Targeting androgen receptor (AR) with a synthetic peptide increases apoptosis in triple negative breast cancer and AR-expressing prostate cancer cell lines.

BACKGROUND: The androgen receptor (AR) has been studied as an approach to cancer therapy. AIMS: We used human breast cancer-derived cells with high, low, and very low expression levels of AR, in addition to prostate cancer-derived LNCaP and DU-145 cells as a positive and negative controls to examine apoptosis caused by a synthetic peptide that targets ARs. METHODS AND RESULTS: The peptide was produced to inhibit AR transactivation in breast cancer cell lines. We then measured cell viability, caspase-3 activity, and the ratio of Bax/Bcl-2. The findings indicated that the peptide (100-500 nM) in the presence of dihydrotestosterone (DHT) reduced cell growth in cells with high and low expression level of AR (p < .001), but not in cells with very low levels of AR. Treatment with 100-500 nM of peptide activated caspase-3 and increased the ratio of Bax/Bcl-2 in cells with high and low expression levels of AR. Also, increasing concentrations of the peptide (100-500 nM) reduced BrdU incorporation in the presence of DHT and promoted apoptosis in cells with high and low expression levels of AR (p < .001). CONCLUSION: The findings indicate the peptide significantly increased apoptosis in cancer cells.

Identification of novel inhibitor against endonuclease subunit of Influenza pH1N1 polymerase: A combined molecular docking, molecular dynamics, MMPBSA, QMMM and ADME studies to combat influenza A viruses.

The influenza H1N1 virus is the causative agent of the flu pandemic in the world. Due to the shortage of effective means of control, it is remained the serious threats to public and avian health. To battle the surge of viral outbreaks, new treatments are crucially needed. The viral RNA polymerase, which is responsible for transcription and replication of the RNA genome, is comprised of subunits PA, PB1 and PB2. PA has endonuclease activity and is a well known target for inhibitor and drug design. In the current study, we employed molecular docking, molecular dynamics (MD), MMPBSA, QMMM and ADME studies to find and propose an inhibitor among 11,873 structures against PA. Our molecular docking, MD, MMPBSA and QMMM studies showed that ZINC15340668 has ideal characteristics as a potent PA inhibitor, and can be used in experimental phase and further development. Also, ADME prediction demonstrated that all physico-chemical parameters are within the acceptable range defined for human use. Molecular mechanism based study revealed that upon inhibitor binding; the flexibility of PA backbone is increased. This observation demonstrates the plasticity of PA active site, and it should be noticed in drug design against PA Influenza A viruses. In the final phase of the study, the efficiency of our proposed hit was tested computationally against mutant drug resistant I38T_PA. Our results exhibited that the hit inhibits the I38T_PA in different manner with high potency.

The Correlation of Cardiac and Hepatic Hemosiderosis as Measured by T2*MRI Technique with Ferritin Levels and Hemochromatosis Gene Mutations in Iranian Patients with Beta Thalassemia Major.

OBJECTIVES: Organ-specific hemosiderosis and iron overload complications are more serious and more frequent in some patients with beta thalassemia major (BTM) compared with others. We investigated whether coinheritance of HFE H63D or C282Y gene mutations in patients with BTM contributes to the phenotypic variation of iron overload complications and assessed the correlation of cardiac and hepatic hemosiderosis with plasma ferritin levels. METHODS: We studied 60 patients with BTM with a mean age of 17.5±9.1 years from the Northwest of Iran. HFE gene mutations were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Cardiac and hepatic hemosiderosis was assessed using T2*magnetic resonance imaging (MRI). Ferritin levels were measured using the enzyme immunoassay method. RESULTS: Ferritin levels showed a strong inverse correlation with hepatic T2*MRI values (r = -0.631, p = 0.001) but a poor correlation with cardiac T2*MRI values (r = -0.297, p = 0.044). The correlation between cardiac T2*MRI values and hepatic T2*MRI values was poor and insignificant (r = 0.287, p = 0.058). Genotype and allele distribution of HFE H63D and C282Y mutation did not differ significantly between patients with and without hepatic or cardiac hemosiderosis (p > 0.050). However, carriers of HFE 63D allele had significantly higher ferritin levels compared with non-carriers (1 903±993 vs. 992±683, p < 0.001). CONCLUSIONS: Cardiac T2*MRI values showed a poor correlation with hepatic T2*MRI values and ferritin levels. Accurate assessment of cardiac iron overload in patients with BTM can only be done using the T2*MRI technique. Additionally, HFE H63D is a significant determinant factor for elevated ferritin levels in BTM patients.

The effect of antimicrobial photodynamic therapy on the expression of novel methicillin resistance markers determined using cDNA-AFLP approach in Staphylococcus aureus.

BACKGROUND: Widespread methicillin resistant Staphylococcus aureus (MRSA) and absence of effective antimicrobial agents has led to limited therapeutic options for treating MRSA infection. We aimed to evaluate the effect of antimicrobial photodynamic therapy (aPDT) on the expression of novel identified methicillin resistance markers (NIMRMs) in S. aureus using complementary DNA-Amplified Fragment Length Polymorphism (cDNA-AFLP) approaches to address the therapeutic alternatives for MRSA infections. MATERIALS AND METHODS: We used cDNA-AFLP to compare MRSA and methicillin susceptible S. aureus (MSSA) for identification of target genes implicated in methicillin resistance. To determine the sub-lethal aPDT (sPDT), MRSA and MSSA clinical isolates photosensitized with toluidine blue O (TBO), and then were irradiated with diode laser. After sPDT, the colony forming units/mL was quantified. Antimicrobial susceptibility against methicillin was assessed for cell-surviving aPDT. Effects of sPDT on the expression of NIMRMs were evaluated by real-time quantitative reverse transcription PCR. RESULTS: According to our results, serine hydrolase family protein (Shfp) encoding gene and a gene encoding a conserved hypothetical protein (Chp) were implicated in methicillin resistance in MRSA. sPDT reduced the minimum inhibitory concentrations of methicillin by 3-fold in MRSA. sPDT could lead to about 10- and 6.2- fold suppression of expression of the Chp and Shfp encoding genes, respectively. CONCLUSION: sPDT would lead to reduction in resistance to methicillin of MRSA in surviving cells by suppressing the expression of the Shfp and Chp encoding genes associated with methicillin resistance. This may have potential implications of aPDT for the treatment of MRSA infections.

Structure-based virtual screening to identify the beta-lactamase CTX-M-9 inhibitors: An in silico effort to overcome antibiotic resistance in E. coli.

Recently, the quick spreads of broad-spectrum beta-lactams antibiotic resistance in pathogenic strains of bacteria have become a major global health problem. These new emerging resistances cause ineffectiveness of antibiotics and increasing the severity of diseases and treatment costs. Among different and diverse resistance targets, we chose a class A beta lactamase, CTX-M-9, with the aim of identifying new chemical entities to be used for further rational drug design. Based on this purpose, a set of 5000 molecules from the Zinc database have been screened by docking experiments using AutoDock Vina software. The best ranked compound, with respect of the previously proved inhibitor compound 19, was further tested by molecular dynamics (MD) simulation. Our molecular modeling analysis demonstrates that ZINC33264777 has ideal characteristics a potent beta lactamase CTX-M-9 inhibitor. In the free form of beta lactamase, NMR relaxation studies showed the extensive motions near the active site and in the Ω-loop. However, our molecular dynamics studies revealed that in the compound 1: beta lactamase complex, the flexibility of Ω-loop was restricted.

Recurrent Epistaxis and Bleeding as the Initial Manifestation of Brucellosis.

Severe thrombocytopenia with bleeding is rarely reported in children with brucellosis, and recurrent epistaxis is extremely rare. Brucellosis with hemorrhage should be differentiated from viral hemorrhagic fever, malignancy, and other blood disorders. Bone marrow aspiration (BMA) is mandatory to differentiate from other blood diseases. An 8-year-old boy was admitted with recurrent epistaxis, petechiae and purpura on face and extremities and bleeding from the gums. During the hospitalization, he was febrile and complained of muscle pain. Leukopenias associated with thrombocytopenia were observed. BMA showed to be normal. Among the multiple tests requested, only serum agglutination test (SAT) and 2-MercaptoEthanol test (2-ME) were positive. He was treated with Intravenous immunoglobulin (IVIG) associated with co-trimoxazole and rifampin. Finally, fever subsided, and he was discharged with good condition and normal platelet count. Brucellosis should be a differential diagnosis in patients with fever and bleeding disorders and a history of consumption of unpasteurized dairy, in endemic areas.

Study of alloimmunization and autoimmunization in Iranian ß-thalassemia major patients.

BACKGROUND: Thalassemia is one of the most common monogenic disorders characterized by reduced production of globin chains. Although regular red blood cell (RBC) transfusion support is the main treatment for these patients, it may be associated with complications such as RBC alloimmunization. AIM: The study aimed to determine the incidence of alloimmunization and autoimmunization to RBC antigens in ß-thalassemia major patients from Zanjan, Zanjan Province, Iran. MATERIALS AND METHODS: A total of 49 ß-thalassemia major patients comprising 24 females and 25 males (mean age: 18.59 ± 8.16 years; range: 2-40 years) from Northwest Iran were included in a cross-sectional study. Alloantibody screening and identification were done using 3-cell and 10-cell reagent red blood cells, respectively. Autoantibody detection was performed using direct Coomb's test. RESULTS: The incidence of alloimmunization was 16.32% with 10 alloantibodies identified in 8 patients. The most common clinically significant alloantibody identified in alloimmunized patients was anti-Kell (K-antigen) (60%) followed by anti-Rhesus (Rh) (E, c-antigens). The rate of alloimmunization was significantly lower in patients transfused with leukoreduced RBCs compared with those transfused with nonleukoreduced RBCs (9.53% vs 57.14%, P = 0.001). There was no significant correlation between alloantibody formation and the age, gender, hemoglobin levels, number of transfused units, and splenectomy. CONCLUSION: Transfusion of leukoreduced and phenotypically matched red blood cells for Kell (K) and Rh (E, c) antigens may help reduce the alloimmunization rate in Iranian ß-thalassemia major patients. Moreover, autoimmunization to RBC antigens was rare in our patients.

Epidemiology of hepatitis B, hepatitis C, and human immunodeficiency virus infecions in patients with beta-thalassemia in Iran: a multicenter study.

BACKGROUND: Though regular blood transfusion improves the overall survival of patients with beta-thalassemia, it carries a definite risk of infection with blood-borne viruses. We carried out this multicenter study to provide epidemiologic data on hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection among Iranian beta-thalassemic patients. Moreover, HCV infection-associated risk factors were investigated in this population. METHODS: Seven hundred and thirty-two patients with beta-thalassemia major or beta-thalassemia intermedia, selected from five provinces of Iran including Tehran (n = 410), Kerman (n = 100), Qazvin (n = 95), Semnan (n = 81), and Zanjan (n = 46), were enrolled in this study. Using ELISA, their sera were tested for HBsAg, HBcAb, HBsAb, HCVAb, and HIVAb. The positive HCVAb results were confirmed by RIBA-2nd generation. RESULTS: The study sample consisted of 413 males and 319 females, with a mean +/- SD age of 17.9 +/- 9.0 years. One hundred forty-one (19.3%) patients were HCVAb positive; 11 (1.5%) were HBsAg positive. No one was HIVAb positive. Univariate analysis showed that beta-thalassemia major (P = 0.01), older age (P = 0.001), longer transfusion duration (P = 0.000), HBsAg seropositivity (P = 0.03), and higher serum ferritin level (P = 0.002) were significantly associated with a higher prevalence of HCV. Furthermore, the prevalence of HCV infection dropped significantly after the implementation of blood donors screening (22.8% vs. 2.6%; P = 0.000). Using multivariate analysis, beta-thalassemia major (P = 0.002), age (P < 0.001), serum ferritin level (P < 0.001), as well as consumption of unscreened blood (P = 0.003), were independent factors associated with HCV infection. CONCLUSION: The prevalence of HCV infection is much higher among Iranian beta-thalassemic patients as compared with HBV and HIV infections. Routine screening of donated blood for HCV is highly recommended.