Chlordiazepoxide against signalling, receptor and regulatory proteins of breast cancer: a structure-based in-silico approach.

Among the most prevalent forms of cancer are breast, lung, colon-rectum, and prostate cancers, and breast cancer is a major global health challenge, contributing to 2.26 million cases with approximately 685,000 deaths worldwide in 2020 alone, typically beginning in the milk ducts or lobules that produce and transport milk during lactation and it is becoming challenging to treat as the tissues are developing resistance, which makes urgent calls for new multitargeted drugs. The multitargeted drug design provides a better solution, simultaneously targeting multiple pathways, even when the drug resists one, it remains effective for others. In this study, we included four crucial proteins that perform signalling, receptor, and regulatory action, namely- NUDIX Hydrolases, Dihydrofolate Reductase, HER2/neu Kinase and EGFR and performed multitargeted molecular docking studies against human-approved drugs using HTVS, SP and extra precise algorithms and filtered the poses with MM\GBSA, suggested a benzodiazepine derivative chlordiazepoxide, used as an anxiolytic agent, can be a multitargeted inhibitor with docking and MM\GBSA score ranging from - 4.628 to - 7.877 and - 18.59 to - 135.86 kcal/mol, respectively, and the most interacted residues were 6ARG, 6GLU, 3TRP, and 3VAL. The QikProp-based ADMET and DFT computations showed the suitability and stability of the drug candidate followed by 100 ns MD simulation in water and MMGBSA on trajectories, resulting in stable performance and many intermolecular interactions to make the complexes stable, which favours that chlordiazepoxide can be a multitargeted breast cancer inhibitor. However, experimental validation is needed before its use.

Exploring Parental Knowledge, Attitudes, and Factors Influencing Decision-Making in Stem Cell Banking: Rising the Future of Medical Treatment.

BACKGROUND AND OBJECTIVES: Stem cell banking (SCB) is a promising area of modern medicine with the potential to yield innovative treatments and cures. To effectively educate parents and implement laws and regulations that address parental concerns and encourage informed decision-making, it is imperative to emphasize parental viewpoints and their consequences for future healthcare. The study aims to establish the Saudi Arabian population's level of understanding regarding SCB and to comprehend the elements influencing parental knowledge, attitudes, and SCB decision-making processes. METHODOLOGY: A cross-sectional study was conducted among the population in the Makkah region of Saudi Arabia. Demographic data, knowledge levels, attitudes, and decision-making variables were gathered from 380 respondents. RESULTS: The study reveals a lack in their comprehension of the objectives and possible uses of SCB, together with the main sources of information on those banks and conveniently available banking choices. It showed varied results regarding attitudes about considering an SCB for their children. In addition, the majority of respondents had not made a consent decision about SCB for their children. It also illuminates the factors that could influence participants' decisions about SCB for their children and shows that a lack of information and understanding is the main obstacle faced by parents regarding SCB. It highlights that participants were generally in favor of learning more about SCB for their children. CONCLUSIONS: This study broadens our understanding of parental decision-making toward SCB and clarifies the elements influencing parents' opinions and worries and offers significant ramifications for lawmakers, medical professionals, and SCB. These implications can be utilized to enhance communication strategies, create instructional programs, and ease the fears of concerned parents.

Serum Pro-Inflammatory Cytokines and Leptin as Potential Biomarkers for Treatment Response and Toxicity in Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Squamous cell carcinoma of the head and neck (HNSCC) is a globally prevalent form of cancer with significant morbidity and mortality rates. The present study examines the relationship of serum pro-inflammatory cytokines and leptin levels with the effectiveness of therapy in individuals with HNSCC and their potential role as biomarkers for treatment response and toxicity. Induction chemotherapy and concomitant chemoradiotherapy were evaluated for efficacy and safety in 52 individuals with HNSCC. Both response and toxicity were evaluated, and serum levels of pro-inflammatory cytokines Interlukin-1 beta (IL-1ß), Interlukin-2 (IL-2), Interlukin-6 (IL-6), and Tumor Necrosis Factor-Alpha (TNF-α) and leptin were measured using enzyme-linked immunoassay before and after treatment. Before treatment, these measurements were made in comparison with a control group with 50 healthy people. The results showed that serum cytokines and leptin levels varied depending on the response to treatment, with patients who had a complete or partial response (PR) showing significant decreases in IL-1 ß, IL-6, and TNF-α levels and significant increases in IL-2 and leptin levels after treatment, with an improvement in cachexia. These results imply that variations in serum pro-inflammatory cytokines and leptin levels are likely related to the therapeutic effectiveness in HNSCC and may act as biomarkers for treatment response.

Influence of COVID-19 infection/vaccination on menstrual regularity and hormonal function in Saudi females of reproductive age.

The COVID-19 pandemic has had a profound impact on women's health, particularly on their menstrual cycles. The menstrual cycle serves as a crucial indicator of fertility and reproduction. Objectives: This study aimed to examine the impact of COVID-19 infection and vaccination on menstrual regularity in Saudi women of childbearing age. Additionally, it sought to explore the potential effects of COVID-19 vaccination on serum hormonal levels during the follicular phase of the menstrual cycle, along with their relationship with Vit.D. Methods: This case‒control study investigated the impact of COVID-19 infection and vaccination on menstrual regularity and hormonal function in Saudi women of reproductive age. Data were collected from 79 women who attended the Outpatient Department of Obstetrics and Gynaecology at King Faisal Medical Complex in Taif, Saudi Arabia. All participants had received COVID-19 vaccines. The data collection process was comprehensive, encompassing various participant characteristics, such as demographic information, history of COVID-19 infection, and details about menstrual patterns before and after infection and vaccination. Furthermore, hormonal measurements, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol, prolactin, thyroid-stimulating hormone (TSH), and vitamin D (Vit.D) levels, were extracted from the participants' medical records. Results: Among the participants, 39.24 % had a history of COVID-19 infection, and following the infection, there was a significant increase in the proportion of women experiencing irregular menstruation. After receiving the COVID-19 vaccine, 72.15 % of the participants continued to have irregular menstrual cycles. The study found that a considerable number of participants had menstrual cycles outside the normal range, with 43.80 % having cycles shorter than 21 days and 35.10 % having cycles longer than 35 days. Comparing participants with regular and irregular cycles after COVID-19 vaccination, no significant changes were observed in most hormonal levels. However, the prolactin hormone showed a significant increase in participants with irregular cycles, while Vit.D levels were significantly decreased in this group. Conclusion: The study findings indicate a higher prevalence of irregular menstruation among participants, particularly after vaccination. Notably, irregular menstrual cycles were found to be associated with elevated levels of prolactin hormone and decreased levels of Vit.D.

Association Between Serum Uric Acid Levels and Oxido-Inflammatory Biomarkers With Coronary Artery Disease in Type 2 Diabetic Patients.

BACKGROUND: Cardiovascular disease signifies a major cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). Serum uric acid (SUA) levels are elevated during the initial phases of impaired glucose metabolism. This work was designed to explore the association between SUA levels, serum oxido-inflammatory biomarkers, and the risk of coronary artery disease (CAD) in T2DM patients as the primary outcome. The secondary outcome was to assess the prognostic role of SUA in the prediction of the risk of CAD in T2DM patients. METHODS: In this case-control study, we enrolled 110 patients with T2DM who were further divided into patients with CAD and without CAD. In addition, 55 control participants were stringently matched to cases by age. RESULTS: Diabetic patients with CAD had significantly higher serum levels of the inflammatory biomarkers and the oxidative malondialdehyde but significantly lower levels of serum total antioxidant capacity (TAC) compared with the controls and diabetic patients without CAD. Significant positive correlations existed between SUA levels and serum levels of the inflammatory biomarkers and malondialdehyde, while a significant negative correlation existed between SUA levels and serum TAC. SUA demonstrated an accepted discrimination ability. SUA can differentiate between T2DM patients with CAD and patients without CAD, an area under the curve of 0.759. CONCLUSIONS: Elevated serum levels of SUA and oxido-inflammatory biomarkers are associated with an increased risk of CAD in T2DM. SUA levels reflect the body's inflammatory status and oxidant injury in T2DM. SUA could be utilized as a simple biomarker in the prediction of CAD risk in T2DM.

Differentiation of Epileptic Brain Abnormalities among Neurological Patients at Taif Region Using MRI.

This study was conducted to assess the prevalence of epilepsy among different age groups and gender of neurological patients in the Taif region and define the most common brain lesion, affecting epileptic patients living in the Taif city using MRI. Data from 150 patients who were clinically diagnosed with epilepsy and had brain MRIs were analyzed using SPSS. Statistical significance was considered when the p value is 0.05. The percentage of epilepsy was generally higher in males than in females in the Taif city, and seizures were different between the studied age groups. However, epilepsy was more pronounced in females than in males at certain age groups. Moreover, white matter lesions were most commonly found in the studied group (27.7%), followed by focal lesions, edema, and stroke with equal percentages (16.9%) and less commonly with congenital diseases (12%) and atrophic changes (9.6%). Epilepsy was more pronounced in females than in males at certain age groups. White matter lesions were identified as the most common lesion, presenting in epilepsy patients in the Taif city.

Soluble Programmed Death-Ligand 1 (sPD-L1) as a Promising Marker for Head and Neck Squamous Cell Carcinoma: Correlations With Clinical and Demographic Characteristics.

Background and objective Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer type that affects the mucosal lining of the upper aerodigestive tract. Soluble programmed death-ligand 1 (sPD-L1) is a significant factor in hindering T cells' function, which prevents cancer cells from being detected by the immune system. This means that sPD-L1 is an essential component in the immune evasion of cancer. This study aimed to explore the potential of sPD-L1 as a prognostic biomarker for patients with HNSCC undergoing concurrent chemotherapy and radiation therapy. Methodology The study included 106 patients with locally advanced HNSCC who received three courses of induction chemotherapy followed by concurrent chemoradiation and 60 healthy subjects as controls. sPD-L1 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit, and the cutoff value was determined based on receiver operating characteristic (ROC) curve analysis. Results The results showed that sPD-L1 levels were significantly higher in HNSCC patients compared to healthy controls, with a cutoff value of 31.51 pg/mL. Higher sPD-L1 levels were associated with poorer overall survival rates. Conclusions These findings suggest that sPD-L1 may serve as a valuable prognostic biomarker for HNSCC patients undergoing concurrent chemotherapy and radiation therapy. The study highlights the importance of exploring new biomarkers and therapeutic strategies for HNSCC to improve patient outcomes and reduce morbidity and mortality rates associated with this disease.

Global genomic epidemiology of chromosomally mediated non-enzymatic carbapenem resistance in Acinetobacter baumannii: on the way to predict and modify resistance.

Introduction: Although carbapenemases are frequently reported in resistant A. baumannii clinical isolates, other chromosomally mediated elements of resistance that are considered essential are frequently underestimated. Having a wide substrate range, multidrug efflux pumps frequently underlie antibiotic treatment failure. Recognizing and exploiting variations in multidrug efflux pumps and penicillin-binding proteins (PBPs) is an essential approach in new antibiotic drug discovery and engineering to meet the growing challenge of multidrug-resistant Gram-negative bacteria. Methods: A total of 980 whole genome sequences of A. baumannii were analyzed. Nucleotide sequences for the genes studied were queried against a custom database of FASTA sequences using the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) system. The correlation between different variants and carbapenem Minimum Inhibitory Concentrations (MICs) was studied. PROVEAN and I-Mutant predictor suites were used to predict the effect of the studied amino acid substitutions on protein function and protein stability. Both PsiPred and FUpred were used for domain and secondary structure prediction. Phylogenetic reconstruction was performed using SANS serif and then visualized using iTOL and Phandango. Results: Exhibiting the highest detection rate, AdeB codes for an important efflux-pump structural protein. T48V, T584I, and P660Q were important variants identified in the AdeB-predicted multidrug efflux transporter pore domains. These can act as probable targets for designing new efflux-pump inhibitors. Each of AdeC Q239L and AdeS D167N can also act as probable targets for restoring carbapenem susceptibility. Membrane proteins appear to have lower predictive potential than efflux pump-related changes. OprB and OprD changes show a greater effect than OmpA, OmpW, Omp33, and CarO changes on carbapenem susceptibility. Functional and statistical evidence make the variants T636A and S382N at PBP1a good markers for imipenem susceptibility and potential important drug targets that can modify imipenem resistance. In addition, PBP3_370, PBP1a_T636A, and PBP1a_S382N may act as potential drug targets that can be exploited to counteract imipenem resistance. Conclusion: The study presents a comprehensive epidemiologic and statistical analysis of potential membrane proteins and efflux-pump variants related to carbapenem susceptibility in A. baumannii, shedding light on their clinical utility as diagnostic markers and treatment modification targets for more focused studies of candidate elements.

Synergistic Power of Piceatannol and/or Vitamin D in Bleomycin-Induced Pulmonary Fibrosis In Vivo: A Preliminary Study.

Oxidative stress and epigenetic alterations, including the overexpression of all class I and II histone deacetylases (HDACs), particularly HDAC2 and HDAC4, have been identified as key molecular mechanisms driving pulmonary fibrosis. Treatment with piceatannol (PIC) or vitamin D (Vit D) has previously exhibited mitigating impacts in pulmonary fibrosis models. The present study investigated the effects of PIC, Vit D, or a combination (PIC-Vit D) on the expression of HDAC2, HDAC4, and transforming growth factor-beta (TGF-ß) in the lungs; the phosphatidylinositide-3-kinase (PI3K)/AKT signaling pathway; and the antioxidant status of the lungs. The objective was to determine if the treatments had protective mechanisms against pulmonary fibrosis caused by bleomycin (BLM) in rats. Adult male albino rats were given a single intratracheal dosage of BLM (10 mg/kg) to induce pulmonary fibrosis. PIC (15 mg/kg/day, oral (p.o.)), Vit D (0.5 µg/kg/day, intraperitoneal (i.p.)), or PIC-Vit D (15 mg/kg/day, p.o. plus 0.5 µg/kg/day, i.p.) were given the day following BLM instillation and maintained for 14 days. The results showed that PIC, Vit D, and PIC-Vit D significantly improved the histopathological sections; downregulated the expression of HDAC2, HDAC4, and TGF-ß in the lungs; inhibited the PI3K/AKT signaling pathway; decreased extracellular matrix (ECM) deposition including collagen type I and alpha smooth muscle actin (α-SMA); and increased the antioxidant capacity of the lungs by increasing the levels of glutathione (GSH) that had been reduced and decreasing the levels of malondialdehyde (MDA) compared with the BLM group at a p-value less than 0.05. The concomitant administration of PIC and Vit D had a synergistic impact that was greater than the impact of monotherapy with either PIC or Vit D. PIC, Vit D, and PIC-Vit D exhibited a notable protective effect through their antioxidant effects, modulation of the expression of HDAC2, HDAC4, and TGF-ß in the lungs, and suppression of the PI3K/AKT signaling pathway.

In vitro studies on the pharmacological potential, anti-tumor, antimicrobial, and acetylcholinesterase inhibitory activity of marine-derived Bacillus velezensis AG6 exopolysaccharide.

In the current study, Bacillus velezensis AG6 was isolated from sediment samples in the Red Sea, identified by traditional microbiological techniques and phylogenetic 16S rRNA sequences. Among eight isolates screened for exopolysaccharide (EPS) production, the R6 isolate was the highest producer with a significant fraction of EPS (EPSF6, 5.79 g L-1). The EPSF6 molecule was found to have a molecular weight (Mw) of 2.7 × 104 g mol-1 and a number average (Mn) of 2.6 × 104 g mol-1 when it was analyzed using GPC. The FTIR spectrum indicated no sulfate but uronic acid (43.8%). According to HPLC, the EPSF6 fraction's monosaccharides were xylose, galactose, and galacturonic acid in a molar ratio of 2.0 : 0.5 : 2.0. DPPH, H2O2, and ABTS tests assessed EPSF6's antioxidant capabilities at 100, 300, 500, 1000, and 1500 µg mL-1 for 15, 60, 45, and 60 minutes. The overall antioxidant activities were dose- and time-dependently increased, and improved by increasing concentrations from 100 to 1500 µg mL-1 after 60 minutes and found to be 91.34 ± 1.1%, 80.20 ± 1.4% and 75.28 ± 1.1% respectively. Next, EPSF6 displayed considerable inhibitory activity toward the proliferation of six cancerous cell lines. Anti-inflammatory tests were performed using lipoxygenase (5-LOX) and cyclooxygenase (COX-2). An MTP turbidity assay method was applied to show the ability of EPSF6 to inhibit Gram-positive bacteria, Gram-negative bacteria, and antibiofilm formation. Together, this study sheds light on the potential pharmacological applications of a secondary metabolite produced by marine Bacillus velezensis AG6. Its expected impact on human health will increase as more research and studies are conducted globally.

Evaluation of TET Family Gene Expression and 5-Hydroxymethylcytosine as Potential Epigenetic Markers in Non-small Cell Lung Cancer.

BACKGROUND/AIM: DNA methylation is the most studied epigenetic modification in cancer. Ten-eleven translocation enzymes (TET) catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in the DNA. In the current research, we aimed to evaluate the role of 5-hmC and TET enzymes in non-small cell lung cancer (NSCLC) patients and their possible association with outcomes. PATIENTS AND METHODS: ELISA was used to measure the 5-hmC levels in genomic DNA and qRT-PCR was used to evaluate TET1, TET2, and TET3 mRNAs expression levels in NSCLC tissues and their paired normal controls. RESULTS: The levels of 5-hmC were significantly lower in NSCLC tissues than in normal tissues, with a mean ±SD of 0.28±0.37 vs. 1.84±0.58, respectively (t=22.77, p<0.0001), and this reduction was correlated with adverse clinical features. In addition, all TET genes were significantly down-regulated in NSCLC tissues in comparison to their matched normal tissues. The mean±SD level of TET1-mRNA was 38.48±16.38 in NSCLC vs. 80.65±11.25 in normal tissues (t=21.33, p<0.0001), TET2-mRNA level in NSCLC was 5.25±2.78 vs. 9.52±1.01 in normal tissues (t=14.48, p<0.0001), and TET3-mRNA level in NSCLC was 5.21±2.8 vs. 9.51±0.86 in normal tissues (t=14.75, p<0.0001). Downregulation of TET genes was correlated with poor clinical features. CONCLUSION: 5-HmC levels as well as TET1, TET2, and TET3 mRNA levels were reduced in NSCLC tissues. The reduced levels of 5-hmC and TET mRNAs were associated with adverse clinical features, suggesting that the level of 5-hmC may serve as a valuable prognostic biomarker for NSCLC.

Natural and commercial antibiotic comparison with drugs modeling cell integrity cell stability of Bio-Kinetics changes under morphological topographies cells with lower toxicological characteristics for multidrug resistances problem.

Antibacterial drug-resistant strains are a serious problem of bacterial treatments nowadays and have a concern. The plant exacts of Adhatoda vasica and Calotropis procera are well-known for their role as antibiotic agents. The extraction of novel antibiotic compounds was done by HPLC-DAD, their yield is quantified by numerous solvents. The complete biological activity with antioxidants, bio-kinematicof four compounds of B-Sitosteryl linoleate, Myristyl diglucoside, D-Triglucopyranoside, and S- allylcysteine acids were studied. The supercritical fluid extraction techniques were the best strategies for higher yield, accuracy clarity, and inter, intra process of all four compounds. A. vasica and C. procera samples and investigated in six different solvents. D-Triglucopyranoside (13.81 ± 0.48%), Myristyl diglucoside (11.81 ± 0.41%), B- Sitosteryl linoleate (12.81 ± 0.48%), and s-allylcysteine acids (14.81 ± 0.31%) were higher. The design and action of compounds were applied to proper compartmental pharmacokinetic modelling for in-depth design understanding. The morphology and structure of bacterial cells with the extracted compounds upheld the permeability of cell membranes, membrane integrity, and membrane potential and lower the bacterial binding capacity the infectious index was measured in transmission electron microscopy (TEM) and their alteration process. Plants have well upheld the cellular permeability The toxicity test was performed on both extracted samples with concentrations (1, 0.4, and 0.8%). The areas under plasma half-life of compounds with their solubility, abortion level were higher in four compounds showed the potential of novel antibiotics. The novel medicinal plants used as antibiotics could be the best sources of infection control as a source of future medicines with antibacterial potential solving multidrug issues of bacteria in the world.

Neutrophil-to-lymphocyte ratio versus platelet-to-lymphocyte ratio in predicting clinical outcomes in acute methanol poisoning.

Acute methanol poisoning is a global health concern. This study was designed to compare the prognostic roles of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and their combination in the prediction of clinical outcomes in methanol-intoxicated patients as well as to evaluate their associations with all initial patients' characteristics. We conducted a cross-sectional study among methanol-intoxicated patients. A total of 109 patients were enrolled in the study. Thirty-four (31%) patients died during hospital admission while 30 (27.5%) patients developed visual loss. Most of the unfavorable findings were evident in patients with high NLR and PLR. Neutrophil-to-lymphocyte ratio and PLR can excellently differentiate between survivors and non-survivors with an area under the curve (AUC) of 0.991 vs 0.923, respectively. Platelet-to-lymphocyte ratio showed an accepted discrimination ability to differentiate between patients who developed and patients who did not develop visual loss, AUC of 0.734, however, NLR showed no discrimination, AUC of 0.558. We concluded that NLR and PLR can serve as valuable tools in risk-stratifying patients and prognosticating outcomes in acute methanol poisoning. Platelet-to-lymphocyte ratio is superior to NLR as a predictive factor in patients with permanent visual impairment. However, a combination of NLR with PLR can develop a more powerful prediction for overall clinical outcomes.

Perftoran ® Inhibits Hypoxia-Associated Resistance in Lung Cancer Cells to Carboplatin.

Perftoran® (perfluorodecalin) is an oxygen carrier, and carboplatin is a common chemotherapy drug used worldwide for lung cancer treatment. Hypoxia is one of the factors that induce resistance of lung cancer cells to carboplatin. This study explored the role of Perftoran®, as an oxygen carrier, in lowering the resistance of lung cancer cells to carboplatin through suppression of hypoxia pathway mediators. The effect of Perftoran® on the resistance of human lung cancer A549 cells to carboplatin was investigated through the evaluation of cytotoxicity by MTT, cell death mode by dual DNA staining, DNA damage by comet assay, DNA platination (DNA/carboplatin adducts) by atomic absorption spectroscopy, hypoxia degree by pimonidazole, HIF-1α/HIF-2α concentrations by ELISA, expression of miRNAs (hypoxamiRs miR-210, miR-21, and miR-181a) by qRT-PCR, and the content of drug resistance transporter MRP-2 by immunocytochemical staining. Results indicated that compared to carboplatin, Perftoran®/carboplatin decreased cell resistance to carboplatin by potentiating its cytotoxicity using only 45% of carboplatin IC50 and inducing apoptosis. Perftoran® induced DNA platination and DNA damage index in cells compared to carboplatin alone. Moreover, compared to treatment with carboplatin alone, co-treatment of cells with Perftoran® and carboplatin inhibited cellular pimonidazole hypoxia adducts, diminished HIF-1α/HIF-2α concentrations, suppressed hypoxamiR expression, and decreased MRP-2. In conclusion, Perftoran® inhibited resistance of lung cancer cells to carboplatin through the inhibition of both hypoxia pathway mediators and the drug resistance transporter MRP-2 and through the induction of DNA/carboplatin adduct formation.

Effect of Combined Perftoran and Indocyanine Green-Photodynamic Therapy on HypoxamiRs and OncomiRs in Lung Cancer Cells.

Indocyanine green (ICG) is a nontoxic registered photosensitizer used as a diagnostic tool and for photodynamic therapy (PDT). Hypoxia is one the main factors affecting PDT efficacy. Perfluorodecalin emulsion (Perftoran®) is a known oxygen carrier. This study investigated the effect of Perftoran® on ICG/PDT efficacy in presence and absence of Perftoran® via evaluation of phototoxicity by MTT; hypoxia estimation by pimonidazole, HIF-1α/ß by ELISA, and 17 miRNAs (tumor suppressors, oncomiRs, and hypoxamiRs) were analyzed by qPCR. Compared to ICG/PDT, Perftoran®/ICG/PDT led to higher photocytotoxicity, inhibited pimonidazole hypoxia adducts, inhibited HIF-1α/ß concentrations, induced the expression of tumor-suppressing miRNAs let-7b/d/f/g, and strongly inhibited the pro-hypoxia miRNA let-7i. Additionally, Perftoran®/ICG/PDT suppressed the expression of the oncomiRs miR-155, miR-30c, and miR-181a and the hypoxamiRs miR-210 and miR-21 compared to ICG/PDT. In conclusion, Perftoran® induced the phototoxicity of ICG/PDT and inhibited ICG/PDT-hypoxia via suppressing HIF-α/ß, miR-210, miR-21, let-7i, miR-15a, miR-30c, and miR-181a and by inducing the expression of let-7d/f and miR-15b.

Anti-hypoxic Effect of Polysaccharide Extract of Brown Seaweed Sargassum dentifolium in Tongue Squamous Cell Carcinoma.

Sargassum dentifolium, (Turner) C. Agarth, 1820, is an edible brown alga collected from red seashores, Egypt. Oral tongue squamous cell carcinoma (OTSCC) is an aggressive malignancy. Hypoxia leads to chemotherapeutic resistance. This work aimed to explore the anti-hypoxia effect of water-soluble polysaccharide fractions of S. dentifolium (SD1-SD3) in CAL-27 OTSCC cells. Cell cytotoxicity assay (MTT); cell death mode (DNA staining); total hypoxia (pimonidazole), HIF-1α (ELISA and immunocytochemistry), HIF-1ß (ELISA), and hsa-miRNA-21-5p and hsa-miRNA-210-3p (qRT-PCR) were investigated. SD1 and SD2 showed a cytotoxic effect due to apoptosis. SD2 and SD3 decreased total cell hypoxia, inhibited miR-210 (p < 0.001 and p < 0.01), miR-21 (p < 0.01 and p < 0.05), and HIF-1α (p < 0.01 and p < 0.05), respectively. However, only SD3 suppressed HIF-1ß (p < 0.05). In conclusion, SD2 showed a potential anti-hypoxia effect through amelioration of HIF-1α regulators, which may help in decreasing hypoxia-induced therapeutic resistance.

B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF.

We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords of ngr1+/+ EAE-induced mice at clinical score 1. Furthermore, increased secretion of immunoglobulins that bound to central nervous system myelin were shown to be generated from isolated NgR1- and NgR3-expressing B-cells of ngr1+/+ EAE-induced mice. In vitro BAFF stimulation of NgR1- and NgR3-expressing B cells, directed them into the cell cycle DNA synthesis phase. However, when we antagonized BAFF signaling by co-incubation with recombinant BAFF-R, NgR1-Fc, or NgR3 peptides, the B cells remained in the G0/G1 phase. The data suggest that B cells express NgR1 and NgR3 during EAE, being localized to infiltrates of the meninges and that their regulation is governed by BAFF signaling.

Cancer Chemopreventive Properties of Sulfated Enterolobium cyclocarpum Extract.

Enterolobium cyclocarpum (EC) is an edible plant and a gum source for food industries. Its sulfated polysaccharide extract (SEC) was examined for cancer chemopreventive properties to estimate its anti-tumor activity. The modulation of carcinogen metabolism and the antioxidant activity revealed that SEC is a potent tumor anti-initiator since it inhibited cytochrome P450-1A (CYP1A) and induced carcinogen detoxification enzyme glutathione-S-transferase. SEC is also a weak scavenger for hydroxyl and peroxyl radicals. SEC was found to modulate macrophage functions into an anti-inflammatory pattern, where it enhanced macrophage proliferation and phagocytosis of fluorescein isothiocyanate-lipopolysaccharide (FITC-LPS). In addition, SEC strongly inhibited the nitric oxide (NO) generation in LPS-stimulated macrophages and induced the binding affinity of FITC-LPS to macrophages. SEC exhibited specific cytotoxicity against human hepatocellular Hep G2 carcinoma cells. SEC disturbed the cell cycle phase, as indicated by the concomitant arrest in S- and G2/M-phases that was associated with necrosis induction. A short-term initiation model for liver cancer was prepared using diethylnitrosamine (DEN) in rats. SEC inhibited the DEN-histopathological findings and reduced both CYP1A and the tumor initiation marker placental glutathione S-transferase (GSTP). Taken together, SEC could be used as an alternative gum in health food industries to provide cancer prevention in high-risk populations.

Clinical significance of p27 Kip1 expression in advanced ovarian cancer

Background: Ovarian cancer is the most common gynecological malignancy. In patients with advanced ovarian cancer, some biological parameters have prognostic implementations. P27kip1 is an inhibitor of a cycline-dependent kinase, its loss, can contribute to tumor progression. Objective: This study aimed to examine the importance of P27KIP1 protein in predicting the prognosis and response to neoadjuvant chemotherapy in patients with advanced ovarian epithelial cancer and to compare the outcomes of immunohistochemistry with Quantitative Real-time PCR. Patients and methods: We have studied P27KIP1expression by both immunohistochemistry and Quantitative Realtime PCR from 88 patients with advanced ovarian carcinomas undergone radical debulking surgery and received Paclitaxel followed by Cisplatin every 3 weeks for a total of 6 cycles. We also studied their association with both chemotherapy response and patient survival. Results: Nuclear expression of p27KIP1 protein was intense in 86 normal ovarian tissues and 42 of 88 carcinomas. The P27kip1mRNA expression level by qRT-PCR was very low in ovarian cancer tissues relative to its adjacent normal tissues. The results were statistically significant by both methods of determination. p27KIP1 expression was significantly related to good prognostic parameters as low stage tumors, differentiated tumors, absence of ascites, residual disease < 2 cm, and response to chemotherapy but not with histopathological type in case of determination by immunohistochemistry. Comparison of P27kip1 by both immunohistochemistry and qRTPCR with different prognostic parameters revealed no significant difference between both methods in the assessment of these parameters. In 4 years of follow-up, 20.5% of patients were alive without evidence of disease. 6.8% were alive with disease. The disease-related four -year survival rate for the whole group was 28.2%. In multivariate analysis, residual disease, histological type, tumor differentiation, ascites was of independent prognostic significance. Conclusion: In ovarian cancer, patients with loss of p27KIP1 expression are at a greater likelihood of disease progression, p27KIP1 may be used as a molecular marker to predict response to chemotherapy and prognosis. Both immunohistochemistry and qRT-PCR have equal reliability in the determination of p27 KIP1

Cancerous Inhibitor of Protein Phosphatase 2A as a Molecular Marker for Aggressiveness and Survival in Oral Squamous Cell Carcinoma.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) has been identified as one of the most commonly altered proteins in human cancers. It blocks the tumor-suppressive action of protein phosphatase 2A (PP2A) complex and enhances malignancy. Thirty-five patients with squamous cell carcinoma of the oral cavity underwent surgical resection of the tumor. CIP2A was assessed by quantitative real-time PCR in the resected tumor tissues and in their adjacent normal tissues. CIP2A was found to be overexpressed in all oral squamous cell carcinoma (OSCC) specimens in comparison to their surrounding normal tissue. CIP2A overexpression was statistically correlated with poor prognostic feature of the tumor. Thus, a high expression level of CIP2A was associated with shorter survival. In conclusion, CIP2A is upregulated in OSCC, and its overexpression is correlated with aggressiveness of the tumor and poor outcome and survival. It may serve as a prognostic marker of OSCC.