Search results for: biological pathway

Authors: Yuexin Liu, Gordon B. Mills, Russell R. Broaddus, John N. Weinstein

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The lethality of endometrioid endometrial cancer (EEC) is primarily attributable to the high-stage diseases. However, there are no available biomarkers that predict EEC patient staging at the time of diagnosis. We aim to develop a predictive scheme to help in this regards. Using reverse-phase protein array expression profiles for 210 EEC cases from The Cancer Genome Atlas (TCGA), we constructed a Protein Scoring of EEC Staging (PSES) scheme for surgical stage prediction. We validated and evaluated its diagnostic potential in an independent cohort of 184 EEC cases obtained at MD Anderson Cancer Center (MDACC) using receiver operating characteristic curve analyses. Kaplan-Meier survival analysis was used to examine the association of PSES score with patient outcome, and Ingenuity pathway analysis was used to identify relevant signaling pathways. Two-sided statistical tests were used. PSES robustly distinguished high- from low-stage tumors in the TCGA cohort (area under the ROC curve [AUC]=0.74; 95% confidence interval [CI], 0.68 to 0.82) and in the validation cohort (AUC=0.67; 95% CI, 0.58 to 0.76). Even among grade 1 or 2 tumors, PSES was significantly higher in high- than in low-stage tumors in both the TCGA (P = 0.005) and MDACC (P = 0.006) cohorts. Patients with positive PSES score had significantly shorter progression-free survival than those with negative PSES in the TCGA (hazard ratio [HR], 2.033; 95% CI, 1.031 to 3.809; P = 0.04) and validation (HR, 3.306; 95% CI, 1.836 to 9.436; P = 0.0007) cohorts. The ErbB signaling pathway was most significantly enriched in the PSES proteins and downregulated in high-stage tumors. PSES may provide clinically useful prediction of high-risk tumors and offer new insights into tumor biology in EEC.

Keywords: endometrial carcinoma, protein, protein scoring of EEC staging (PSES), stage

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Authors: Mohammadjavad Sotoudeheian

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Heart failure (HF) prevalence, as a global cardiovascular problem, is increasing gradually. A variety of molecular mechanisms contribute to HF. Proteins involved in cardiac contractility regulation, such as ion channels and calcium handling proteins, are altered. Additionally, epigenetic modifications and gene expression can lead to altered cardiac function. Moreover, inflammation and oxidative stress contribute to HF. The progression of HF can be attributed to mitochondrial dysfunction that impairs energy production and increases apoptosis. Molecular mechanisms such as these contribute to the development of cardiomyocyte defects and HF and can be therapeutically targeted. The heart's contractile function is controlled by cardiomyocytes. Calpain, and its related molecules, including Bax, VEGF, and AMPK, are among the proteins involved in regulating cardiomyocyte function. Apoptosis is facilitated by Bax. Cardiomyocyte apoptosis is regulated by this protein. Furthermore, cardiomyocyte survival, contractility, wound healing, and proliferation are all regulated by VEGF, which is produced by cardiomyocytes during inflammation and cytokine stress. Cardiomyocyte proliferation and survival are also influenced by AMPK, an enzyme that plays an active role in energy metabolism. They all play key roles in apoptosis, angiogenesis, hypertrophy, and metabolism during myocardial inflammation. The role of calpains has been linked to several molecular pathways. The calpain pathway plays an important role in signal transduction and apoptosis, as well as autophagy, endocytosis, and exocytosis. Cell death and survival are regulated by these calcium-dependent cysteine proteases that cleave proteins. As a result, protein fragments can be used for various cellular functions. By cleaving adhesion and motility proteins, calcium proteins also contribute to cell migration. HF may be brought about by calpain-mediated pathways. Many physiological processes are mediated by the calpain molecular pathways. Signal transduction, cell death, and cell migration are all regulated by these molecular pathways. Calpain is activated by calcium binding to calmodulin. In the presence of calcium, calmodulin activates calpain. Calpains are stimulated by calcium, which increases matrix metalloproteinases (MMPs). In order to develop novel treatments for these diseases, we must understand how this pathway works. A variety of myocardial remodeling processes involve calpains, including remodeling of the extracellular matrix and hypertrophy of cardiomyocytes. Calpains also play a role in maintaining cardiac homeostasis through apoptosis and autophagy. The development of HF may be in part due to calpain-mediated pathways promoting cardiomyocyte death. Numerous studies have suggested the importance of the Ca2+ -dependent protease calpain in cardiac physiology and pathology. Therefore, it is important to consider this pathway to develop and test therapeutic options in humans that targets calpain in HF. Apoptosis, autophagy, endocytosis, exocytosis, signal transduction, and disease progression all involve calpain molecular pathways. Therefore, it is conceivable that calpain inhibitors might have therapeutic potential as they have been investigated in preclinical models of several conditions in which the enzyme has been implicated that might be treated with them. Ca 2+ - dependent proteases and calpains contribute to adverse ventricular remodeling and HF in multiple experimental models. In this manuscript, we will discuss the calpain molecular pathway's important roles in HF development.

Keywords: calpain, heart failure, autophagy, apoptosis, cardiomyocyte

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Authors: Danilo G. De Quadros

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Biofuels are a priority in the renewable energy agenda. The utilization of tropical grasses to ethanol production is a real opportunity to Brazil reaches the world’s leadership in biofuels production because there are 100 million hectares of sown pastures, which represent 20% of all land and 80% of agricultural areas. Basically, nowadays tropical grasses are used to raise livestock. The results obtained in this research could bring tremendous advance not only to national technology and economy but also to improve social and environmental aspects. Thus, the objective of this work was to estimate, through well-established international models, the potential of biofuels production using sown tropical pastures as feedstocks and to compare the results with sugarcane ethanol, considering state-of-art of conversion technology, advantages and limitations factors. There were used data from national and international literature about forage yield and biochemical conversion yield. Some scenarios were studied to evaluate potential advantages and limitations for cellulosic ethanol production, since non-food feedstock appeal to conversion strategies, passing through harvest, densification, logistics, environmental impacts (carbon and water cycles, nutrient recycling and biodiversity), and social aspects. If Brazil used only 1% of sown pastures to ethanol production by biochemical pathway, with average dry matter yield of 15 metric tons per hectare per year (there are results of 40 tons), resulted annually in 721 billion liters, that represents 10 times more than sugarcane ethanol projected by the Government in 2030. However, more research is necessary to take the results to commercial scale with competitive costs, considering many strategies and methods applied in ethanol production using cellulosic feedstock.

Keywords: biofuels, biochemical pathway, cellulosic ethanol, sustainability

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Authors: Launcelot McGrath

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A comprehensive understanding of physiological data is a vital aid to the anaesthesiologist in monitoring and maintaining the well-being of a patient undergoing surgery. Bio signal analysis is one of the most important topics that researchers have tried to develop over the last century to understand numerous human diseases. Understanding which biological signals are most important during anaesthesia is critically important. It is important that the anaesthesiologist understand both the signals themselves and the limitations introduced by the processes of acquisition. In this article, we provide an overview of different types of biological signals as well as the mechanisms applied to acquire them.

Keywords: biological signals, signal acquisition, anaesthesiology, patient monitoring

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Authors: David Karasek, Veronika Kubickova, Ondrej Krystynik, Dominika Goldmannova, Lubica Cibickova, Jan Schovanek

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Introduction: Adiponectin, adipocyte-fatty acid-binding protein (A-FABP), and Wnt1 inducible signaling pathway protein-1 (WISP-1) are adipokines particularly associated with insulin resistance. The aim of the study was to compare their levels in women with gestational diabetes (GDM), type 2 diabetes mellitus (T2DM) and healthy controls and determine their relation with metabolic parameters. Methods: Fifty women with GDM, 50 women with T2DM, and 35 healthy women were included in the study. In addition to adipokines, anthropometric, lipid parameters, and markers, insulin resistance, and glucose control were assessed in all participants. Results: Compared to healthy controls only significantly lower levels of adiponectin were detected in women with GDM, whereas lower levels of adiponectin, higher levels of A-FABP and of WISP-1 were present in women with T2DM. Women with T2DM had also lower levels of adiponectin and higher levels of A-FABP compared to women with GDM. In women with GDM or T2DM adiponectin correlated negatively with body mass index (BMI), triglycerides (TG), C-peptide and positively with HDL-cholesterol; A-FABP positively correlated with BMI, TG, waist, and C-peptide. Moreover, there was a positive correlation between WISP-1 and C-peptide in women with T2DM. Conclusion: Adverse adipokines production detecting dysfunctional fat tissue is in women with GDM less presented than in women with T2DM, but more expressed compared to healthy women. Acknowledgment: Supported by AZV NV18-01-00139 and MH CZ DRO (FNOl, 00098892).

Keywords: adiponectin, adipocyte-fatty acid binding protein, wnt1 inducible signaling pathway protein-1, gestational diabetes, type 2 diabetes mellitus

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Authors: Ronald Villamar-Torres, Michael Staudt, Christopher Viot

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Cotton Gossypium hirsutum L. is one of the most important industrial crops, producing the world leading natural textile fiber, but is very prone to arthropod attacks that reduce crop yield and quality. Cotton cultivation, therefore, makes an outstanding use of chemical pesticides. In reaction to herbivorous arthropods, cotton plants nevertheless show natural defense reactions, in particular through volatile organic compounds (VOCs) emissions. These natural defense mechanisms are nowadays underutilized but have a very high potential for cotton cultivation, and elucidating their genetic bases will help to improve their use. Simulating herbivory attacks by mechanical wounding of cotton plants in greenhouse, we studied by qPCR the changes in gene expression for genes of the terpenoids biosynthesis pathway. Differentially expressed genes corresponded to higher levels of the terpenoids biosynthesis pathway and not to enzymes synthesizing particular terpenoids. The genes were mapped on the G. hirsutum L. reference genome; their global relationships inside the general metabolic pathways and the biosynthesis of secondary metabolites were visualized with iPath2. The chromatographic profiles of VOCs emissions indicated first monoterpenes and sesquiterpenes emissions, dominantly four molecules known to be involved in plant reactions to arthropod attacks. As a result, the study permitted to identify potential key genes for the emission of volatile terpenoids by cotton plants in reaction to an arthropod attack, opening possibilities for molecular-assisted cotton breeding in benefit of smallholder cotton growers.

Keywords: biosynthesis pathways, cotton, mechanisms of plant defense, terpenoids, volatile organic compounds

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Authors: T. R. Sreekrishnan, Mukesh Khare, Dinesh Upadhyay

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In a Rotating Biological Contactor (RBC), the biological film responsible for removal of pollutants is formed on the surface of discs. Evaluation studies of a pilot RBC designed to treat sewage of 150 persons with BOD Loading Rate: 8.2–26.7 g/m2/d, Discharge: 57.6 – 115.2 m3/day, HRT 1.25 – 2.5 hrs, at STP Yamuna Vihar Delhi. Removal of organic materials through use of fixed film reactors such as RBC is accomplished by means of a biological film on the fixed media. May and June in Delhi are dry summer months where the ambient temperature is in the range of 35oC to 45oC. July is a wet monsoon month that receives occasional precipitation, cloud cover, high humidity, with ambient temperature in the range of 30oC to 35oC. The organic and inorganic loads to the RBC employed in this study are actual city sewage conditions. Average in fluent BOD concentrations have been 330 mg/l, 245 mg/l and 160 mg/l and the average COD concentrations have been 670 mg/l, 500 mg/l, and 275 mg/l. The city sewage also has high concentration of ammonia, phosphorous, total suspended solids (TSS). pH of the city sewage is near neutral. Overall, the substrate conditions of city sewage are conducive for biological treatment though aerobic process. The presentation is a part of the ongoing collaborative research initiative between IIT Delhi and Karlsruhe Institute of Technology, Germany which is going on for last 15 years or so in the treatment of sewage waste of Delhi using semi-decentralized treatment system based on Rotating Biological Contactor.

Keywords: Rotating Biological Contactor (RBC), COD, BOD, HRT, STP

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Authors: D. Bhowmik, Y. Tian, Q. Yin, F. Zhu

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Cyclic GMP-AMP synthase (cGAS), recognises cytoplasmic double-stranded DNA (dsDNA), indicative of bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. Viruses also have developed numerous strategies to antagonize the cGAS-STING pathway. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human DNA tumor virus that is the causative agent of Kaposi’s sarcoma and several other malignancies. To persist in the host, consequently causing diseases, KSHV must overcome the host innate immune responses, including the cGAS-STING DNA sensing pathway. We already found that ORF52 or KicGAS (KSHV inhibitor of cGAS), an abundant and basic gamma herpesvirus-conserved tegument protein, directly inhibits cGAS enzymatic activity. To better understand the mechanism, we have performed the biochemical and structural characterization of full-length KicGAS and various mutants in regarding binding to DNA. We observed that KicGAS is capable of self-association and identified the critical residues involved in the oligomerization process. We also characterized the DNA-binding of KicGAS and found that KicGAS cooperatively oligomerizes along the length of the double stranded DNA, the highly conserved basic residues at the c-terminal disordered region are crucial for DNA recognition. Deficiency in oligomerization also affects DNA binding. Thus DNA binding by KicGAS sequesters DNA and prevents it from being detected by cGAS, consequently inhibiting cGAS activation. KicGAS homologues also inhibit cGAS efficiently, suggesting inhibition of cGAS is evolutionarily conserved mechanism among gamma herpesvirus. These results highlight the important viral strategy to evade this innate immune sensor.

Keywords: Kaposi's sarcoma-associated herpesvirus, KSHV, cGAS, DNA binding, inhibition

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Authors: Laura Cochrane

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The United States Centers for Disease Control and Prevention has established three categories of biological agents based on their ease of spread and the severity of the disease they cause. Category A biological agents are the highest priority because of their high degree of morbidity and mortality, ease of dissemination, the potential to cause social disruption and panic, special requirements for public health preparedness, and past use as a biological weapon. Despite the threat of Category A biological agents, opportunities for medical intervention exist. This work summarizes public information, consolidated and reviewed across the situational usefulness and disease awareness to offer discussion to three specific Category A agents: anthrax (Bacillus anthracis), botulism (Clostridium botulinum toxin), and smallpox (variola major), and provides an overview on the management of medical countermeasures available to treat these three (3) different types of pathogens. The medical countermeasures are discussed in the setting of pre-exposure prophylaxis, post-exposure prophylaxis, and therapeutic treatments to provide a framework for requirements in public health preparedness.

Keywords: anthrax, botulism, smallpox, medical countermeasures

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Authors: Igor Sukhotnik

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Objectives: Notch signaling is thought to act to drive cell versification in the lining of the small intestine. When Notch signaling is blocked, proliferation ceases, and epithelial cells become secretory. The purpose of the present study was to evaluate the role of Notch signaling pathway in stem cell differentiation in a rat model of intestinal ischemia-reperfusion (IR). Methods: Male Sprague-Dawley rats were randomly divided into four experimental groups: Sham-24 and Sham-48 rats underwent laparotomy and were killed 24 or 48 h later, respectively; IR-24 and IR-48 rats underwent occlusion of SMA and portal vein for 30 min followed by 24 or 48 h of reperfusion, respectively. Notch-related gene and protein expression were determined using Real Time PCR, Western blotting and immunohistochemistry. Wax histology and immunohistochemistry was used to determine cell differentiation toward absorptive (enterocytes) or secretory progenitors (goblet cells, enteroendocrine cells or Paneth cells). Results: IR-48 rats exhibited a significant decrease in Notch-1 protein expression (Western blot) that was coincided with a significant decrease in the number of Notch-1 positive cells (immunohistochemistry) in jejunum and ileum as well as Hes-1 positive cells in jejunum and ileum compared to Sham-48 rats. A significant down-regulation of Notch signaling related genes and proteins in IR animals was accompanied by a significant increase in the number of goblet and Paneth cells and decreased number of absorptive cells compared to control rats. Conclusions: Forty-eight hours following intestinal IR in rats, inhibited Notch signaling pathway was accompanied by intestinal stem cells differentiation toward secretory progenitors.

Keywords: Intestine, notch, ischemia-reperfusion, cell differentiation, secretory

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Authors: Agustyas Tjiptaningrum, Intanri Kurniati, Fadilah Fadilah, Linda Erlina, Tiwuk Susantiningsih

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Coronavirus disease-19 (COVID-19) is still one of the health problems. It can be a severe condition that is caused by a cytokine storm. In a cytokine storm, several proinflammatory cytokines are released massively. It destroys epithelial cells, and subsequently, it can cause death. The anti-inflammatory agent can be used to decrease the number of severe Covid-19 conditions. Melaleuca cajuputi is a plant that has antiviral, antibiotic, antioxidant, and anti-inflammatory activities. This study was carried out to analyze the prediction mechanism of the M. cajuputi extract from Lampung, Indonesia, as an anti-inflammatory agent for COVID-19. This study constructed a database of protein host target that was involved in the inflammation process of COVID-19 using data retrieval from GeneCards with the keyword “SARS-CoV2”, “inflammation,” “cytokine storm,” and “acute respiratory distress syndrome.” Subsequent protein-protein interaction was generated by using Cytoscape version 3.9.1. It can predict the significant target protein. Then the analysis of the Gene Ontology (GO) and KEGG pathways was conducted to generate the genes and components that play a role in COVID-19. The result of this study was 30 nodes representing significant proteins, namely NF-κβ, IL-6, IL-6R, IL-2RA, IL-2, IFN2, C3, TRAF6, IFNAR1, and DOX58. From the KEGG pathway, we obtained the result that NF-κβ has a role in the production of proinflammatory cytokines, which play a role in the COVID-19 cytokine storm. It is an important factor for macrophage transcription; therefore, it will induce inflammatory gene expression that encodes proinflammatory cytokines such as IL-6, TNF-α, and IL-1β. In conclusion, the blocking of NF-κβ is the prediction mechanism of the M. cajuputi extract as an anti-inflammation agent for COVID-19.

Keywords: antiinflammation, COVID-19, cytokine storm, NF-κβ, M. cajuputi

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Authors: Xi Yu, Lili Gu, Huizhu Wang, Xiao Wei, Dandan Sheng, Xiaoyan Jiang, Min Hong

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Introduction: Hypersensitivity disease is difficult to cure completely because of its recurrence, yupingfengsan (YPFS) is used to treat the diseases with the advantage of reducing the recurrence,but the precise mechanism is not clear. Previous studies of our laboratory have shown that the extract of YPFS can inhibit Th2-type allergic contact dermatitis(ACD) induced by FITC.Besides, thymic stromal lymphopoietin(TSLP) have been proved to be a master switch for allergic inflammation. Based on these studies, we want to establish a mouse model of TSLP production based on Th2 cell-mediated allergic inflammation to explore the regulating mechanisms of YPFS on TSLP in Th2 cell-mediated allergic inflammation. Methods: Th2-type ACD mouse model: The mice were topically sensitized on the abdomens (induction phase) and elicited on its ears skin 6 day later (excitation phase) with FITC solution, and the ear swelling was measured to evaluate the allergic inflammation；A mouse model of TSLP production based on Th2 cell-mediated allergic inflammation (TSLP production model): the skin of the ear was sensitized on two consecutive days with FITC solution causing the production of TSLP；Mice were treated with YPFS extract，ELISA、Real-time PCR and Western-blotting were using to examine the mRNA and protein levels of TSLP\TSLPR and TLRs ect. Results: YPFS extract can attenuates Th2-type allergic inflammatory in mice；in TSLP production model, YPFS can inhibit the expression of TSLP、 TSLPR、TLRs and MyD88, So we deduce the possible mechanisms of YPFS to play a role of intervention is through TLRs- MyD88 dependent and independent pathway to reduce TSLP production.

Keywords: YPFS, TSLP, TLRs, Th2-type allergic contact dermatitis

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Authors: Michal Kielbik, Izabela Szulc-Kielbik, Anna Brzostek, Jaroslaw Dziadek, Magdalena Klink

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The goal of many research groups in the world is to find new components that are important for survival of mycobacteria in the host cells. Mycobacterium tuberculosis (Mtb) possesses a number of enzymes degrading cholesterol that are considered to be an important factor for its survival and persistence in host macrophages. One of them - cholesterol oxidase (ChoD), although not being essential for cholesterol degradation, is discussed as a virulence compound, however its involvement in macrophages’ response to Mtb is still not sufficiently determined. The recognition of tubercle bacilli antigens by pathogen recognition receptors is crucial for the initiation of the host innate immune response. An important receptor that has been implicated in the recognition and/or uptake of Mtb is Toll-like receptor type 2 (TLR2). Engagement of TLR2 results in the activation and phosphorylation of intracellular signaling proteins including IRAK-1 and -4, TRAF-6, which in turn leads to the activation of target kinases and transcription factors responsible for bactericidal and pro-inflammatory response of macrophages. The aim of these studies was a detailed clarification of the role of Mtb cholesterol oxidase as a virulence factor affecting the TLR2 signaling pathway in human macrophages. As human macrophages the THP-1 differentiated cells were applied. The virulent wild-type Mtb strain (H37Rv), its mutant lacking a functional copy of gene encoding cholesterol oxidase (∆choD), as well as complimented strain (∆choD–choD) were used. We tested the impact of Mtb strains on the expression of TLR2-depended signaling proteins (mRNA level, cytosolic level and phosphorylation status). The cytokine and bactericidal response of THP-1 derived macrophages infected with Mtb strains in relation to TLR2 signaling pathway dependence was also determined. We found that during the 24-hours of infection process the wild-type and complemented Mtb significantly reduced the cytosolic level and phosphorylation status of IRAK-4 and TRAF-6 proteins in macrophages, that was not observed in the case of ΔchoD mutant. Decreasement of TLR2-dependent signaling proteins, induced by wild-type Mtb, was not dependent on the activity of proteasome. Blocking of TLR2 expression, before infection, effectively prevented the induced by wild-type strain reduction of cytosolic level and phosphorylation of IRAK-4. None of the strains affected the surface expression of TLR2. The mRNA level of IRAK-4 and TRAF-6 genes were significantly increased in macrophages 24 hours post-infection with either of tested strains. However, the impact of wild-type Mtb strain on both examined genes was significantly stronger than its ΔchoD mutant. We also found that wild-type strain stimulated macrophages to release high amount of immunosuppressive IL-10, accompanied by low amount of pro-inflammatory IL-8 and bactericidal nitric oxide in comparison to mutant lacking cholesterol oxidase. The influence of wild-type Mtb on this type of macrophages' response strongly dependent on fully active IRAK-1 and IRAK-4 signaling proteins. In conclusion, Mtb using cholesterol oxidase causes the over-activation of TLR2 signaling proteins leading to the reduction of their cytosolic level and activity resulting in the modulation of macrophages response to allow its intracellular survival. Supported by grant: 2014/15/B/NZ6/01565, National Science Center, Poland

Keywords: Mycobacterium tuberculosis, cholesterol oxidase, macrophages, TLR2-dependent signaling pathway

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Authors: Diab Z., Hamad A., Dixit A., Al-Rikabi M., Keshaverzi F.

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Introduction: According to the NICE guidelines, 2020Prasugrel is the recommended first line treatment in adults with acute coronary syndromes (ACS) in patients with ST-segment-elevation myocardial infarction (STEMI), defined as ST elevation or new left bundle branch block on ECG , that cardiologists intend to treat with primary percutaneous coronary intervention (PCI). The current literature suggests that this is largely due to safety and efficacy, and cost effectiveness. We wanted to do an audit to examine the adherence of the MRI hospital with guidelines in using prasugrel as first-line therapy in patients with STEMI and undergoing PPCI. AIM: To examine the adherence of the MRI hospital with guidelines in using prasugrel as first-line therapy in patients with STEMI and undergoing PPCI Methods: We looked at the patients presented to MRI during1^st of January 2022 to 28th February 2022. We included all the people who were above 18 and were brought to the hospital through the PPCI pathway and diagnosed as ACS and underwent PPCI. We excluded Patients who were brought to the hospital through the PPCI pathway and underwent coronary angiography and their diagnosis was found other than STEMI or if the outcome was death before discharge or they were above age >75 (as per guideline increase bleeding risk of prasugrel in a person aged 75 or older). Results: The total number of patients was 100. There were a total of seventy patients who had STEMI and fit the criteria for inclusion. Out of these, only 72.9% (51) were given Prasugrel as a first line. Seventeen (17) 24.3% STEMI patients were candidates for prasugrel as first-line therapy but were instead offered (clopidogrel/ticagrelor). Two 2 (2.9%) STEMI patients were not given prasugrel as first-line therapy because of C/I (CVA) or the use of anticoagulant Nine 9 (9%) of them died before discharge. Eleven 11 (11%) were above the age of 75. Ten 10 (10%) of patients had a diagnosis other than STEMI. Conclusions and recommendations: Our audit has shown the need to increase awareness amongst staff re: the first line use of Prasugrel as per NICE guidelines. We aim to arrange awareness sessions for staff and increase visibility of the guidelines for the staff to encourage them to adhere to the guideline. Further research is needed to find the optimum treatment in patients above 75.

Keywords: pasurgrel, PCI, NICE, STEMI

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Authors: Matthew I. Bellgard

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The field of bioinformatics has made, and continues to make, substantial progress and contributions to life science research and development. However, this paper contends that a systems approach integrates bioinformatics activities for any project in a defined manner. The application of critical control points in this bioinformatics systems approach may be useful to identify and evaluate points in a pathway where specified activity risk can be reduced, monitored and quality enhanced.

Keywords: bioinformatics, food security, personalized medicine, systems approach

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Authors: Elham Shakerian, Reza Afarin

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The hepatic disease causes approximately 2 million deaths/year worldwide. Liver fibrosis is the last stage of numerous chronic liver diseases, and until now there is no definite cure or drug for it. Activation of hepatic stellate cells (HSCs) is the main reason for fibrosis. Transforming growth factor (TGF-β), as a main profibrogenic cytokine, if increased in these cells, leads to liver fibrosis through smad3 signaling pathways and increasing the expressions of Collagen type I and III, and actin-alpha smooth muscle (αSMA) genes. Curcumin (CUR) is a polyphenolic compound and an active ingredient derived from the rhizome of the turmeric plant that exerts effective antioxidant, anti-inflammatory, and antimicrobial activity. It has been shown that daily consumption of curcumin may have a protective effect on the liver against oxidative stress associated with alcohol consumption. In this study, we investigate the role of Curcumin in decreasing HSC activation and treating liver fibrosis. First, the human HSCs were treated with 2 ng/ml of (TGF-β) for 24 hours to become activated, then with Silibinin for 24 hours. Total RNAs were extracted, reversely transcribed into cDNA, Quantitative Real-time PCR, and western blot were performed. The mRNA expression levels of Collagen type I and III, αSMA genes, and the level of smad3 phosphorylation in TGF-β activated human HSCs treated with Curcumin were significantly reduced compared to human HSCs untreated with Curcumin. Curcumin is effective in reducing the expression of fibrogenic genes in the activated human HSCs treated with TGFB through downregulation of the TGF-β/smad3 signaling pathway. Therefore, Curcumin possesses significant antifibrotic properties in hepatic fibrosis

Keywords: hepatic fibrosis, human HSCs, curcumin, fibrogenic genes

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Authors: Pureun-Haneul Lee, Byeong-Gon Kim, Sun-Hye Lee, An-Soo Jang

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Background: Nanoparticles may pose adverse health effects due to particulate matter inhalation. Nanoparticle exposure induces cell and tissue damage, causing local and systemic inflammatory responses. The inflammasome is a major regulator of inflammation through its activation of pro-caspase-1, which cleaves pro-interleukin-1β (IL-1β) into its mature form and may signal acute and chronic immune responses to nanoparticles. Objective: The aim of the study was to identify whether nanoparticles exaggerates inflammasome pathway leading to airway inflammation and hyperresponsiveness in an allergic mice model of asthma. Methods: Mice were treated with saline (sham), OVA-sensitized and challenged (OVA), or titanium dioxide nanoparticles. Lung interleukin 1 beta (IL-1β), interleukin 18 (IL-18), NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and caspase-1 levels were assessed with Western Blot. Caspase-1 was checked by immunohistochemical staining. Reactive oxygen species were measured for the marker 8-isoprostane and carbonyl by ELISA. Results: Airway inflammation and hyperresponsiveness increased in OVA-sensitized/challenged mice and these responses were exaggerated by TiO2 nanoparticles exposure. TiO2 nanoparticles treatment increased IL-1β and IL-18 protein expression in OVA-sensitized/challenged mice. TiO2 nanoparticles augmented the expression of NLRP3 and caspase-1 leading to the formation of an active caspase-1 in the lung. Lung caspase-1 expression was increased in OVA-sensitized/challenged mice and these responses were exaggerated by TiO2 nanoparticles exposure. Reactive oxygen species was increased in OVA-sensitized/challenged mice and in OVA-sensitized/challenged plus TiO2 exposed mice. Conclusion: Our data demonstrate that inflammasome pathway activates in asthmatic lungs following nanoparticles exposure, suggesting that targeting the inflammasome may help control nanoparticles-induced airway inflammation and responsiveness.

Keywords: bronchial asthma, inflammation, inflammasome, nanoparticles

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Authors: Ejovi Eghwubare Augustine

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This study delved into the traditional mechanisms of conflict resolution in Africa, a pathway to sustainable peace in Nigeria. It deployed the quantitative and qualitative methods of data collection and content analysis. The work adopted the Peace Process theory propounded by John Darby and Roger Macunity. It ascertained that disputes or disagreements are unarguably and necessarily an inevitable part of human existence, flowing directly from communication, interaction, and relationships which can occur at individual and national levels, even at international levels in view of the current trend of globalization. The alternative Dispute Resolution (ADR) mechanism is a basket of procedures outside the traditional process of litigation or strict determination of legal rights. It may also be elucidated as a range of procedures that serve as generally involve the intercession and assistance of a neutral and impartial third party. The traditional mechanisms of conflict resolution in Africa are alien to the Western world; this paper is of utmost importance to the Western world and also enriched their pool of literature. Nigeria is a country that is dominated by various ethnic groups anchored on diverse cultures, customs, and traditions. It is, therefore, not surprising to see conflicts arise, and despite the various attempts at resolving these conflicts through litigation, they still remained unabated. The paper investigated the lessons learned from Traditional Mechanisms of Conflict resolution; it also interrogated its impact and the way forward. In light of the lessons that were learned and the impact of the traditional mechanisms of conflict resolution, suggestions on how to attain a sustainable, peaceful society were proffered. In conclusion, the study crystallized reforms on the alternative dispute resolution introduced through the traditional mechanism, which includes, amongst others, that constitutional recognition should be given to traditional institutions of conflict resolution to enable quick dispensation of matters.

Keywords: traditional, conflict, peace, resolution

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Authors: Ali Bolat, Ali Bayat, Mustafa Gullu

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Maize can be cultivated both under main and second crop conditions in Turkey. Main pests of maize under second crop conditions are Sesamia nonagrioides Lefebvre (Lepidoptera: Noctuidae) and Ostrinia nubilalis Hübner (Lepidoptera: Crambidae). Aerial spraying applications to control these two main maize pests can be carried out until 2006 in Turkey before it was banned due to environmental concerns like drifting of sprayed pestisides and low biological efficiency. In this context, pulverizers which can spray tall maize plants ( > 175 cm) from the ground have begun to be used. However, the biological efficiency of these sprayers is unknown. Some methods have been tested to increase the success of ground spraying in field experiments conducted in second crop maize in 2008 and 2009. For this aim, 6 spraying methods (air assisted spraying with TX cone jet, domestic cone nozzles, twinjet nozzles, air induction nozzles, standard domestic cone nozzles and tail booms) were used at two application rates (150 and 300 l.ha-1) by a sprayer. In the study, biological efficacy evaluations of each methods were measured in each parcel. Biological efficacy evaluations included counts of number of insect damaged plants, number of holes in stems and live larvae and pupa in stems of selected plants. As a result, the highest biological efficacy value (close to 70%) was obtained from Air Assisted Spraying method at 300 l / ha application volume.

Keywords: air assisted sprayer, drift nozzles, biological efficiency, maize plant

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Authors: Giselle Maggie-Fer Castañeda Lozano

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The main objective of this research was to explore the role of neural network architectures in simulating behavioral phenomena as a potential explanation for selective associations, specifically related to biological constraints on learning. Biological constraints on learning refer to the limitations observed in conditioning procedures, where learning is expected to occur. The study involved simulations of five different experiments exploring various phenomena and sources of biological constraints in learning. These simulations included the interaction between response and reinforcer, stimulus and reinforcer, specificity of stimulus-reinforcer associations, species differences, neuroanatomical constraints, and learning in uncontrolled conditions. The overall results demonstrated that by manipulating neural network architectures, conditions can be created to model and explain diverse biological constraints frequently reported in comparative psychology literature as learning typicities. Additionally, the simulations offer predictive content worthy of experimental testing in the pursuit of new discoveries regarding the specificity of learning. The implications and limitations of these findings are discussed. Finally, it is suggested that this research could inaugurate a line of inquiry involving the use of neural networks to study biological factors in behavior, fostering the development of more ethical and precise research practices.

Keywords: comparative psychology, connectionism, conditioning, experimental analysis of behavior, neural networks

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Authors: Inam Ridha, Christine L. Kuryla, Madhuranga Thilakasiri Madugoda Ralalage Don, Norman J. Kleiman, Yunro Chung, Jin Park, Vel Murugan, Joshua LaBaer

Abstract:

To date, more than 275 million people worldwide have been diagnosed with COVID-19 and the rapid spread of the omicron variant suggests many millions more will soon become infected. Many infections are asymptomatic, while others result in mild to moderate illness. Unfortunately, some infected individuals exhibit more serious symptoms including respiratory distress, thrombosis, cardiovascular disease, multi-organ failure, cognitive difficulties, and, in roughly 2% of cases, death. Studies indicate other coronaviruses can alter the host cell's epigenetic profile and lead to alterations in the immune response. To better understand the mechanism(s) by which SARS-CoV-2 infection causes serious illness, DNA methylation profiles in peripheral blood mononuclear cells (PBMCs) from 90 hospitalized severely ill COVID-19 patients were compared to profiles from uninfected control subjects. Exploratory epigenome-wide DNA methylation analyses were performed using multiplexed methylated DNA immunoprecipitation (MeDIP) followed by pathway enrichment analysis. The findings demonstrated significant DNA methylation changes in infected individuals as compared to uninfected controls. Pathway analysis indicated that apoptosis, cell cycle control, Toll-like receptors (TLR), cytokine interactions, and T cell differentiation were among the most affected metabolic processes. In addition, changes in specific gene methylation were compared to SARS-CoV-2 induced changes in RNA expression using published RNA-seq data from 3 patients with severe COVID-19. These findings demonstrate significant correlations between differentially methylated and differentially expressed genes in a number of critical pathways.

Keywords: COVID19, epigenetics, DNA mathylation, viral infection

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Authors: L. B. Naves, L. Almeida

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The development of Drugs Delivery System (DDS), has been wildly investigated in the last decades. In this paper, first a general overview of traditional and modern wound dressing is presented. This is followed by a review of what scientist have done in the medical environment, focusing the possibility to develop a new alternative for DDS through transdermal pathway, aiming to treat melanoma skin cancer.

Keywords: cancer therapy, dressing polymers, melanoma, wound healing

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Authors: Evar C. Umeozor, Experience I. Nduagu, Ian D. Gates

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The energy requirements of carbon dioxide utilization (CDU) technologies/processes are diverse, so also are their environmental footprints. This paper explores the energy and environmental impacts of systems for CO₂ conversion to fuels, chemicals, and materials. Energy needs of the technologies and processes deployable in CO₂ conversion systems are met by one or combinations of hydrogen (chemical), electricity, heat, and light. Likewise, the environmental footprint of any CO₂ utilization pathway depends on the systems involved. So far, evaluation of CDU systems has been constrained to particular energy source/type or a subset of the overall system needed to make CDU possible. This introduces limitations to the general understanding of the energy and environmental implications of CDU, which has led to various pitfalls in past studies. A CDU system has an energy source, CO₂ supply, and conversion units. We apply a holistic approach to consider the impacts of all components in the process, including various sources of energy, CO₂ feedstock, and conversion technologies. The electricity sources include nuclear power, renewables (wind and solar PV), gas turbine, and coal. Heat is supplied from either electricity or natural gas, and hydrogen is produced from either steam methane reforming or electrolysis. The CO₂ capture unit uses either direct air capture or post-combustion capture via amine scrubbing, where applicable, integrated configurations of the CDU system are explored. We demonstrate how the overall energy and environmental impacts of each utilization pathway are obtained by aggregating the values for all components involved. Proper accounting of the energy and emission intensities of CDU must incorporate total balances for the utilization process and differences in timescales between alternative conversion pathways. Our results highlight opportunities for the use of clean energy sources, direct air capture, and a number of promising CO₂ conversion pathways for producing methanol, ethanol, synfuel, urea, and polymer materials.

Keywords: carbon dioxide utilization, processes, energy options, environmental impacts

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Authors: Beth Taylor, Kojima Mituaki, Atsushi Senda, Koji Morishita, Yasuhiro Otomo

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Intestinal ischaemia-reperfusion injury drives systemic inflammation and organ failure following trauma/haemorrhagic shock (T/HS), through the release of pro-inflammatory mediators into the mesenteric lymph (ML). However, changes in the biological function of ML are not fully understood, and therefore, a specific model of intestinal ischaemia-reperfusion injury is required to obtain ML for the study of its biological function upon inflammatory cells. ML obtained from a model of intestinal ischaemia-reperfusion injury was used to assess biological function upon inflammatory cells and investigate changes in the biological function of individual ML components. An additional model was used to determine the effect of vagal nerve stimulation (VNS) upon biological function. Rat ML was obtained by mesenteric lymphatic duct cannulation before and after occlusion of the superior mesenteric artery (SMAO). ML was incubated with human polymorphonuclear neutrophils (PMNs), monocytes and lymphocytes, and the biological function of these cells was assessed. ML was then separated into supernatant, exosome and micro-vesicle components, and biological activity was compared in monocytes. A model with an additional VNS phase was developed, in which the right cervical vagal nerve was exposed and stimulated, and ML collected for comparison of biological function with the conventional model. The biological function of ML was altered by intestinal ischaemia-reperfusion injury, increasing PMN activation, monocyte activation, and lymphocyte apoptosis. Increased monocyte activation was only induced by the exosome component of ML, with no significant changes induced by the supernatant or micro-vesicle components. VNS partially attenuated monocyte activation, but no attenuation of PMN activation was observed. Intestinal ischaemia-reperfusion injury induces changes in the biological function of ML upon both innate and adaptive inflammatory cells, supporting the role of intestinal ischaemia-reperfusion injury in driving systemic inflammation following T/HS. The exosome component of ML appears to be critical to the transport of pro-inflammatory mediators in ML. VNS partially attenuates changes in innate inflammatory cell biological activity observed, presenting possibilities for future novel treatment development in multiple organ failure patients.

Keywords: exosomes, inflammation, intestinal ischaemia, mesenteric lymph, vagal stimulation

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Authors: Azin Nasrollah Zadeh

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A factorial experiment was applied to evaluate the effect of chemical and biological fertilizer on yield, total nitrogen uptake and NHI of rice. Four biological treatments including:(M1:no fertilizer),( M2:10 ton/ha cow dung ),(M3:20 ton/ha cow dung) and (M4:5 ton/ha azolla compost) and four chemical fertilizer treatments including: (S1: no fertilizer),(S2:40 kg N /ha),(S3:60 kg N /ha) and ( S4:80 kg N /ha ) were compared. Results showed that highest rate of yield (3387 kg/ha) and total nitrogen uptake (81.4 kg/ha) were reached the highest value at M4. Among the chemical fertilizers the highest grain yield (3373 kg/ha) and total nitrogen uptake (87.7) belonged to highest nitrogen level (S4).Also biological and chemical fertilizers were no significant on Harvest index (NHI). Interaction effect of chemical × biological fertilizers didn't show significant difference between all parameters except of yield, as the most grain yield were obtained in M4S4. So it can be concluded that using of bioilogical fertilizers at appropriate rate and type, considering plant requirement, may improve grain yield, nitrogen uptake and use efficiency in rice.

Keywords: azolla, fertilizer, nitrogen uptake, rice, yield

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Authors: Ashir Ahmed

Abstract:

Generally, radicalization happens when a person's thinking and behaviour become significantly different from how most of the members of their society and community view social issues and participate politically. Radicalization often leads to violent extremism that refers to the beliefs and actions of people who support or use violence to achieve ideological, religious or political goals. Studies on radicalization negate the common myths that someone must be in a group to be radicalised or anyone who experiences radical thoughts is a violent extremist. Moreover, it is erroneous to suggest that radicalisation is always linked to religion. Generally, the common motives of radicalization include ideological, issue-based, ethno-nationalist or separatist underpinning. Moreover, there are number of factors that further augments the chances of someone being radicalised and may choose the path of violent extremism and possibly terrorism. Since there are numbers of factors (and sometimes quite different) contributing in radicalization and violent extremism, it is highly unlikely to devise a single solution that could produce effective outcomes to deal with radicalization, violent extremism and terrorism. The pathway to deradicalization, like the pathway to radicalisation, is different for everyone. Considering the need of having customized deradicalization resolution, this study proposes a multi-tier framework, called ‘pyramid of deradicalization’ that first help identifying the stage at which an individual could be on the radicalization pathway and then propose a customize strategy to deal with the respective stage. The first tier (tier 1) addresses broader community and proposes a ‘universal approach’ aiming to offer community-based design and delivery of educational programs to raise awareness and provide general information on possible factors leading to radicalization and their remedies. The second tier focuses on the members of community who are more vulnerable and are disengaged from the rest of the community. This tier proposes a ‘targeted approach’ targeting the vulnerable members of the community through early intervention such as providing anonymous help lines where people feel confident and comfortable in seeking help without fearing the disclosure of their identity. The third tier aims to focus on people having clear evidence of moving toward extremism or getting radicalized. The people falls in this tier are believed to be supported through ‘interventionist approach’. The interventionist approach advocates the community engagement and community-policing, introducing deradicalization programmes to the targeted individuals and looking after their physical and mental health issues. The fourth and the last tier suggests the strategies to deal with people who are actively breaking the law. ‘Enforcement approach’ suggests various approaches such as strong law enforcement, fairness and accuracy in reporting radicalization events, unbiased treatment by law based on gender, race, nationality or religion and strengthen the family connections.It is anticipated that the operationalization of the proposed framework (‘pyramid of deradicalization’) would help in categorising people considering their tendency to become radicalized and then offer an appropriate strategy to make them valuable and peaceful members of the community.

Keywords: deradicalization, framework, terrorism, violent extremism

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Authors: Shirin jalili, Hadi Shirzad, Samaneh Nabavi, Somayeh Khanjani

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Biosensors in forensic analysis are ideal biological tools that can be used for rapid and sensitive initial screening and testing to detect of suspicious components like biological and chemical agent in crime scenes. The wide use of different biomolecules such as proteins, nucleic acids, microorganisms, antibodies and enzymes makes it possible. These biosensors have great advantages such as rapidity, little sample manipulation and high sensitivity, also Because of their stability, specificity and low cost they have become a very important tool to Forensic analysis and detection of crime. In crime scenes different substances such as rape samples, Semen, saliva fingerprints and blood samples, act as a detecting elements for biosensors. On the other hand, successful fluid recovery via biosensor has the propensity to yield a highly valuable source of genetic material, which is important in finding the suspect. Although current biological fluid testing techniques are impaired for identification of body fluids. But these methods have disadvantages. For example if they are to be used simultaneously, Often give false positive result. These limitations can negatively result the output of a case through missed or misinterpreted evidence. The use of biosensor enable criminal researchers the highly sensitive and non-destructive detection of biological fluid through interaction with several fluid-endogenous and other biological and chemical contamination at the crime scene. For this reason, using of the biosensors for detecting the biological fluid found at the crime scenes which play an important role in identifying the suspect and solving the criminal.

Keywords: biosensors, forensic analysis, biological fluid, crime detection

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Authors: Panadda Rojpibulstit, Suthathip Kittisenachai, Songchan Puthong, Sirikul Manochantr, Pornpen Gamnarai, Sasichai Kangsadalampai, Sittiruk Roytrakul

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Hepatocellular carcinoma (HCC) is the most primary hepatic cancer worldwide. Nowadays a targeted therapy via monoclonal antibodies (mAbs) specific to tumor-associated antigen is continually developed in HCC treatment. In this regard, after establishing and consequently exploring Hep88 mAb’s tumoricidal effect on hepatocellular carcinoma cell line (HepG2 cell line), the Hep88 mAb’s specific Ag from both membrane and cytoplasmic fractions of HepG2 cell line was identified by 2-D gel electrophoresis and western blot analysis. After in-gel digestion and subsequent analysis by liquid chromatography-mass spectrometry (LC-MS), mortalin (HSPA9) and alpha-enolase were identified. The recombinant proteins specific to Hep88 mAb were cloned and expressed in E.coli BL21 (DE3). Moreover, alteration of HepG2 and Chang liver cell line after being induced by Hep88 mAb for 1-3 days was investigated using a transmission electron microscope. The result demonstrated that Hep88 mAb can bind to the recombinant mortalin (HSPA9) andalpha-enolase. In addition, gradual appearance of mitochondria vacuolization and endoplasmic reticulum dilatation were observed. Taken together, paraptosis-like programmed cell death (PCD) of HepG2 is induced by binding of mortalin (HSPA9) and alpha-enolase to Hep88 mAb. Mortalin depletion by formation of Hep88 mAb-mortalin (HSPA9) complex might initiate transcription-independent of p53-mediated apoptosis. Additionally, Hep88 mAb-alpha-enolase complex might initiate HepG2 cells energy exhaustion by glycolysis pathway obstruction. These results imply that Hep88 mAb might be a promising tool for development of an effective treatment of HCC in the next decade.

Keywords: Hepatocellular carcinoma, Monoclonal antibody, Paraptosis-like program cell death, Transmission electron microscopy, mortalin (HSPA9), alpha-enolase

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Authors: Mahan Qwamizadeh, Kun Zhou, Zuoqi Zhang, Yong Wei Zhang

Abstract:

Typical load-bearing biological materials like bone, mineralized tendon and shell, are biocomposites made from both organic (collagen) and inorganic (biomineral) materials. This amazing class of materials with intrinsic internally designed hierarchical structures show superior mechanical properties with regard to their weak components from which they are formed. Extensive investigations concentrating on static loading conditions have been done to study the biological materials failure. However, most of the damage and failure mechanisms in load-bearing biological materials will occur whenever their structures are exposed to dynamic loading conditions. The main question needed to be answered here is: What is the relation between the layout and architecture of the load-bearing biological materials and their dynamic behavior? In this work, a staggered model has been developed based on the structure of natural materials at nanoscale and Finite Element Analysis (FEA) has been used to study the dynamic behavior of the structure of load-bearing biological materials to answer why the staggered arrangement has been selected by nature to make the nanocomposite structure of most of the biological materials. The results showed that the staggered structures will efficiently attenuate the stress wave rather than the layered structure. Furthermore, such staggered architecture is effectively in charge of utilizing the capacity of the biostructure to resist both normal and shear loads. In this work, the geometrical parameters of the model like the thickness and aspect ratio of the mineral inclusions selected from the typical range of the experimentally observed feature sizes and layout dimensions of the biological materials such as bone and mineralized tendon. Furthermore, the numerical results validated with existing theoretical solutions. Findings of the present work emphasize on the significant effects of dynamic behavior on the natural evolution of load-bearing biological materials and can help scientists to design bioinspired materials in the laboratories.

Keywords: load-bearing biological materials, nanostructure, staggered structure, stress wave decay

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Authors: Katarína Koňariková, Georgios A. Perdikaris, Lucia Andrezálová, Zdeňka Ďuračková, Lucia Laubertová, Helena Gbelcová, Ingrid Žitňanová

Abstract:

Introduction: The continuous demand for new anti-cancer drugs has stimulated chemotherapeutic research based on the use of essential metalloelements with the aim to develop potential drugs with lower toxicity and higher antiproliferative activity against tumors. Copper(II) and its complexes play an important role as suitable species for antiproliferative tests. Objectives: The central objective of the current study was to investigate the potential in vitro anti-proliferative effects of N-salicylidene-L-glutamato copper (II) complexes and molecular mechanism of apoptosis induced by tested complexes. In our project we tested N-salicylidene-L-glutamato copper (II) complexes ZK1 - [Cu(N-salicylidene-L-glutamato)(H2O)2].H2O; MK0 - ([Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O); MK1 - [Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O; MK3 - transbis(ethanol)tetrakis(imidazol)Cu(II)(2+)bis(N-salicylidene-D,L-glutamato-N,O)-KO:KO´-(imidazol); MK5 - [Cu(N-salicylidene-D,L- glutamato)(2-methylimidazol] at concentration range 0.001-100 µmol/L against human colon carcinoma cell line HT-29 and human breast carcinoma cell line MCF-7. Methods: Viability was assessed by direct counting of 0.4% trypan blue dye-excluding cells after 24, 48 and 72 hour cultivations with or without copper complex and by MTT assay. To analyze the type of cell death and its mechanism induced by our copper complex we used different methods. To distinguish apoptosis from necrosis we used electrophoretic analysis, to study the activity of caspases 8 and 9 – luminometric analysis and caspase activity 3 colorimetric assay. Results: The observed anti-proliferative effect of the copper complexes appeared to be dose-, time- and cell line- dependent. Human colon carcinoma cells HT-29 appeared to be more sensitive to the complex MK0 ([Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O) than to ZK1 ([Cu(N-salicylidene-L-glutamato)(H2O)2].H2O) and MK1 ([Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O)). Human colon carcinoma cells HT-29 appeared to be more sensitive to the complex than human breast carcinoma cells MCF-7. IC50 decreased with time of incubation (24, 48 and 72h) for HT-29, but increased for MCF-7. By electrophoresis we found apoptotic cell death induced by our copper complexes in HT-29 at concentrations 1, 10, 50 and 100 µmol/L after 48h (ZK1) and 72h (MK0, MK1) and in MCF-7 we did not find apoptosis. We also studied molecular mechanism of apoptosis in HT-29 induced by copper complexes. We found active caspase 9 in HT-29 after ZK1 ([Cu(N-salicylidene-L-glutamato)(H2O)2].H2O) and MK1 ([Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O)) influence and active caspase 8 after MK0 ([Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O) influence. Conclusion: Our copper complexes showed cytotoxic activities against human colon carcinoma cells HT-29 and breast cancer cell line MCF-7 in vitro. Apoptosis was activated by mitochondrial pathway (intrinsic pathway) in case of ZK1 [Cu(N-salicylidene-L-glutamato)(H2O)2].H2O; MK1 [Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O; MK3 - transbis(ethanol)tetrakis(imidazol)Cu(II)(2+)bis(N-salicylidene-D,L-glutamato-N,O)-KO:KO´-(imidazol) and MK5 - [Cu(N-salicylidene-D,L- glutamato)(2-methylimidazol] copper complexes and by death receptors (extrinsic pathway) in case of MK0 [Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O copper complex in HT-29.

Keywords: apoptosis, copper complex, cancer, carcinoma cell line

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