Triple-Negative Breast Cancer (TNBC) is one of the most aggressive and hot BC subtypes. Our research group has recently shed the light on the utility of natural compounds as effective ...immunotherapeutic agents. The aim of this study is to investigate the role of a methoxylated quercetin glycoside (MQG) isolated from
Cleome droserifolia
in harnessing TNBC progression and tuning the tumor microenvironment and natural killer cells cytotoxicity. Results showed that MQG showed the highest potency (IC
50
= 12 µM) in repressing cellular proliferation, colony-forming ability, migration, and invasion capacities. Mechanistically, MQG was found to modulate a circuit of competing endogenous RNAs where it was found to reduce the oncogenic MALAT-1 lncRNA and induce TP53 and its downstream miRNAs; miR-155 and miR-146a. Accordingly, this leads to alteration in several downstream signaling pathways such as nitric oxide synthesizing machinery, natural killer cells' cytotoxicity through inducing the expression of its activating ligands such as MICA/B, ULBP2, CD155, and ICAM-1 and trimming of the immune-suppressive cytokines such as TNF-α and IL-10. In conclusion, this study shows that MQG act as a compelling anti-cancer agent repressing TNBC hallmarks, activating immune cell recognition, and alleviating the immune-suppressive tumor microenvironment experienced by TNBC patients.
Recently, a novel crosstalk between non-coding RNAs (ncRNAs) has been casted. However, this has been seldom investigated in metastatic BC (mBC). H19 and miR-486-5p role in mBC are controversial. ...ICAM-1 is a recently recognized metastatic engine in mBC. Natural compounds were recently found to alter ncRNAs/target circuits. Yet, Hesperitin's modulatory role in altering such circuits has never been investigated in mBC.
The aim of this study is to investigate the impact of hesperitin on miR-486-5p/H19/ICAM-1 axis.
BC patients (n=20) were recruited in the study. Bioinformatic analysis was performed using different prediction softwares. MDA-MB-231 and MCF-7 cells were cultured and transfected using several oligonucleotides or treated with serial dilutions of hesperitin. RNA was extracted and gene expression analysis was performed using q-RT-PCR. ICAM-1 protein levels were assessed using human ICAM-1 Elisa Kit. Cytotoxic potential of hesperitin against normal cells was assessed by LDH assay. Several functional analysis experiments were performed such as MTT, colony forming and migration assays.
The study showed that miR-486-5p and H19 had paradoxical expression profiles in BC patients. miR- 486-5p mimics and H19 siRNAs repressed ICAM-1 and halted mBC hallmarks. A novel crosstalk between miR- 486-5p and H19 was observed highlighting a bi-directional relationship between them. Hesperetin restored the expression of miR-486-5p, inhibited H19 lncRNA and ICAM-1 expression and selectively regressed mBC cell aggressiveness.
miR-486-5p and H19 are inter-connected upstream regulators for ICAM-1 building up miR-486- 5p/H19/ICAM-1 axis that has been successfully tuned in mBC cells by hesperitin.
Triple Negative Breast Cancer (TNBC) immunotherapy has recently shown promising approach. However, some TNBC patients presented with resistance. One of the reasons was attributed to the excessive ...release of cytokines at the tumor microenvironment (TME) such as Tumor necrosis factor alpha (TNF-α) and Interleukin-10 (IL-10). Fine regulation of these cytokines’ levels via non-coding RNAs (ncRNAs) might alleviate the immune quiescent nature of TME at TNBC tumors. However, the extrapolation of ncRNAs as therapeutic tools is highly challenging. Therefore, disentanglement the nature for the isolation of natural compounds that could modulate the ncRNAs and their respective targets is an applicable translational therapeutic approach. Hence, this study aimed to targeting the chief immune suppressive cytokines at the TME (TNF-α and IL-10) via ncRNAs and to examine the effects of Rosemary aerial parts extract on the expression levels of these ncRNAs in TNBC. Results revealed miR-17-5p as a dual regulator of TNF-α and IL-10. Moreover, an intricate interaction has been shown between miR-17-5p and the oncogenic lncRNAs: MALAT1 and H19. Knocking down of MALAT1 and/or H19 caused an induction in miR-17-5p and reduction in TNF-α and IL-10 expression levels. miR-17-5p was found to be down-regulated, while TNF-α, IL-10, MALAT1 and H19 were up-regulated in BC patients. Forced expression of miR-17-5p in MDA-MB-231 cells reduced TNF-α, IL-10, MALAT1 and H19 expression levels, as well as several BC hallmarks. In a translational approach, ursolic acid (UA) isolated from rosemary induced the expression of miR-17-5p, MALAT1 and decreased H19 expression levels. In conclusion, this study suggests miR-17-5p as a tumor suppressor and an immune-activator miRNA in BC through tuning up the immunological targets TNF-α, IL-10 at the TME and the oncological mediators MALAT1 and H19 lncRNAs.
Introductions
Improved aerosol delivery of bronchodilators to chronic obstructive pulmonary disease (COPD) subjects is a cornerstone in the treatment approach. Drug delivery and response are improved ...with the use of accessory devices spacers and valved holding chambers (VHCs) with metred‐dose inhalers (pMDIs). However, different accessory devices are available in the market with different properties that could affect aerosol delivery. Thus, this study aimed to assess the relative lung deposition and systemic bioavailability and compare bronchodilator response of salbutamol delivered using different accessory devices attached to pMDIs.
Methods
Twelve healthy subjects and twelve COPD subjects inhaled 300 μg salbutamol (3 pMDI puffs) using five different accessory devices with either masks or mouthpieces (Able, Aerochamber plus flow Vu, Dolphin chamber, Tipshaler spacer, and modified Drink bottle spacer). Urine samples were collected thirty minutes post‐dosing and cumulatively for the next twenty‐four hours, to determine and compare the relative lung deposition 0‐0.5 hour excretion of urinary salbutamol (USAL0.5) and systemic bioavailability 0.5‐24 hours excretion of urinary salbutamol (USAL24) of salbutamol from the selected accessory devices. Also, the difference between pre and post‐inhalation forced expiratory volume in one second (ΔFEV1%) of predicted was determined for each accessory device.
Results
Urinary excretion of salbutamol (both USAL0.5 and USAL24 samples) in COPD subjects was significantly (P < .05) lower than in healthy subjects for all accessory devices. USAL0.5 and USAL24 in non‐antistatic spacers (modified Drink bottle spacer and Dolphin chamber spacers) were significantly lower (P < .05) than that for antistatic spacers (Aerochamber plus flow Vu, Able and Tips‐haler). No significant difference in USAL0.5 and USAL24 was observed between facemasks and mouthpieces.
There was a significant difference (P < .05) in ΔFEV1% of predicted values between COPD subjects and healthy subjects. However, within the COPD group and the healthy group there was no significant difference in ΔFEV1% of predicted values between all accessory devices or between with mouthpiece or with a mask.
Conclusions
COPD subjects had lower aerosol delivered compared with healthy subjects. Anti‐static accessory devices delivered a higher amount of aerosol compared with non‐antistatic accessory devices. Even though the presence of a significant difference in aerosol delivery between non‐antistatic and antistatic accessory devices no significant difference was found in the ΔFEV1% between all accessory devices.
Background
Helicobacter pylori infection has become more and more resistant to conventional first‐line treatment regimens. So, there is a considerable interest in evaluating new antibiotic ...combinations and regimens. Nitazoxanide is an anti‐infective drug with demonstrated activity against protozoa and anaerobic bacteria including H. pylori. This work is designed to evaluate the efficacy and safety of a unique triple nitazoxanide‐containing regimen as a treatment regimen in Egyptian patients with H. pylori infection.
Methods
Two hundred and 24 patients with upper gastrointestinal tract (GIT) dyspeptic symptoms in whom H. pylori ‐induced GIT disease was confirmed were included in the study. They have been randomized to receive either nitazoxanide 500 mg b.i.d., clarithromycin 500 mg b.i.d., and omeprazole 40 mg twice daily for 14 days or metronidazole 500 mg b.i.d., clarithromycin 500 mg b.i.d., and omeprazole 40 mg twice daily for 14 days. Laboratory evaluation for H. pylori antigen within the stool was performed 6 weeks after cessation of H. pylori treatment regimens to assess the response.
Results
The response to treatment was significantly higher in group 1 of nitazoxanide treatment regimen than group 2 of traditional treatment regimen. One hundred and six cases (94.6%) of 112 patients who completed the study in group 1 showed complete cure, while only 63 cases (60.6%) of 104 patients who completed the study in group 2 showed the same response according to per‐protocol (PP) analysis (P<.001). The regimen was well tolerated by all the patients enrolled in the study.
Conclusion
Nitazoxanide‐containing triple therapy is a promising therapy for the first‐line eradication of H. pylori. (ClinicalTrials.gov Identifier: NCT02422706).
Abstract
Background
We aimed to investigate the effect of transforaminal injection of Magnesium sulphate versus Ozone on pain intensity, functional disability and the oxidative stress biomarkers; ...superoxide dismutase (SOD) and Glutathione (GSH) in patients with lumbar disc prolapse.
Methods
This randomized controlled trial was conducted on 135 patients having symptomatic lumbar disc prolapse, received either transforaminal injection of Magnesium sulphate with steroids, Ozone with steroids, or steroids alone. Assessment of pain severity and functional disability were done before intervention, 2 weeks, 1, 3, and 6 months after intervention. Serum SOD and GSH were measured for all included patients before and 2 weeks after intervention.
Results
There was a statistically significant improvement in pain intensity and functional disability 2 weeks after intervention in the three groups, but at 1-month and 3-months after intervention, the significant improvement was in Mg sulphate and Ozone groups only. At 6-months follow up, Mg sulphate group only showed a significant improvement. There was a statistically significant increase in SOD and GSH serum levels, 2-weeks after intervention in both Magnesium sulphate (
P
-value = 0.002, 0.005 respectively) and ozone groups (
P
-value < 0.001, < 0.001), but there was no statistically significant change in SOD and GSH serum levels in control group.
Conclusion
Transforaminal injection of Mg sulphate in patients with lumbar disc prolapse causes significant long-term improvement (up to 6 months) in pain intensity and functional disability. The serum levels of SOD and GSH were significantly increased at 2 weeks following both transforaminal injection of Mg sulphate and ozone.
Background
The chemokine, C-X-C motif ligand 13 (CXCL13) plays an important role in B cell recruitment within the central nervous system (CNS). CXCL13 has been implicated as key regulatory factor in ...inflammatory CNS disorders including autoimmune CNS diseases.
Aim of the Work
To compare between the serum level of CXCL13 in patients diagnosed with acute central or peripheral demyelination and in healthy age and gender matched controls.
Patients and Methods
Twenty patients (patients’ group) diagnosed with acute demyelinating diseases (acute disseminated encephalomyelitis (ADEM; n = 7), acute necrotizing encephalopathy of childhood (ANEC; n = 3), autoimmune encephalitis (AE; n = 3), transverse myelitis (TM; n = 3), Guillain-Barré syndrome (GBS; n = 4) and 40 healthy age and gender matched children (control group), were enrolled in the study. All patients were subject to full history, examination and measurement of serum levels of CXCL13 in both cases and controls.
Results
Serum CXCL13 level status was significantly higher in cases compared to controls (p < 0.001). The mean serum CXCL13 level in cases was (341.75 ± 164.71 pg/ml) and in control was (51.5 ± 18.99 pg/ml).
Conclusion
Serum CXCL13 levels are significantly increased in pediatric patients with acute acquired central and peripheral demyelinating diseases of the nervous system.
The cancer chemopreventive activity of quinoxaline derivatives 1–20 has been evaluated by studying the inhibitory effect on Epstein–Barr virus early antigen (EBV-EA) activation. The quinoxaline ...derivatives 1–20 showed inhibitory effect on EBV-EA activation without cytotoxicity on Raji cells. All compounds exhibited dose dependent inhibitory activities, most of them showed significant activity at 1000 mol ratio/12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 7 and 9 exhibited stronger inhibitory effects on the EBV-EA activation than that of the representative control, oleanolic acid, at the highest measured concentration. In addition, compounds 7–10 showed potent and selective inhibition of human tyrosine kinase (TRK) in liver cancer HepG2 and breast cancer MCF-7 cell lines similar to the positive control, doxorubicin.
Display omitted The protein tyrosine kinase inhibition and molecular docking studies of new quinoxaline derivatives were performed in order to rationalize their studied chemopreventive activity.
•Synthesis of quinoxaline derivatives 1–20.•Studying of the possible inhibitory effects of synthesized the quinoxalines on Epstein–Barr virus early antigen activation.•Studying of the inhibition of human tyrosine kinase (TRK).•Molecular docking study.
Summary Background Colorectal cancer (CRC) is one of the most common malignant neoplasms in Egypt, and interestingly in young age. Adenomatous polyps and inflammatory bowel diseases (IBD) are ...considered the commonest pre-malignant lesions for CRC. A possible diagnostic role for different microRNAs on CRC has been suggested by numerous studies. Aim of work To assess the serum expression of 3 microRNA markers (miR-29a, miR-92a and miR-145) in pre-malignant and malignant colorectal lesions. Patients and methods The 60 patients studied were divided into 4groups: CRC group (25patients), IBD group (11patients), adenomatous polyps group (14 patients) and control group (10 patients). The serum expression of the 3 markers (miR-29a, miR-92a and miR-145) has been assessed by RT-PCR. Results All CRCs were sporadic cases. Significant downregulation of miR-145 in CRC group was reported at all levels, i.e. when compared to normal, among the 3 studied groups, and when compared between CRC and non-CRC groups. Significant upregulation of miR-29a in CRC was reported when compared to normal, but no significant difference existed either among the 3 studied groups or between CRC and the other 2 groups. All 3 miRNAs studied were positively inter-correlated. Conclusions miR-145 may be considered a promising non-invasive reliable diagnostic marker in CRC. Extended studies are needed to ascertain the diagnostic role of miRNAs in CRC.
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