Association of TERT (rs2736098 and rs2736100) genetic variants with elevated risk of hepatocellular carcinoma: a retrospective case-control study.

Hepatocellular carcinoma (HCC) is an inflammatory problematic issue with higher mortality among different ethnic populations. The telomerase reverse transcriptase (TERT) gene has an imperative role in the proliferation of various cancerous illnesses, particularly HCC. Moreover, the TERT (rs2736098 and rs2739100) variants were correlated with the HCC susceptibility and telomere shortening, but with unconvincing outcomes. The main purpose of this outward work is to assess the correlation between these significant variants within the TERT gene and the elevated risk of HCC with the aid of various computational bioinformatics tools. This study included 233 participants [125 cancer-free controls and 108 HCC patients] from the same locality. In addition, 81.5% of HCC patients were positive for HCV autoantibodies, while 73.1% of HCC patients were positive for cirrhotic liver. Genomic DNA of the TERT (rs2736098 and rs2736100) variants were characterized utilizing the PCR-RFLP method. Interestingly, the frequencies of TERT (rs2736098*A allele) and TERT (rs2736100*T allele) conferred a significant correlation with increased risk of HCC compared to healthy controls (p-value = 0.002, and 0.016, respectively). The TERT (rs2736098*A/A) genotype indicated a definite association with positive smoking and splenomegaly (p-value < 0.05), while the TERT (rs2736100*T/T) genotype observed a significant difference with higher levels of HCV autoantibodies (p-value = 0.009). In conclusion, this significant work confirmed the contribution of the TERT (rs2736098*A and rs2736100*T) alleles with elevated risk of HCC progression and telomere shortening among Egyptian subjects.

Rifampicin efficacy against doxorubicin-induced cardiotoxicity in mice.

BACKGROUND: The toxic effect of doxorubicin on the heart limits its clinical usage in cancer therapy. This work intended to investigate, for the first time, the efficacy of rifampicin administration against doxorubicin-induction of cardiotoxicity in mice. Forty adult male albino mice were distributed into four sets: Control, Doxorubicin, Doxorubicin + Rifampicin 0.107, and Doxorubicin + Rifampicin 0.214, with n = 10 for each. Heart histopathology and biochemical assays for heart function tests [creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), cardiac troponin I (cTnI), atrial natriuretic peptide (ANP), and vascular endothelial growth factor (VEGF)], oxidative stress [malondialdehyde (MDA) and superoxide dismutase (SOD)], and minerals [phosphorus, sodium, potassium, and calcium] were done. RESULTS: Doxorubicin-induced cardiotoxicity using a total dose of 15 mg/kg was confirmed histologically. Cardiomyocytes showed congestion, necrosis, edema, and inflammatory cell infiltration. Biochemically, elevations in LDH, CK, and AST activities, p < 0.001, as well as increases in cTnI and ANP levels, p < 0.001, increased oxidative stress (MDA, p < 0.001), high minerals (Na, K, p < 0.001, P, p < 0.01, and Ca, p < 0.05), with reduced VEGF concentration, p < 0.001, and low antioxidant (SOD, p < 0.001) were observed in the Doxorubicin group compared to control. Co-treatment with rifampicin significantly (p < 0.001) reduced the increased oxidative stress, high Na and K, increased LDH, CK, AST, cTnI, and ANP, and elevated the low SOD toward the normal ranges. Our histological data supported our biochemical data; rifampicin dose 0.214 mg/kg showed better improvements than dose 0107. CONCLUSIONS: Our results demonstrated that rifampicin could help protect the body against doxorubicin-induced cardiotoxicity through its antioxidative effect.

Glycine protects against doxorubicin-induced heart toxicity in mice.

Doxorubicin (DOXO) is a well-known cancer chemotherapeutic. However, its toxic effect on the heart limits its clinical application. This study aimed to assess the effectiveness of glycine administration to counteract the DOXO-induction of cardiomyopathy in mice. Fifty male albino mice were divided into five groups (n = 10/group) as follows: control, DOXO, Gp100, Gp150, and Gp200. Histopathological examination of the heart, and biochemical examinations for heart function (creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST)), inflammation (tumor necrosis factor-alpha (TNF-α) and interleukin 10 (IL-10)), oxidative stress (malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase, nitric oxide (NO), and uric acid), kidney function (urea and creatinine), and minerals (calcium, phosphorus, sodium, and potassium) were carried out. Cardiomyopathy induced by DOXO treatment (15 mg/kg total dose) was ascertained via pathological alterations seen in heart tissue and verified biochemically via increases (P < 0.001) in CPK, LDH, AST, TNF-α, IL-10, MDA, NO, Na, and K levels along with decreases (P < 0.001) in GSH, SOD, catalase, and uric acid. Glycine co-treatment, using doses of 100, 150, and 200 mg/kg, in a dose-dependent manner, displayed ameliorated heart architecture, significantly (P < 0.001) improved biochemical heart function tests, reduced oxidative stress and inflammation, and controlled mineral levels. The positive actions of glycine in DOXO-induced cardiotoxicity amelioration via modulating oxidative stress, inflammation, and immunity are confirmed. Glycine antioxidative properties may be behind its positive outcomes. Finally, we present glycine as a worthy possible option against DOXO-induced heart damage after more validation.

Biochemical and pathophysiological improvements in rats with thioacetamide induced-hepatocellular carcinoma using aspirin plus vitamin C.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, so we should be concerned and look for effective/less-harmful treatments than chemotherapeutics already clinically in application. Aspirin works well ''in conjunction'' with other therapies for HCC since aspirin can boost the sensitivity of anti-cancer activity. Vitamin C also was shown to have antitumor effects. In this study, we examined the anti-HCC activities of synergistic combination (aspirin and vitamin C) vs. doxorubicin on HCC-bearing rats and hepatocellular carcinoma (HepG-2) cells. METHODS: In vitro, we evaluated IC50 and selectivity index (SI) using HepG-2 and human lung fibroblast (WI-38) cell lines. In vivo, four rat groups were used: Normal, HCC (intraperitoneally (i.p.) administered 200 mg thioacetamide/kg/twice a week), HCC + DOXO (HCC-bearing rats i.p. administered 0.72 mg doxorubicin (DOXO)/rat/once a week), and HCC + Aspirin + Vit. C (i.p. administered vitamin C (Vit. C) 4 g/kg/day after day concomitant with aspirin 60 mg/kg/orally day after day). We evaluated biochemical factors [aminotransferases (ALT and AST), albumin, and bilirubin (TBIL) spectrophotometrically, caspase 8 (CASP8), p53, Bcl2 associated X protein (BAX), caspase 3 (CASP3), alpha-fetoprotein (AFP), cancer antigen 19.9 (CA19.9), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) using ELISA], and liver histopathologically. RESULTS: HCC induction was accompanied by significant time-dependent elevations in all measured biochemical parameters except the p53 level significantly declined. Liver tissue architecture organization appeared disturbed with cellular infiltration, trabeculae, fibrosis, and neovascularization. Following drug medication, all biochemical levels significantly reversed toward normal, with fewer signs of carcinogenicity in liver tissues. Compared to doxorubicin, aspirin & vitamin C therapy ameliorations were more appreciated. In vitro, combination therapy (aspirin & vitamin C) exhibited potent cytotoxicity (HepG-2 IC50 of 17.41 ± 1.4 µg/mL) and more excellent safety with a SI of 3.663. CONCLUSIONS: Based on our results, aspirin plus vitamin C can be considered reliable, accessible, and efficient synergistic anti-HCC medication.

MUC7 VNTR polymorphism and association with bronchial asthma in Egyptian children.

Overproduction of mucins in the airways donates largely to airway blockage in asthma patients. Glycoprotein MUC7 plays a role in the clearance of bacteria and has anti-candidacidal criteria. Our goal was to investigate the association between the MUC7 variable number of tandem repeats (VNTR) polymorphism and bronchial asthma among Egyptian children. The MUC7 VNTR polymorphism was investigated among 100 children with bronchial asthma and 100 healthy controls using polymerase chain reaction (PCR) method. Serum levels of immunoglobulin E (IgE), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta1 (TGF-ß1) were assessed by enzyme-linked immunosorbent assay (ELISA) technique. The frequencies of 6*5 genotype, 5*5 genotype, (6*5 + 5*5) genotypes, and MUC7*5 allele of the MUC7 VNTR variant were significantly lower among asthmatic patients than controls (p < 0.015, OR = 0.39, 95% CI = 0.19-0.81; p = 0.03, OR = 0.18, 95% CI = 0.04-0.86; p < 0.001, OR = 0.29, 95% CI = 0.15-0.58; p < 0.001, OR = 0.3, 95% CI = 0.17-0.55, respectively). The (6*5 + 5*5) genotypes of the MUC7 VNTR variant were not associated with the clinical manifestations and serum levels of IgE, TNF-α, and TGF-ß1 among asthmatic patients (p ˃ 0.05). In conclusion, the (6*5 + 5*5) genotypes of the MUC7 VNTR variant may have a protective role for bronchial asthma in Egyptian children.

Association of the Gelatinase B/Metalloproteinase 9 (MMP-9) Gene Haplotype in Systemic Lupus Erythematosus (SLE) in the Pediatric Egyptian Population.

Permanent systemic inflammation is a defining feature of systemic lupus erythematosus (SLE), which affects multiple organs. Gelatinase B/matrix metalloproteinase-9 (MMP-9) is an essential protease investigated in inflammation that has been linked to SLE. The study's objective was to investigate the relationship between the rs3918249 T/C and rs17576 A/G SNPs in the MMP-9 gene with SLE. The study was conducted with 100 SLE cases and 100 age/sex-matched healthy individuals. TaqManTM SNP was used for genotyping by real time PCR on the Artus Rotor-Gene Qiagen equipment. Haplotypes (TG: OR = 0.226, 95% CI = 0.119−0.429) and (CA: OR = 0.36, 95% CI = 0.2206−0.631), both with a p-value < 0.001 were substantially linked to a lower incidence of SLE. Conversely, the risk of SLE was not associated with the individual SNPs studied. The haplotype analysis was more significant than the SNP analysis and may correlate with the decreased risk of SLE in children and adolescents in Egypt.

A Newly Synthesized Derivative and a Natural Parent Molecule: Which Would Be More Beneficial as a Future Antitumor Candidate? Docking and In Vivo Study.

Seeking for new effectual anticancer drugs is of great importance. In this study, a newly synthesized and well-characterized chromene derivative (ethyl 2-amino-4-phenyl-4H-benzo(h)chromene-3-carboxylate) "C" was prepared. Molecular docking studies were done. The new compound "C" in compare to the natural parent Quercetin "Q," as a well-known natural chromene derivative with antioxidant and antitumor activities, were tested for their antitumor activity against Ehrlich ascites carcinoma (EAC)-bearing mice. Both reduced ascites volume, decreased viable EAC cells, and prolonged EAC-bearing mice life span. They normalized troponin, creatine kinase-MB, lactate dehydrogenase, and urea levels, reversed liver enzyme activities towards normal, and increased antioxidant levels while reduced tumor necrosis factor-alpha (TNF-α) levels. Compared to each other, the new synthetic derivative "C" showed stronger antineoplastic effects than the natural parent "Q" may via the anti-inflammatory activities. Therefore, the newly synthesized chromene derivative is more promising as a future antitumor candidate than the natural parent molecule "Quercetin." Finally, our results encourage researchers to pay more attention to developing more novel natural-based derivatives that would be more beneficial as future therapeutics than their natural parents.

Palladium(II) Schiff base complex arrests cell cycle at early stages, induces apoptosis, and reduces Ehrlich solid tumor burden: a new candidate for tumor therapy.

Although many cancer drugs are clinically approved, they still suffer from no adequate efficiency or drug resistance, or bad side effects. Therefore, developing safer alternatives of competitive efficiency is needed. This study aimed to investigate, for the first time, the antitumor and apoptotic activities of palladium(II) 2-hydroxyimino-3-(2-hydrazonopyridyl)-butane complex against Ehrlich carcinoma. In vitro, EAC cells were incubated with the complex, and the cells' viability, caspase 8 activity, and cell cycle changes were evaluated. In vivo, eighty adult female Swiss albino mice were distributed randomly in the following groups (n = 10): Normal, EAC, EAC + Cisplatin, and four groups EAC + Complex as well as Normal + Complex. Bodyweight changes were noted. On day 22 mice were sacrificed. Tumors' volume and weight were recorded. Blood picture was routinely investigated. The median survival time (MST) and percent increase in life span (%ILS) were monitored. In vitro, the complex reduced the %viable EAC cells, increased caspase 8 activity, arrested cell cycle at G0/G1, and reduced G2(M) population indicating antiproliferative and antitumor activities via inducing apoptosis. Treatment with the complex in a dose-dependent mode significantly decreased tumor volume and weight, extended the MST and the %ILS, increased mice body weight gain, and improved the blood indexes. Treatment of EAC-bearing mice with the complex highest dose showed more desirable outcomes than treatment with cisplatin. The Normal + Complex group showed no pathological changes indicating safety. In conclusion, our outcomes recommend the Pd(II) complex as a new optimistic candidate for tumor therapy after further studies for validation.

Occupational exposure to gasoline in gasoline station male attendants promotes M1 polarization in macrophages.

Several studies have reported the toxicological implications of exposure to petroleum hydrocarbon fumes in animal models. There is little documentation on the effect of such exposure on oxidative stress levels and immune response. To our knowledge, no documentation of M1 polarization in macrophages in gasoline station male attendants. Therefore, this study aimed to evaluate the harmful effects of gasoline vapors in 62 male attendants (16-70 years) compared to 29 age- and sex-matched-unexposed controls. The attendants were recruited from Damietta governorate gasoline stations. Gasoline exposure induced a significant increase in tumor necrosis factor-α (TNF-α) level (p < 0.05) as well as a slight but non-significant increase in the activity of acidic mammalian chitinase (AMCase) (p > 0.05). Further TNF-α/AMCase ratio was significantly increased (p < 0.01) in sera of the attendants when compared to those of the healthy controls. Also, the total leucocytic and lymphocytic counts were significantly increased (p < 0.01 and p < 0.001, respectively). On contrary, neutrophils to lymphocytes ratio (NLR) and platelets to lymphocytes ratio (PLR) were significantly decreased (p < 0.05 and p < 0.001, respectively). In addition, significant reduction in hemoglobin (Hb) concentration, plasma glutathione reduced form (GSH), and catalase, as well as superoxide dismutase (SOD) activities in red blood cells were observed in the exposed attendants. As a result, malondialdehyde (MDA), nitric oxide (NO) levels, and NO/AMCase ratio were significantly increased (p < 0.05). In conclusion, this study inferred that prolonged gasoline exposure can mediate immune activation, especially M1 macrophages polarization, possibly via oxidative stress-mediated mechanism.

Association of CD14 genetic variants and circulating level with systemic lupus erythematosus risk in Egyptian children and adolescents.

Aim: To demonstrate whether sCD14 and CD14 (rs2569190 A/G and rs2569191 C/T) genetic variants are associated with systemic lupus erythematosus (SLE) risk, for the first time, in Egyptian pediatrics and adolescents. Materials & methods: sCD14 concentrations were determined in plasma of 95 SLE cases and 98 healthy controls using ELISA assay. Genotyping was performed using TaqMan technology. Results: sCD14 levels were elevated in SLE. Individuals with T, CT and TT genotypes in rs2569191 were of significant risk (odds ratio = 1.471-2.035, 95% CI = 1.138-3.471) and those with combined CT+TT and haplotype GT were of higher risk of SLE (odds ratio = 1.660-1.758, 95% CI = 1.003-3.106, p < 0.05). sCD14 levels and CD14 polymorphism were not correlated with SLE clinical and laboratory features. Conclusion: In SLE, sCD14 levels are associated with rs2569190 A/G. Genotype CT+TT in rs2569191 C/T and haplotype GT are associated with SLE risk in Egyptian pediatric and adolescents.

Livin/BIRC7 gene expression as a possible diagnostic biomarker for endometrial hyperplasia and carcinoma.

BACKGROUND: Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family which are implicated in development of cancer through the inhibition of apoptosis process. This case-control study was intended to investigate livin/BIRC7 gene expression in endometrial hyperplasia and carcinoma and its correlation to some oxidative stress markers in addition to its possible diagnostic performance. METHODS: This study included 90 participants [30 endometrial hyperplasia patients, 30 endometrial carcinoma patients, and 30 healthy controls]. Livin/BIRC7 gene expression was analyzed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Serum catalase activity was assessed by enzyme-linked immunosorbent assay (ELISA) and malondialdehyde level was measured by the colorimetric method. RESULTS: Livin/BIRC7 gene expression was significantly (p < 0.001) higher in endometrial carcinoma from patients with endometrial hyperplasia when compared to controls. A positive correlation was found between livin/BIRC7 expression and serum catalase activity and malondialdehyde level in endometrial hyperplasia and carcinoma. The detection of livin/BIRC7 in endometrial carcinoma has excellent sensitivity and specificity. CONCLUSIONS: Livin/BIRC7 was overexpressed in endometrial carcinoma with excellent power to differentiate endometrial carcinoma from endometrial hyperplasia or healthy subjects, suggesting that it might be a useful molecular marker for endometrial carcinoma diagnosis.

Plasma interleukin-22 level, variants in interleukin-22 gene polymorphism, and the severity of systemic lupus erythematosus among Egyptian pediatric and adolescents.

OBJECTIVES: Our purpose was to investigate, for the first time, genotypes and alleles distribution of two single nucleotide polymorphisms (SNPs) of interleukin 22 (IL-22) (rs1012356 and rs2227485) in Egyptian pediatric and adolescents with systemic lupus erythematosus (SLE) and to evaluate the plasma IL-22 levels and their association with gene polymorphism and SLE risk and severity. METHODS: The TaqMan™ SNP genotyping assay on a real-time polymerase chain reaction (PCR) system was employed to evaluate the polymorphism's genotypes. Plasma IL-22 levels were determined by using an enzyme-linked immunoabsorbent assay (ELISA). RESULTS: The frequencies and genotypes of rs2227485 and rs1012356 in IL-22 between SLE patients and controls also haplotypes formed by the same SNPs revealed no statistically significant difference (p > 0.05). Otherwise, logistic regression analysis revealed that patients carrying rs1012356 "TA + AA" genotype had increased risk for prediction of SLE activity (OR = 1.610, 95% CI = 1.339-2.760, p = 0.034) by lowering plasma IL-22 level. CONCLUSIONS: Among Egyptian pediatric and adolescents, we confirm a combined model "TA + AA" in rs1012356 (A/T) of IL-22 in regression analysis, as an independent predictor for SLE activity by lowering IL-22 plasma levels. Despite neither SNP rs2227485 A/G in IL-22 gene nor haplotypes formed by the same two SNPs (rs2227485 A/G and rs1012356 A/T) were significantly associated with the clinical and/or laboratory manifestations of SLE.

Schiff base 4-ethyl-1-(pyridin-2-yl) thiosemicarbazide up-regulates the antioxidant status and inhibits the progression of Ehrlich solid tumor in mice.

Cisplatin is an approved cancer therapeutic drug used to treat many solid tumors but its accumulation in the kidney, which causes nephrotoxicity, limits its clinical use. Therefore, investigators seek new alternatives to cisplatin that may be more effective and/or safer. Thiosemicarbazides are of great significance due to their expected biological activity including anticancer activities. The aim of this work is the study of the antitumor effect of Schiff base 4-ethyl-1-(pyridin-2-yl) thiosemicarbazide (HEPTS) on Ehrlich solid tumor-bearing mice in comparison to cancer therapeutic drug cisplatin. The experiment was run using sixty adult female Swiss albino mice. Mice were allocated into six groups (n = 10 mice). Healthy control, EAC control (untreated tumor), EAC + cisplatin, EAC + HEPTS, Healthy + HEPTS, and Healthy + solvent. After scarification, blood samples, liver organs, and solid tumors were collected. Tumor weights and volumes were registered. The concentrations of malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase (CAT), total antioxidant capacity (TAC), nitric oxide (NO), uric acid, creatinine, and urea were assessed. Median survival time (MST) and the percentage increase in lifespan (%ILS) were also calculated. Treatment of tumorized mice with HEPTS significantly reduced both tumor volume and weight while it significantly increased the MST, antioxidant marks and prolonged the %ILS. It also, significantly reduced MAD, creatinine, urea, uric acid, and NO levels. Compared to cisplatin, HEPTS effects were better. Our results recommend HEPTS as one of the probable cisplatin-alternatives for tumor treatment after more validation.

Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay.

BACKGROUND: Diagnosis of breast cancer is more complicated due to lack of minimal invasive biomarker with sufficient precision. DNA methylation is a promising marker for cancer diagnosis. In this study, authors evaluated methylation patterns for PTEN and SMAD4 in blood samples using EpiTect Methyl II QPCR assay quantitative PCR technology. RESULTS: Methylation status for PTEN and SMAD4 were statistically significant as breast cancer patients reported hypermethylation compared to benign and control groups (77.1 ± 17.9 vs. 24.9 ± 4.5 and 15.1 ± 1.4 and 70.1 ± 14.4 vs. 28.2 ± 0.61 and 29.5 ± 3.6, respectively). ROC curve analysis revealed that both PTEN (AUC = 0.992) and SMAD4 (AUC = 0.853) had good discriminative power for differentiating BC from all non-cancer individuals (benign and healthy combined) compared to routine tumor markers CEA (AUC = 0.538) and CA15.3 (AUC = 0.686). High PTEN methylation degree was associated with late stages (84.2 ± 17.4), positive lymph node (84.2 ± 18.5), positive ER (81.3 ± 19.7), positive PgR (79.5 ± 19.1), and positive HER2 (80.7 ± 19.0) vs. 67.4 ± 13.8, 70.6 ± 14.8, 72.8 ± 14.9, 72.5 ± 14.7, and 70.2 ± 13.5 in early stages, negative lymph node, negative ER, negative PgR, and negative HER2, respectively. Similar results were obtained regarding SMAD4 methylation. Sensitivity, specificity, positive and negative predictive values, and accuracy for methylated PTEN were 100%, 95%, 99.1%, 100%, and 95%, respectively when differentiated BC from all-non cancer controls. Interestingly, PTEN could distinguish early BC stages with good sensitivity 84.4%, 51.4%, 69.1%, 72%, and 70%, respectively. CONCLUSION: Methylation status of PTEN and SMAD4 is a promising blood marker for early detection of breast cancer. Future studies are needed for their role as prognostic markers.

HCl-induced acute lung injury: a study of the curative role of mesenchymal stem/stromal cells and cobalt protoporphyrin.

BACKGROUND: This study was designed to investigate bone marrow mesenchymal stem/stromal cells (BM-MSCs) and cobalt protoporphyrin (CoPP) curable effects on HCl-induced acute lung injury (ALI) and its underlying mechanisms hoping this might aid to offer a therapeutic opportunity for ALI. RESULTS: Forty male Sprague Dawley rats were randomly allocated into four groups; normal (normal rats), ALI (rats injected with 2 ml hydrochloric acid (HCl)/kg via trachea), ALI + BM-MSCs (ALI rats intravenously injected twice with 1 × 106 BM-MSCs/rat/week), and ALI + CoPP (ALI rats intraperitoneally injected twice with CoPP (0.5 mg/100 g/week)). White blood cells (WBCs), red blood cells (RBCs), hemoglobin (Hb), serum tumor necrosis factor-alpha (TNF-α), lung histopathology, apoptosis markers (caspase-3 and Bcl2), and oxidative stress markers (malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT)) were measured. ALI caused increases in WBCs, TNF-α, caspase-3, and MDA, and morphological damage score of lungs with decreases in RBCs, Hb, Bcl2, SOD, and CAT (p < 0.05). BM-MSCs or CoPP treatment reversed these ALI-induced changes (p < 0.05) towards normal. CONCLUSIONS: BM-MSCs and CoPP could attenuate ALI by modulation of inflammation, oxidative stress, and apoptosis. Curative roles of BM-MSCs were more effective than those of CoPP. This highlights BM-MSCs as a potent therapy for HCl-associated ALI.

Single-nucleotide polymorphisms (SNPs) of antioxidant enzymes SOD2 and GSTP1 genes and SLE risk and severity in an Egyptian pediatric population.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with increased oxidative stress that participates in immune dysregulation, and injury resulting in loss of immune tolerance and increased auto-antibody production. This study was designed to investigate the effects of genetic polymorphisms of the antioxidant enzymes genes that code for SOD2 (rs2758332) and GSTP1 (rs1695) on SLE risk and severity in Egyptian children and adolescents cohort from Delta region. METHODS: The frequencies of these genes polymorphic variants were compared between 100 SLE children and adolescents and 100 healthy control subjects. Single-nucleotide polymorphisms (SNPs) of the two antioxidants were determined using TaqMan SNP genotyping assay. RESULTS: Individuals with the TT and CT genotypes of rs2758332 in the SOD2 gene were of significant risk for SLE patients (OR = 1.831, 95% CI = 1.082-3.101, P = 0.024) and (OR = 1.864, 95% CI = 1.136-3.059, P = 0.014), respectively. Cases who have combined CT + TT genotype were of significant higher risk of SLE (OR = 1.851, 95% CI = 1.156 - 2.962, P = 0.010). While, they did not show any significant association between SOD2 genotypes or alleles with SLE clinical features. In case of the SNP rs1695 in the GSTP1 gene, no significant associations of genotypes or alleles with SLE risk or with SLE clinical features were detected. CONCLUSIONS: This study among Egyptian children and adolescents showed a strong association of the SOD2 rs2758332 not GSTP1 rs1695 polymorphism with the risk of SLE disease.

Loading of some quinoxaline derivatives in poly (l-lactic) acid/Pluronic® F-127 nanofibers enhances their anticancer efficiency and induces a p53 and p21 apoptotic-signaling pathway.

The objective of this study was to evaluate the anticancer activity on cancer cell models of a drug delivery system consisting of poly (l-lactic) acid/Pluronic® F-127 (PLLA/PF127) loaded with the new N-butylpyridoquinoxaline 1,4-dioxide (NBPQD) or 2-amino-3-cyano-6-methylquinoxaline 1,4-dioxide (ACMQD) that was synthesized using an electrospinning process compared to free NBPQD and ACMQD. PLLA/PF127-NBPQD and PLLA/PF127-ACMQD nanofibers were prepared, and their shape, size, Fourier-transform infrared spectroscopy (FTIR), thermogravimetric (TGA) analysis, water contact angel (WCA), drug release, anticancer activity against five human cancer cell lines, and flowcytometeric analyses of cell cycle, p21 and p53 activities were investigated. PLLA/PF127 nanofibers with NBPQD or ACMQD were smooth, and no NBPQD or ACMQD clusters were found on nanofibers surface. FTIR analysis indicated that intermolecular hydrogen bonding between NBPQD or ACMQD and the polymer matrix is present. PLLA/PF127 nanofibers with NBPQD or ACMQD showed quite stable thermal stability with degradation at about 400 °C, and showed high WCA values of 68.72 ± 3.83° and 110.59 ± 0.21°, respectively. They showed higher in vitro anticancer activity towards all investigated cell lines compared to free NBPQD or free ACMQD. The lowest IC50 value for PLLA/PF127-NBPQD was 1.7 µg/ml with colorectal carcinoma (HCT-116) and was 4.5 µg/ml for PLLA/PF127-ACMQD with hepatocellular carcinoma (HepG2). PLLA/PF127 nanofibers with NBPQD or ACMQD increased anticancer efficiency via inducing cancer cell apoptosis through activation of a p53 and p21 apoptotic-signaling pathway.

Encapsulation of a new quinoxaline derivative in PLGA alters the pattern of its anticancer potency and induces apoptosis.

PURPOSE: Searching for novel anticancer therapeutics which are effective and primarily less toxic is urgently needed. Drug encapsulation provides more protection of drug within the body with more stable drug circulation levels thus avoiding drug peak-related adverse effects. We aimed first to develop and characterize a nano-particulate drug delivery system using poly(lactic-co-glycolic acid) (PLGA) for the new compound N-butylpyridoquinoxaline 1,4-dioxide (NBPQD), and second to investigate its anticancer effect and the probable mechanism. METHODS: NBPQD-PLGA nano-particles were prepared and their shape, size, zeta potential, encapsulation efficiency (EE%), drug loading (DL%), drug release, anticancer activity against six human cancer cell lines, DNA binding ability, and flow cytometric analyses of apoptosis, cell cycle and caspase-3 activity were investigated. RESULTS AND CONCLUSIONS: NBPQD-PLGA nano-particles were spherical with diameter around 54 nm. Zeta potential, EE%, and DL% values were - 20.4 mV, 88% and 21.8%, respectively. Nano-particles exhibited higher marked anticancer activities (much lower IC50s) and changed the anticancer potency pattern towards all the studied cell lines compared to free NBPQD with superior potency against colorectal carcinoma (HCT-116, IC50 of 12.2 µg/mL). NBPQD-PLGA acts by induction of cancer cell apoptosis through oxidative stress, DNA damage, and activating a caspase-3 signaling pathway.

Development of New Potential Anticancer Metal Complexes Derived from 2-Hydrazinobenzothiazole.

BACKGROUND: Due to the side effects of clinically approved anticancer drugs there is a great need to explore and develop new metal-based anticancer drug molecules of high efficiency with less or no side effects. OBJECTIVE: To synthesize new metal complexes of 2-hydrazinobenzothiazole (hbt) and to investigate their potential anticancer characteristics. METHODS: New five complexes; [VO(hbt)2SO4].4H2O (1), [Ru(hbt)2Cl3(H2O)] (2), [M(hbt)2Cl2] [M(II) = Pd (3), Pt (4)] and [Ag(hbt)2].NO3 (5) were prepared and their structure was investigated by means of FTIR, 1H NMR, ESI-MS and UV-Vis spectra, elemental and thermal analysis, magnetic and molar conductance measurements. The ligand and its complexes were examined as anticancer agents against Ehrlich ascites carcinoma (EAC) and human cancer cells (hepatocellular carcinoma Hep-G2, mammary gland breast cancer MCF-7 and colorectal carcinoma HCT-116). This feature is further supported by the DNAmetal complexes binding ability. In addition, anti-oxidation activity of the complexes was investigated. RESULTS: Complex (5) shows the highest anticancer activity with IC50 of 5.15, 9.9, 13.1 and 17.7 µg/mL for EAC, HePG-2, MCF-7 and HCT-116, respectively. Complexes (2) and (3) show promising cytotoxicity against EAC and HePG-2 cells with IC50 5.49 and 16.2 µg/mL, respectively. While, complexes (1) and (4) show optimistic cytotoxicity against EAC with IC50 of 9.63 and 11.25 µg/mL, respectively. The order of DNA binding ability of the complexes is (5) > (3) > (2) > (1) > (4). Among the five complexes, complex (5) shows the best anti-oxidation activity. CONCLUSION: Complex (5) showed the highest DNA binding ability, anti-oxidation and anticancer activities.