antischistosomal drug candidates.

Effects of an explain-simulate-practice-communicate-support intervention on quality of life for patients with chronic heart failure: A randomized control trial.

Background: Patients with New York Heart Association (NYHA) grade III chronic heart failure (CHF) present with low capacity for daily activities, severe self-perceived burden, and poor quality of life. Effective nursing interventions may reduce patients' self-perceived burden and improve their quality of life. Objectives: To explore the effects of an explain-simulate-practice-communicate-support intervention on the self-perceived burden, cardiac function, and activities of daily living (ADL) ability in patients with New York Heart Association grade III chronic heart failure. Methods: Of the 100 patients with New York Heart Association grade III chronic heart failure who were electronically randomized and equally divided into control and intervention groups, data from 88 patients who completed our study were analyzed. The primary outcome was quality of life; secondary outcomes were self-perceived burden, 6-min walking test distances, serum N-terminal pro-brain natriuretic peptide levels, New York Heart Association cardiac function classification, and ability to perform activities of daily living. Results: After 12 weeks' intervention, the intervention group had significantly lower self-perceived burden, Minnesota Living with Heart Failure Questionnaire scores, N-terminal pro-brain natriuretic peptide levels, and New York Heart Association grades compared with the control group, while 6-min walking test distances, left ventricular ejection fraction, and modified Barthel Index scale scores were significantly higher than those in the control group (P > 0.05). Conclusions: The explain-simulate-practice-communicate-support intervention improved patients' quality of life through reducing the level of self-perceived burden, and improving cardiac function and activities of daily living ability. This intervention was found to be effective for patients with New York Heart Association grade III chronic heart failure.

The effectiveness of optimal exercise-based strategy for patients with hip fracture: a systematic review and Bayesian network meta-analysis.

The implementation of exercise intervention (EI) presents a promising and economical way for patients with hip fracture. However, the optimal type of EI remains unclear. The objective of this study is to evaluate the efficacy of various EI approaches and identify the optimal intervention for improving the prognosis of patients with hip fracture. A comprehensive search of Medline (via PubMed), Web of Science, Embase, Cochrane Central Register of Controlled Trials, CINAHL, CNKI, Wan Fang, VIP, and CBM was conducted from their earliest records to June 2022. The included randomized controlled trials (RCTs) included at least one type of exercise for patients with hip fracture. The methodological quality of these trials was assessed using the Cochrane Collaboration Risk of Bias Tool. All direct and indirect comparisons were analyzed by Stata 14.0 and OpenBUGS 3.2.3 software. The primary outcome was hip function, and the secondary outcomes were activity of daily living (ADL), walking capacity and balance ability of patients. Based on the ranking probabilities, resistance exercise (RE) was ranked as the most effective among all exercise interventions (surface under cumulative ranking curve values [SUCRA]: 94.8%, [MD]: - 11.07, [Crl]: - 15.07 to - 7.08) in improving the efficacy of patients' hip function, followed by balance exercise (BE) ([SUCRA]:81.1%, [MD]: - 8.79, [Crl]: - 13.41 to - 4.18) and muscle strength exercise ([SUCRA]:57.6%, [MD]: - 5.35, [Crl]: - 9.70 to - 0.95). For the improvement of ADL for patients with hip fracture, BE ([SUCRA]:98.4%, [MD]: - 17.38, [Crl]: - 23.77 to - 11.04) may be the best EI. The findings of this study indicate that RE and BE might be the best approach to improve prognosis for patients with hip fracture. However, further rigorous and meticulously planned RCTs are required to substantiate the conclusions drawn from this study.

Interleukin 6-triggered ataxia-telangiectasia mutated kinase activation facilitates epithelial-to-mesenchymal transition in lung cancer by upregulating vimentin expression.

Matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) contribute to metastasis. As shown in our previous studies, interleukin-6 (IL-6) induces ATM phosphorylation to increase MMP expression and metastasis in lung cancer. However, the exact roles of ATM activation in the IL-6-induced epithelial-mesenchymal transition and lung cancer metastasis are currently unclear. Here, ATM phosphorylation exerts its pro-metastatic effect via vimentin-mediated epithelial-mesenchymal transition, which was supported by the evidence described below. Firstly, IL-6 treatment increases vimentin expression via the ATM-NF-κB pathway. Second, ATM inactivation not only abolishes IL-6-induced increases in vimentin expression but also inhibits IL-6-induced nest formation in a xenograft lung metastasis model. Moreover, close positive correlations were observed between ATM phosphorylation and vimentin upregulation, IL-6 levels and metastasis in lung cancer specimens. Hence, ATM modulates vimentin expression to facilitate IL-6-induced epithelial-mesenchymal transition and metastasis in lung cancer, indicating that ATM and vimentin might be potential therapeutic targets for inflammation-associated lung cancer metastasis.

TIPE attenuates the apoptotic effect of radiation and cisplatin and promotes tumor growth via JNK and p38 activation in Raw264.7 and EL4 cells.

Tumor necrosis factor α­induced protein 8 (TIPE) is highly expressed in many types of malignancies. Apoptosis is the process of programmed cell death which maintains the balance of cell survival and death. TIPE is involved in the carcinogenesis of many tumor types, yet the exact role of TIPE in defective apoptosis­associated carcinogenesis remains uncertain. In the present study, TIPE­overexpressing Raw264.7 and EL4 cells and vector control cells were treated with 4 mJ/cm2 ultraviolet radiation or 2 µg/ml cisplatin. Following ultraviolet irradiation, TIPE overexpression decreased the percentage of apoptotic cells as detected by flow cytometric and reversed the cisplatin­mediated decrease in mitochondrial membrane potential by JC­1 assay. Western blot analyses also revealed that TIPE overexpression inhibited cisplatin­induced activation of caspase­3 and ­9 and PARP. Secondly, TIPE overexpression increased the levels of phosphorylated JNK, MEK and p38. Moreover, inhibition of JNK and p38, but not MEK, efficiently abolished the cell pro­survival effect of TIPE. Most importantly, an in vivo tumor implantation model revealed that TIPE overexpression augmented the volume and weight of the implanted tumors, indicating that TIPE facilitated tumor formation. We found that TIPE exhibited an anti­apoptotic effect via JNK and p38 activation, which ultimately promoted tumor. Hence, the present study revealed that activation of JNK and p38 kinases contribute to the TIPE­mediated anti­apoptotic effect, indicating that JNK and p38 may be potential therapeutic molecules for TIPE overexpression­associated diseases.

Effects of different bolus and swallow patterns on esophageal manometry in patients with gastroesophageal reflux disease / 西安交通大学学报(医学版)

Objective To investigate the effects of different bolus and swallow patterns on esophageal manometry in patients with gastroesophageal reflux disease by high resolution manometry .Methods Patients with gastroesophageal reflux disease questionnaire score of more than 8 points and positive 24-hour pH monitoring were included in the study .All the patients were detected by liquid swallow ,solid swallow and continuous swallow .The parameters and comprehensive diagnosis were in accordance with the Chicago Standard .Results A total of 42 patients with gastroesophageal reflux disease were enrolled . Compared with the dynamic parameters of liquid swallow ,the residual pressure of upper esophageal sphincter [(11 .07 ± 3 .97 ,5 .29 ± 3 .36)mmHg] decreased ,the distal latency [(6 .28 ± 1 .87 ,8 .98 ± 2 .25)s] ,and lower esophageal sphincter relaxation time [(7 .79 ± 0 .98 ,10 .69 ± 13 .04)s] prolonged significantly (all P<0 .05) .In the comprehensive diagnosis of esophageal motility ,compared with liquid swallow (38 .1% ) , continuous liquid swallow showed a more sensitive positive diagnostic rate of ineffective esophageal motility (IEM) (63 .2% ) ,with a significant difference (P=0 .008) .Compared with that of liquid swallow ,the diagnostic rate (45 .2% ) of IEM by the solid swallow did not differ significantly (P=0 .581) . Among the ineffective contraction ,the rate of failed contraction (44.3% ) of solid swallow was higher than that of liquid swallow (22 .6% ) .Conclusion Solid swallow is more likely to induce severe esophageal hypomotility disorders than liquid swallow.Continuous swallow has more sensitivity in the diagnosis of IEM.Therefore.it can be used as a supplement to routine manometry in patients with eastroesophageal reflux disease.

Nicotine promotes cell proliferation and induces resistance to cisplatin by α7 nicotinic acetylcholine receptor­mediated activation in Raw264.7 and El4 cells.

Although nicotine is a risk factor for carcinogenesis and atherosclerosis, epidemiological data indicate that nicotine has therapeutic benefits in treating Alzheimer's disease. Our previous studies also showed that nicotine-treated dendritic cells have potential antitumor effects. Hence, the precise effects of nicotine on the biological characterizations of cells are controversial. The aim of the present study was to assess the roles of α7 nicotinic acetylcholine receptors (nAChRs), Erk1/2-p38-JNK and PI3K-Akt pathway in nicotine-mediated proliferation and anti-apoptosis effects. The results firstly showed that nicotine treatment clearly augmented cell viability and upregulated PCNA expression in both Raw264.7 and El4 cells. Meanwhile, nicotine afforded protection against cisplatin-induced toxicity through inhibiting caspase-3 activation and upregulating anti-apoptotic protein expression. Further exploration demonstrated that nicotine efficiently abolished cisplatin-promoted mitochondria translocation of Bax and the release of cytochrome c. The pretreatment of α-bungarotoxin and tubocurarine chloride significantly attenuated nicotine-augmented cell viability, abolished caspase-3 activation and α7 nAChR upregulation. Both Erk-JNK-p38 and PI3K-Akt signaling pathways could be activated by nicotine treatment in Raw264.7 and El4 cells. Notably, when Erk-JNK and PI3K-Akt activities were inhibited, nicotine-augmented cell proliferation and anti-apoptotic effects were abolished accordingly. The results presented here indicate that nicotine could achieve α7 nAChR-mediated proliferation and anti-apoptotic effects by activating Erk-JNK and PI3K-Akt pathways respectively, providing potential therapeutic molecules to deal with smoking-associated human diseases.

Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells.

Multidrug resistance (MDR) formation is an important problem in lung cancer chemotherapy. Our study showed that both camptothecin and cisplatin could not only induce ATM and NF-κB activation but also upregulate expression of the MDR-related genes ABCG2, MRP2 in NCI-H446 cells. Moreover, camptothecin and cisplatin-induced ABCG2 and MRP2 upregulation could be impaired by ATM and NF-κB inhibitors, indicating a relationship between ATM, NF-κB activation and MDR formation in lung cancer chemo-therapy. Our study indicates that ATM may serve as a potential molecular target for MDR formation in lung cancer chemotherapy.

TGF-ß of lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generation.

The effects of TGF-ß on dendritic cells (DCs) on the tumor microenvironment are not well understood. We report, here, the establishment of an in vitro lung cancer microenvironment by co-incubation of seminaphtharhodafluor (SNARF) labeled Lewis lung cancer (LLC) cells, carboxyfluorescein succinimidyl ester (CFSE) labeled fibroblasts and 4-chloromethyl-7-hydroxycoumarin (CMHC) labeled DCs. Raw 264.7, EL4 and NCI-H446 cells were able to synthesize TGF-ß which was determined by flow cyto-metry and western blotting, respectively. Furthermore, TGF-ß efficiently increased regulatory T-cell (Treg) expansion and upregulated DC B7H1 and GITRL expression. TGF-ß and the co-incubation of LLC cells, fibroblasts with DCs could augment the expression of B7H1 and GITRL molecules of DCs. The data presented here indicate that the B7H1 and GITRL molecules may play an important role in TGF-ß-induced Treg expansion of lung cancer microenvironment.

Lipopolysaccharide and dose of nicotine determine the effects of nicotine on murine bone marrow-derived dendritic cells.

The reported effects of nicotine on dendritic cells (DCs) are controversial. To investigate the factors which determine the effects of nicotine on DCs, immature dendritic cells (imDCs) induced from murine bone marrow were treated with different doses of nicotine with or without lipopolysaccharides (LPS). The morphology and expression of the co-stimulatory molecules CD80, CD86, CD40 and CD54 were observed and determined by microscopy and flow cytometry, respectively. The results showed that, firstly, nicotine treatment promoted the development of DC precursors into imDCs with a semi-mature phenotype revealed by a higher expression of CD11c and more branched projections. Secondly, lower doses of nicotine (16.5 ng/ml), but not higher (200 µg/ml), up-regulated the expression of the co-stimulatory molecules CD80, CD40 and CD54 on imDCs. Co-administration of LPS and nicotine revealed differential effects on co-stimulatory molecule expression on imDCs. Thirdly and importantly, treatment with lower doses of nicotine (16.5 ng/ml) did not augment expression of the CD80, CD86, CD40 and CD54 molecules in mature DCs. Fourthly and interestingly, high doses of nicotine (more than 165 µg/ml) revealed pro-apoptotic activity but lower doses of nicotine (16.5-0.165 ng/ml) achieved an anti-apoptotic effect on imDCs. All data presented here indicate that the controversial effects of nicotine on DCs may be due to the LPS of the nicotinic environment and the dose of nicotine used.

Minimally invasive treatment for severely displaced proximal humeral fractures in children using titanium elastic nails.

OBJECTIVE: To evaluate the preliminary results of minimally invasive treatment for severely displaced proximal humeral fractures in children using titanium elastic nails (TENs). METHODS: Twenty-five cases of TEN treatment of severely displaced proximal humerus fractures in children were evaluated clinically and radiographically. Complications were assessed. The 14 males and 11 females were between 6 and 15 years of age at the time of surgery. Of the 10 left and 15 right humeri treated, 3 were open fractures and 2 were associated with polytrauma. Two laterally inserted retrograde TENs were used in 22 cases. In the remaining 3 cases, 1 medial and 1 lateral TEN were inserted retrograde. RESULTS: Follow-up ranged from 7 to 40 months. All fractures showed both clinical and radiographic evidence of healing within 2 months. There were no major complications related to the treatment. There were 3 cases of skin irritation adjacent to prominent distal ends of the nails, of which the 2 nails in 1 child were removed prematurely at 3 weeks without sequelae. The nails in the other 2 cases were removed at the planned 6-month postoperative time with complete resolution of symptoms. Function of the fractured arm returned to normal quickly in all cases. CONCLUSIONS: TEN for the treatment of severely displaced humerus fractures in children is an effective method with a low complication rate.