Biology subjects

Afifi, M.

Publications and source records attributed to Afifi, M..

4 recordsLinked to original sources

bioRxiv2024

Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by MAP3K13) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified MAP3K13. A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules. Inhibition of LZK catalytic activity suppressed tumor growth in HNSCC PDX models with amplified MAP3K13. We found that the kinase activity of LZK stabilized c-MYC and that LZK stabilized gain-of-function (GOF) p53 through a kinase-independent mechanism. Therefore, we designed proteolysis-targeting chimeras (PROTACs) and demonstrate that our lead PROTAC promotes LZK degradation and suppresses expression of GOF p53 and c-MYC leading to impaired viability of HNSCC cell lines. This research provides a strong basis for development of therapeutics targeting LZK in HNSCCs with amplification of the gene. One Sentence SummaryThis study establishes the kinase LZK as a therapeutic target for HNSCC through regulation of c-MYC expression.

cancer biology↗

bioRxiv2023

RNA Helicase DDX3 Regulates RAD51 Localization and DNA Damage Repair in Ewing Sarcoma

We previously demonstrated that RNA helicase DDX3X (DDX3) can be a therapeutic target in Ewing sarcoma (EWS), but its role in EWS biology remains unclear. The present work demonstrates that DDX3 plays a unique role in DNA damage repair (DDR). We show that DDX3 interacts with several proteins involved in homologous recombination, including RAD51, RECQL1, RPA32, and XRCC2. In particular, DDX3 colocalizes with RAD51 and RNA:DNA hybrid structures in the cytoplasm of EWS cells. Inhibition of DDX3 RNA helicase activity increases cytoplasmic RNA:DNA hybrids, sequestering RAD51 in the cytoplasm, which impairs nuclear translocation of RAD51 to sites of double-stranded DNA breaks thus increasing sensitivity of EWS to radiation treatment, both in vitro and in vivo. This discovery lays the foundation for exploring new therapeutic approaches directed at manipulating DDR protein localization in solid tumors.

cancer biology↗

bioRxiv2020

Protective effect of Morus macroura Miq. fruit extract against acetic acid-induced ulcerative colitis in rats: Involvement of miRNA-223 and TNFα/NFκB/NLRP3 inflammatory pathway

Tumor necrosis factor receptor (TNFR) activation and nuclear factor kappa B (NF{kappa}B) expression play a significant role in the activation of nod-like receptor pyrin domain-1 containing 3 (NLRP3) inflammasome inflammatory pathway, which is involved in the pathogenesis of ulcerative colitis (UC). Furthermore, miRNA-223 expression was shown to exert counter-regulatory effect on NLRP3 expression. Interestingly, polyphenols are attaining increased importance for their potential effectiveness in ameliorating certain diseases owing to their antioxidant and anti-inflammatory activity. In accord, our study attempted to investigate the effect of mulberry tree (Morus macroura) fruit extract (MFE) against acetic acid (AA)- induced UC in rats, which is not previously investigated, based on previous promising results for MFE in alleviating gastric ulcer in rats. First, total phenolic (TPC), total flavonoid (TFC), and total anthocyanin content (TAC) were determined in MFE. Then, MFE (300 mg/kg) and sulfasalazine (Sulfa), as a standard treatment (100 mg/kg), were given orally for seven days before intra-rectal induction of UC by AA (2 ml, 4% v/v) on day eight. The extent of UC was evaluated macroscopically and microscopically. Biochemically, the colonic TNFR1, NLRP3, p- NF{kappa}B p65, TNF, interleukin-1 beta (IL-1{beta}), IL-18 levels, miRNA-223 expression and caspase-1 activity were assayed. MFE significantly reduced macroscopic and microscopic scores, colonic levels of TNFR1, NLRP3, p-NF{kappa}B p65, TNF, IL-1{beta}, IL-18, and caspase-1 activity, and showed increased miRNA-223 expression, almost similarly to Sulfa effects. In conclusion, our study provided a novel impact for MFE against AA-induced UC in rats through affecting miRNA-223 expression and halting TNF/NF{kappa}B/NLRP3 inflammatory pathway.

pharmacology and toxicology↗

bioRxiv2020

In vetro study on the toxic effects of acrylamide on blood antioxidants, ameliorative effects of vitamin C

BackgroundAcrylamide (ACR) is a naturally occurring, widely used compound, it is generated during cocking carbohydrate rich food at high temperature. Ingestion of large amounts of ACR underlies several health concerns and teratogenicity. Ascorbic acid (vit C) is a strong reducing agent greatly used to clean free radicals. Materials and methodsBlood sample was obtained from 46 years old, healthy nonsmoking man in heparinized tubs. Blood sample was immediately divided into seven parts as triplet for each. The first one was leaved as control, 2nd, 3rd and the 4th were treated with acrylamide in a concentration of 25,50 and 100 mM respectively, the 5th, 6th and the 7th were treated with acrylamide as the mentioned concentrations and vitamin C in a concentration of 100mM. Samples (one mile litter) from each tube were taken after four and 24 hours and were used for preparation of hemolysates, that were kept at -80{degrees}C till investigation of the biochemical parameters. ResultsThe concentrations of Malondialdehyd (MDA), nitric oxide (NO) and hydrogen peroxide (H2O2) increased in ACR and/or vit. C treated samples as compared with control. The concentration of reduced glutathione (GSH) and activities of Catalase (CAT), Superoxide dismutase (SOD), Glutathione reductase (GR), Glutathione peroxidase (GPx) and glucose 6 phosphate dehydrogenase (G6PDH) decreased significantly in ACR and/or vit. C treated samples as compared with control. Meanwhile, The concentrations of MDA, NO and H2O2 decreased in samples treated with both ACR and vit. C as compared with that treated with ACR only. The concentration of GSH and activities CAT, SOD, GR, GPx and G6PDH increased significantly in samples treated with both ACR and vit. C as compared with that treated with ACR only. ConclusionACR produce its toxic effect through its deleterious action on the antioxidant system through induction of pro-oxidants leading to exhausting of antioxidants. Vitamin C has an ameliorative action on the deleterious action exerted by ACR through improving the balance between pro-oxidants and antioxidant.

biochemistry↗