Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive. Methods: Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The 'in vivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2SR and Huh7SR xenografts. Molecular docking was done with Swiss dock and Auto Dock Vina. Results: PH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3Tyr705 level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway. Conclusion: Our data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1-mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations. Graphical abstract: [Figure not available: see fulltext]. - 2019 The Author(s).The publication of this article was funded by the Qatar National Library, Qatar. The graphical abstract was created with BioRender.comScopu

Gold-containing compound BDG-I inhibits the growth of A549 lung cancer cells through the deregulation of miRNA expression

Gold complex bis(diethyldithiocarbamato-gold(I)) bis(diphenylphosphino) methane (BDG-I) is cytotoxic toward different cancer cell lines. We compared the cytotoxic effect of BDG-I with that of cisplatin in the A549 lung cancer cell line. Additionally, we investigated the molecular mechanism underlying the toxic effect of BDG-I toward the A549 cell line and the identification of cancer-related miRNAs likely to be involved in killing the lung cancer cells. Further, X-ray crystallographic data of the compound were acquired. Using microarray, global miRNA expression profiling in BDG-I-treated A549 cells revealed 64 upregulated and 86 downregulated miRNAs, which targeted 4689 and 2498 genes, respectively. Biological network connectivity of the miRNAs was significantly higher for the upregulated miRNAs than for the downregulated miRNAs. Two of the 10 most upregulated miRNAs (hsa-mir-20a-5p and hsa-mir-15b-5p) were associated with lung cancer. AmiGo2 server and Panther pathway analyses indicated significant enrichment in transcription regulation of miRNA target genes that promote intrinsic kinase-mediated signaling, TGF-?, and GnRH signaling pathways, as well as oxidative stress responses. BDG-I crystal structure X-ray diffraction studies revealed gold?gold intramolecular interaction [Au?Au = 3.1198 (3) �] for a single independent molecule, reported to be responsible for its activity against cancer. Our present study sheds light on the development of novel gold complex with favorable anti-cancer therapeutic functionality.The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through the Research Project No. R5-16-02-14 .Scopu

Genotoxic impact of long-term cigarette and waterpipe smoking on DNA damage and oxidative stress in healthy subjects

Although a plethora of studies have examined tobacco smoke-cancer disease association, the involvement of cellular genetic toxicity remains unclear. Therefore, the present study provides molecular evidence for a pathway involved in the DNA damage induced by long-term cigarette and waterpipe smoke in human subjects. The study population consisted of 45 subjects who were divided into three groups; healthy nonsmokers group, cigarette smokers group, and waterpipe smokers group. A questionnaire and consent form was distributed and signed by all participants. Total RNA was extracted from the blood using PAXgene Blood RNA Kit and mRNA expression levels of target genes were quantified by RT-PCR. Our results showed that 80% of the participants smoke 20-39 cigarettes/day, whereas 12% smoke more than 40 cigarettes/day. With regard to waterpipe smoke, the majority (46%) smoke more than 5 times/week. Both cigarette and waterpipe smokers showed increased the plasma levels 8-hydroxy-2'-deoxyguanosine (8-OHdG), of DNA damage marker. In addition, the mRNA expression levels of DNA repair genes (OGG1 and XRCC1) were significantly inhibited in both cigarette and waterpipe smokers groups by 30% and 60%, respectively. This was associated with a marked decrease (50%) in the expression of detoxifying genes (NQO1 and GSTA1) with an increase in CYP1A1 mRNA expression, a cancer-activating gene. Both cigarette and waterpipe smokers increased in the plasma concentrations of several toxic heavy metals such as Cd (130%), Pb (47%), and Ni (30%). In conclusion: the present findings clearly explore the genotoxic effect of cigarette and waterpipe smoking on human DNA.The present study demonstrates the first evidence of the genotoxic effect of cigarette and waterpipe smoke in humans. This is supported by the following findings: First, induction of oxidative DNA damage marker (8-OHdG) and inhibition of DNA repair genes (OGG1 and XRCC1) by both cigarette and waterpipe smoke at the mRNA and activity levels. Second, inhibition of cytoprotective and antioxidant genes (NQO1 and GST). Third, induction of cancer-activating gene (CYP1A1).Scopu

Meteorological Factors and Seasonal Stroke Rates: A Four-year Comprehensive Study

Introduction: There is a growing body of evidence suggesting that acute cardiovascular events including stroke are not distributed randomly over time but instead depend on months/season of the year. We report the impact of meteorological variables in extremely hot and arid climate on stroke. Methods: Acute stroke patients admitted from January 2014 to December 2017 were included. The data included demographics, clinical risk factors, temperature, solar radiation, relative humidity, dew point, wind speed, and atmospheric pressure. We calculated stroke rates/100,000/month. Results: There were 3654 cases of stroke (ischemic stroke [IS]: 2956 [80.9%]; and intracerebral hemorrhage [ICH]: 698 [19.1%]) with no difference in hematocrit, creatinine, and blood urea between hot and cold seasons (p > .05). We observed a positive significant correlation of IS with the mean temperature (AOR: 1.023; 95% CI: 1.009-1.036; P = .001) and mean solar radiation (AOR: 1.268; 95% CI: 1.021-1.575; P = .032) showing a 2.3% and 26.8% higher risk relative to ICH respectively, a negative correlation between IS with relative humidity (AOR: 0.99; 95% CI: 0.984-0.997; P = .002), and atmospheric pressure (AOR: 0.977; 95% CI: 0.966-0.989; P < .001) was observed, 1% increase in the relative humidity correlate with 2.4% and 1% lower risk of IS incidence relative to ICH respectively. Conclusion: We demonstrated a distinct seasonal pattern in the incidence of stroke with an increase in IS rates relative to ICH during the summer months with higher solar radiations that cannot be explained by physiological measures suggestive of dehydration or hem-concentration. - 2019 Elsevier Inc.Scopu