A biochemical assessment of apoptosis-inducing impact of Salinomycin in combination with ciprofloxacin on human leukemia KG1-a stem-like cells in the presence and absence of insulin.

BACKGROUND: Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin. METHODS: This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24-72 h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR. RESULTS: CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL. CONCLUSION: Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition.

Bacteriophages and Green Synthesized Zinc Oxide Nanoparticles in Combination Are Efficient against Biofilm Formation of Pseudomonas aeruginosa.

Bacteriophages (phages) are viruses that infect the bacteria within which their reproduction cycle takes place, a process that ends in the lysis and death of the bacterial cell. Some phages are also able to destroy bacterial biofilms. Due to increased antibiotics resistance, Pseudomonas aeruginosa, another biofilm-forming pathogen, is a problem in many parts of the world. Zinc oxide (ZnO) and other metal nanoparticles (NPs) are biologically active and also possess anti-biofilm properties. ZnO-NPs were prepared by the green synthesis method using orange peels. The vibrational peaks of the ZnO-NPs were analyzed using FTIR analysis, and their size and morphological properties were determined using scanning electron microscopy (SEM). The ability of the ZnO-NPs to reduce or eliminate P. aeruginosa biofilm alone or in combination with phages PB10 and PA19 was investigated. The P. aeruginosa cells were effectively killed in the preformed 48 h biofilms during a 24 h incubation with the ZnO-NP-phage combination, in comparison with the control or ZnO-NPs alone. The treatments on growing biofilms were most efficient in the final stages of biofilm development. All five treatment groups showed a significant biofilm reduction compared to the control group (p < 0.0001) at 48 h of incubation. The influence of the ZnO-NPs and phages on the quorum sensing system of P. aeruginosa was monitored by quantitative real-time PCR (qRT-PCR) of the autoinducer biosynthesis gene lasI. While the ZnO-NPs repressed the lasI gene transcription, the phages slightly activated it at 24 and 48 h of incubation. Also, the effect of the ZnO-NPs and phage PA19 on the viability of HFF2 cells was investigated and the results showed that the combination of NPs with PA19 reduced the toxic effect of ZnO-NPs and also stimulated the growth in normal cells.

Hesperidin/Salinomycin Combination; a Natural Product for Deactivation of the PI3K/Akt Signaling Pathway and Anti-Apoptotic Factors in KG1a Cells.

AML is a highly aggressive malignant clonal disease of hematopoietic origin. Hesperidin as a polyphenol glycoside, Activates the apoptotic pathway and salinomycin as a k + selective ionophore. We examined how hesperidin and salinomycin induce pro-apoptotic effects in KG1a cells. Cells were divided into four groups; 1) control cells (CRTL), 2) cells treated with hesperidin 85 µM, 3) cells treated with 2 µM salinomycin, 4) cells treated with combination of salinomycin and hesperidin. The MTT assay was implemented to determine the IC50 of hesperidin and salinomycin in KG1a cell lines. Propidium iodide staining and flow cytometry were used to analyze the distribution of the cell cycle. The level of ROS was evaluated by fluorescent microscopy and spectrophotometry. Additionally, Akt, XIAP, Bad, and FOXO1 gene expression was analyzed by real-time PCR. Hesperidin/Salinomycin decreased the viability of KG1a leukemic cells more than Hesperidin and Salinomycin separately. Changes in the shape of apoptotic cells and rise in ROS levels were detected after Hesperidin/Salinomycin treatment. Our findings showed that following Hesperidin/Salinomycin treatment, the expression of PI3K/AKT signaling pathway related genes (AKT, PTEN and FOXO1), were in line with the destruction of KG-1a cells. Furthermore, XIAP and BAD mRNA were regulated to trigger apoptosis in cancer cells. The study discovered that hesperidin and salinomycin, could effectively hinder the PI3K/Akt signaling pathway in leukemia cancer cells. Also, the combination of hesperidin and salinomycin has the potential to be a treatment option for acute myeloid leukemia.

Advancing CEA quantification: Designing a sensitive electrochemical immunosenor using MWCNT/Ni(OH)2 nanocomposite.

An ultra-sensitive immunosensor was designed for the accurate determination of Carcinoembryonic Antigen (CEA). To enhance the performance of immunosensor, an MWCNT/Ni(OH)2 nanocomposite was utilized as the electrochemical interface and modifier of the electrode surface. The simple preparation procedures for MWCNT/Ni(OH)2 composite were provided. Its characteristics and properties were investigated by HRTEM, FESEM, XRD, and FTIR techniques. Leveraging the unique electrochemical characteristics shown by the MWCNT/Ni(OH)2 nanocomposite and its correlation with CEA, high accuracy in CEA detection was achieved. Experimental findings provide evidence that the proposed immunosensor has the ability to detect CEA in laboratory samples. This research contributes towards achieving precise and rapid CEA detection in cancer diagnosis and prognosis. Across a wide concentration range of CEA, the designed immunosensor demonstrated a linear response from 0.0001 ng/mL to 2 ng/mL, and its limit of detection (LOD) was just 0.076 pg/mL. To evaluate the practical applicability of the electrochemical immunosensor, blood serum samples were examined, revealing the immunosensor's remarkable specificity and longevity. Its high accuracy and stability make it a valuable tool in clinical settings and biomedical research, paving the way for improved cancer management and patient outcomes.

An Active Compound from the Pyrazine Family Induces Apoptosis by Targeting the Bax/Bcl2 and Survivin Expression in Chronic Myeloid Leukemia K562 Cells.

BACKGROUND: It has been established that pyrazine derivatives, which have widespread bioactivities, can effectively treat cancer. OBJECTIVES: In this study, we investigated the effects of 2-methoxy-5-(oxiran-2-ylmethyl) phenyl pyrazine-2- carboxylate (2-mOPP), a new pyrazine derivative, on proliferation, viability, and apoptosis induction in human leukemia K562 cells. METHODS: For this purpose, the K562 cells were treated with various concentrations (20-120 µM) of the 2-mOPP for 24-72 hours. Cell viability was determined by MTT growth inhibition assay. Apoptotic activity of 2-mOPP was investigated morphologically by Hoechst staining, cell surface expression assay of phosphatidylserine by Annexin-V/PI technique, as well as DNA fragmentation assay. The effect of 2-mOPP on the K562 cell cycle was studied by flow cytometry. To determine the impact of 2-mOPP on the expression of intrinsic apoptosis-related genes, Bcl2 (anti-apoptotic), Bax (pro-apoptotic), and Survivin genes expression levels were evaluated before and after treatment with 2-mOPP through Real-Time PCR analysis. RESULTS: The results revealed that 2-mOPP inhibited viability with IC50 of 25µM in 72 h. Morphological changes assessment by fluorescence microscopy, Annexin V/PI double staining by flow cytometry, and DNA ladders formation upon cell treatment with the 2-mOPP showed that this compound induces apoptosis at IC50 value. Cell cycle arrest was observed in the G0/G1 phase, and the sub-G1 cell population (the sign of apoptosis) increased in a time-dependent manner. Low expression levels of Bcl2 and Survivin in K562 cells were observed 24-72 h after treatment. Along with the down-regulation of Survivin and Bcl2, the expression of Bax was increased after treatment with 2-mOPP. CONCLUSION: These findings demonstrate that the new pyrazine derivative plays a crucial role in blocking the proliferation of the leukemic cells by inducing cell cycle arrest and apoptosis.

The Assessment of Cytotoxicity, Apoptosis Inducing Activity and Molecular Docking of a new Ciprofloxacin Derivative in Human Leukemic Cells.

The fluoroquinolone class of antibiotics includes derivatives of the drug ciprofloxacin. These substances have recently been advocated for the treatment of cancer. In the current study, we examined the cytotoxicity and apoptosis-inducing potential of a novel synthetic ciprofloxacin derivative in the human myeloid leukemia KG1-a cell line. With an IC50 of 25µM, this ciprofloxacin derivative, 7-(4-(2-(benzhydryloxy)-2-oxoethyl) piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4 dihydroquinoline-3- carboxylic acid (4-BHPCP), was an active drug. Through Hoechst 33,258 staining and Annexin V/PI double staining experiments, the apoptotic activity of the 4-BHPCP was assessed morphologically. Real-time quantitative PCR was used to assess changes in the expression level of certain apoptosis-related genes, including Bcl-2, Bax, and Survivin (qRT PCR). The results of the qRT PCR analysis demonstrated that 4-BHPCP promotes apoptosis in the KG1-a cell line by down-regulating Survivin and Bcl2, up-regulating Bax, and increasing the Bax/Bcl2 transcripts in a time-dependent manner. These results imply that this novel chemical may be a promising therapy option for acute myeloid leukemia.

Observation of increased levels of autophagy-related genes and proteins in women with preeclampsia: a clinical study.

BACKGROUND: Preeclampsia is a type of pregnancy-related disease that is not fully understood underlying mechanisms of it till now. Reported results from autophagy-related studies in PE show some controversial roles of this mechanism in PE development and progression. In this study, we aimed to evaluate the autophagy process in preeclampsia women. MATERIALS AND METHODS: Peripheral blood was taken from 50 preeclampsia women and 50 healthy pregnant women. After PBMC isolation, Total RNA and total protein were extracted from PBMCs to cDNA synthesis and real-time PCR and western blotting, respectively. Atg5, Atg7, beclin1, LC3B, FOXO1, FOXO3a, FOXO4, and FOXO6 genes were evaluated using real-time PCR. Atg5, beclin1, LC3B, and FOXO1 expression at the protein level was evaluated by the western blot technique. RESULTS: Real-time PCR results showed an increased expression of Atg5, Atg7, beclin1, LC3B, FOXO1, FOXO3a, FOXO4, and FOXO6 genes in PE patients compared to the healthy pregnant women and also in LOPE patients in comparison with EOPE cases. Western blotting results revealed higher expression of Atg5, beclin1, LC3B, and FOXO1 proteins in PE women compared to healthy pregnant group and in LOPE patients in comparison with EOPE cases. Our findings revealed a positive correlation between proteinuria and protein levels of Atg5, beclin1, LC3B, and FOXO1 in LOPE patients. CONCLUSION: Our investigation showed an elevated activation of autophagy in PE women in comparison with healthy pregnant women which is in controversy with some other studies. More targeted and comprehensive studies regarding the relationship of autophagy in pre-eclamptic women are needed.

Peri-implant cell differentiation in delayed and immediately-loaded dental implant: A mechanobiological simulation.

OBJECTIVE: This study aimed to investigate the effect of immediate versus delayed dental implant placement strategies on cell differentiation in a dental callus. DESIGN: The implant was placed in the mandible with two nearby teeth using an idealized two-dimensional finite element model. Eight weeks after surgery, the mechanobiological modeling of healing was used to estimate cell differentiation. It was assumed that the callus was initially filled by mesenchymal cells. The model then transformed mechanical stimuli received by the callus from loadings in terms of distortional and dilatational strains into predictions of the cellular phenotypes, including fibroblasts, chondrocytes, and osteoblasts, or whether they would remain unchanged or die. RESULTS: The results demonstrated that delayed loading led to greater bone formation than immediate loading. Osteoblast colonies were observed in the base of threads in the immediately-loaded implant, whereas the delayed loading caused distant bone formation from the surrounding bone side towards the implant. The osteoblasts were differentiated from both intramembranous and endochondral mechanisms of ossification. After eight weeks, approximately 61 % of the callus was ossified in the delayed placement model compared to 35 % in the immediate placement model, resulting in a greater amount of fibrocartilaginous tissue on the bone side of the callus. CONCLUSIONS: Immediate and delayed loading models generated different results. In the delayed strategy, bone cells were supplied appropriately during the first few weeks following surgery, whereas the immediate loading caused fibrocartilaginous tissue differentiation. In the form of distant osseointegration, the secondary stability of the dental implant was higher and faster due to the delayed placement.

Silymarin in combination with ATRA enhances apoptosis induction in human acute promyelocytic NB4 cells.

Although all-trans retinoic acid (ATRA) is an efficient pattern in acute promyelocytic leukemia (APL) therapy, further studies are required due to the extant clinical limitations of ATRA. It has been reported that Silymarin, an anti-cancer herbal substance extracted from milk thistle (Silybum marianum), is able to regulate apoptosis in various types of cancer cells through different mechanisms of action. This study investigated the apoptosis-inducing effect of Silymarin (SM) alone and in combination with ATRA on human acute promyelocytic NB4 cells. Examination using MTT assay indicated that SM treatment leads to growth inhibition in NB4 cells in a dose-dependent manner. The IC50 values of SM and ATRA were calculated 90 µM and 2 µM, respectively. Cell cycle analysis by flow cytometry revealed that a more increase in the sub-G1 phase (a sign of apoptosis) when cells were exposed to SM in combination with ATRA. The incidence of apoptosis was confirmed through Hoechst 33258 staining and Annexin V-FITC analysis. The results showed that Silymarin enhances ATRA-induced apoptosis. The flow cytometric analysis also indicated an enhancement in levels of ROS in the treated cells with both compounds. The real-time PCR illustrated that SM targets apoptosis by down-regulation in Survivin and Bcl-2 while up-regulation in Bax. The findings showed that the combination of the two compounds is more effective in the induction of apoptosis in NB4 cells. Molecular docking studies indicated that Sylibin, as a primary compound of the SM, binds to the BH3 domain of Bcl-2 and the BIR domain of Survivin with various affinities. Based on the findings, it seems that SM used alone and in combination with ATRA may be beneficial for inducing apoptosis in APL cells.

The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation.

Neuronal loss is one of the striking causes of various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features and clinical manifestations, they share some common mechanisms of disease pathology. Progressive regional loss of neurons in patients is responsible for motor, memory, and cognitive dysfunctions, leading to disabilities and death. Neuronal cell death in neurodegenerative diseases is linked to various pathways and conditions. Protein misfolding and aggregation, mitochondrial dysfunction, generation of reactive oxygen species (ROS), and activation of the innate immune response are the most critical hallmarks of most common neurodegenerative diseases. Thus, endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation are the major pathological factors of neuronal cell death. Even though the exact mechanisms are not fully discovered, the notable role of mentioned factors in neuronal loss is well known. On this basis, researchers have been prompted to investigate the neuroprotective effects of targeting underlying pathways to determine a promising therapeutic approach to disease treatment. This review provides an overview of the role of ER stress, oxidative stress, and neuroinflammation in neuronal cell death, mainly discussing the neuroprotective effects of targeting pathways or molecules involved in these pathological factors.

Cord blood stem cell-generated KIR+NK cells effectively target leukemia cell lines.

Acute lymphoid (ALL) and myeloid leukemia (AML) are known to be invasive and highly lethal hematological malignancies. Because current treatments are insufficient and have a variety of side effects, researchers are looking for new and more effective therapeutic methods. Interestingly, ongoing efforts to find the best approach to optimize NK cell anti-leukemia potential shed light on the successful treatment of cancer. Mature KIR+NK cells ability to remove HLA Class-I deficient cells has been exploited in cancer immunotherapy. Here, we generated KIR+NK cells from cord blood stem cells using IL-2 and IL-15 cytokines. Our finding underlined the importance of KIR expression in the cytotoxic function of NK cells. Taken together, this study presented an effective in vitro method for the expansion and differentiation of KIR+NK cells using cytokines without any feeder cells. Furthermore, the presented culture condition could be useful for the generation of mature and pure NK cells from limited numbers of CD34+ cord blood cells and might be used as a novel method to improve the current state of cancer therapy.

Evidence for Hesperidin as an Effective Factor in Initiating the Intrinsic Pathway of Apoptosis in KG1a Leukemia Cells.

Acute myeloid leukemia (AML) is the most common subtype of leukemia, accounting for 62% of all leukemia fatalities. As a polyphenol glycoside, hesperidin triggers the apoptotic pathway, which might positively affect combating cancer cells. In this study, we investigated the pro-apoptotic effects of hesperidin in KG1a cells. The MTT assay was used to determine the IC50 of hesperidin in KG1a cell lines. For the apoptotic cell morphology study, we used Hoechst 33 258 staining. Activation of the caspase-3 enzyme was evaluated by the caspase-3 assay and spectrophotometry. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Moreover, p21, survivin, Bax, and Bcl2 gene expression was investigated by real-time PCR. Hesperidin decreased the viability of KG1a leukemic cell4s, but not that of HFF2, a non-cancer cell line. Apoptotic cell morphological alterations and increase in caspase-3 activity were observed after hesperidin treatment. Our results revealed that the expression of anti-apoptotic genes survivin and Bcl2 significantly decreased with hesperidin treatment, and pro-apoptotic gene Bax and cell cycle regulator p21 increased compared to the control group. These findings revealed that hesperidin may be an effective factor in initiating the intrinsic pathway of apoptosis and may be good candidate for the treatment of AML.

The Effects of Sesquiterpene Lactones on the Differentiation of Human or Animal Cells Cultured In-Vitro: A Critical Systematic Review.

Cellular differentiation is pivotal in health and disease. Interfering with the process of differentiation, such as inhibiting the differentiation of adipocytes and inducing the differentiation of cancer cells, is considered a therapeutic approach. Sesquiterpene lactones, primarily found in plants, have been attracted attention as differentiating/dedifferentiating agents tested on various human or animal cells. However, a consensus on sesquiterpene lactones' effects and their mechanism of action is required. In this sense, through a systematic review, we have investigated the differentiating/dedifferentiating effects of sesquiterpene lactones on human or animal cells. 13 different cell lines originated from humans, mice, and rats, in addition to the effects of a total of 21 sesquiterpene lactones, were evaluated in the included studies. These components had either inducing, inhibiting, or no effect on the cells, mediating their effects through JAK-STAT, PI3K-Akt, mitogen-activated protein kinases, NFκB, PPARγ pathways. Although nearly all inducing and inhibiting effects were attributed to cancerous and normal cells, respectively, this is likely a result of a biased study design. Few studies reported negative results along with others, and no study was found reporting only negative results. As a result, not only are the effects and mechanism of action of sesquiterpene lactones not vivid but our knowledge and decisions are also misconducted. Moreover, there is a significant knowledge gap regarding the type of evaluated cells, other sesquiterpene lactones, and the involved signaling pathways. In conclusion, sesquiterpene lactones possess significant effects on differentiation status, leading to potentially efficient therapy of obesity, osteoporosis, and cancer. However, reporting negative results and further investigations on other cells, sesquiterpene lactones, and signaling pathways are highly suggested to pave the path of sesquiterpene lactones to the clinic more consciously.

In vitro study of redroot pigweed effects as weed plant species on leukemia.

Redroot pigweed is a well-known allelopathic weed worldwide with diverse organic compounds which involving in its allelopathic interactions as well. Preliminary tests of redroot pigweed extract against leukemia and various human phatogenic microorganisms revealed that amaranth extract inhibits the viability and proliferation of NB4 cells in a time- and dose-dependent manner and has an excellent anti-bacterial effect on gram-positive bacteria and Candida fungi. Interestingly, the anti-luekemia effects of redroot pigweed is reported for the first time. Phytochemical analysis of redroot pigweed extract, led to the identification amaranth bioactive compounds that largely were including terpenoid compounds (51.71%) as the main group and Carvacrol (11.33%) was the key compound. Redroot pigweed contains various organic compounds with allelopathic and therapeutic properties and current investigation is a promising revelation for the pharmaceutical importance of this plant.

DNA binding ability and cytotoxicity, cell cycle arrest and apoptosis inducing properties of a benzochromene derivative against K562 human leukemia cells.

Chromene and its derivatives are generally spread in nature. Heterocylic-based compounds like chromenes have displayed pharmacological activities. Chromene derivatives are critical due to some biological features such as anticancer activity. CML, chronic myelogenous leukemia, is a fatal malignancy determined by resistance to apoptosis and contains the Philadelphia chromosome. Induction of apoptosis is one of the main approaches in cancer therapy. In this research, benzochromene derivative, 2-amino-4-(4-methoxy phenyl)-4H-benzochromene-3-carbonitrile (4-MC) was tested for cytotoxic and apoptotic induction activities in the human leukemic K562 cell line. The MTT growth inhibition assay was used to determine the cellular growth and survival. Moreover, the binding attribute of 4-MC with double helix DNA was assessed by some spectroscopic and viscosity measurement, and also for docking analysis. 4-MC exhibited good cytotoxicity on K562 cell line and the IC50 value was calculated to be 30 µM. Furthermore, the mechanisms of apoptosis induction were determined morphologically by fluorescence dual staining with acridine orange and ethidium bromide and cell cycle analysis was based on DNA content, as well as the presence of phosphatidyl serine on the outside of the cells by the flow cytometric method. The results showed that 4-MC had potent cytotoxic activity via sub-G1 cell cycle arrest and induction of apoptosis. The experimental and simulation studies reported that 4-MC binds to ctDNA through groove binding mode with the binding constant (Kb) of 2.5 × 103 M-1. These data represent a considerable anticancer potential of 4-MC and could be suggested for further pharmacological studies.

Preparation and in-vitro evaluation of mesoporous biogenic silica nanoparticles obtained from rice and wheat husk as a biocompatible carrier for anti-cancer drug delivery.

In this study, mesoporous silica nanocarriers were synthesized from natural sources such as rice and wheat husk for drug delivery application. First, the biogenic silica in cereals husk was extracted by acid leaching and then converted to sodium silicate as a silica precursor. Mesoporous silica nanoparticles were then synthesized by adding sodium silicate to the template mixture by continuous and discrete modes during the sol-gel process. The effects of natural sources type and precursor addition method on nanocarriers' morphological and physicochemical properties were investigated by XRD, FT-IR, BET and SEM analysis. Our results showed rice husk-based spherical nanocarriers were more crystalline with slit-shaped pores, while wheat husk-based nanocarriers had been composed of spherical nanoparticles with narrow cylindrical pores. The results also showed that by adding the precursor discretely, their hydrophilicity, particle size and pore size increased compared with the continuous mode, probably due to the high initial concentration of the precursor in the reaction mixture. Doxorubicin (Dox), as a model anticancer drug was loaded into the nanocarriers, and the drug release behavior was studied at two different pH values (7.4 and 5.4). In general, the accumulated released drug at pH 5.4 was approximately twice as much as pH 7.4 due to the higher solubility of doxorubicin at acidic environment. Also, the accumulated released drug at pH 5.4 for nanocarriers which had been synthesized by discrete mode, was higher than continuous mode, due to the larger pore diameter of them. The biocompatibility and cytotoxicity of nanocarriers and Dox-loaded nanocarriers were also investigated on the HFF-2 and MCF-7 cell lines, respectively. Moreover, apoptosis, as the mechanism of cell death, was evaluated by morphological study of the MCF-7 cells. Within acceptable toxicity limits and apoptosis induction, the Dox-loaded nanocarriers, especially discrete mode synthesized nanocarriers, exhibited high-efficiency anticancer effect on the MCF-7 cell line.

The role of KIR positive NK cells in diseases and its importance in clinical intervention.

Natural killer (NK) cells are essential for the elimination of the transformed and cancerous cells. Killer cell immunoglobulin-like receptors (KIRs) which expressed by T and NK cells, are key regulator of NK cell function. The KIR and their ligands, MHC class I (HLA-A, B and C) molecules, are highly polymorphic and their related genes are located on 19 q13.4 and 6 q21.3 chromosomes, respectively. It is clear that particular interaction between the KIRs and their related ligands can influence on the prevalence, progression and outcome of several diseases, like complications of pregnancy, viral infection, autoimmune diseases, and hematological malignancies. The mechanisms of immune signaling in particular NK cells involvement in causing pathological conditions are not completely understood yet. Therefore, better understanding of the molecular mechanism of KIR-MHC class I interaction could facilitate the treatment strategy of diseases. The present review focused on the main characteristics and functional details of various KIR and their combination with related ligands in diseases and also highlights ongoing efforts to manipulate the key checkpoints in NK cell-based immunotherapy.

Gemini Curcumin Suppresses Proliferation of Ovarian Cancer OVCAR-3 Cells via Induction of Apoptosis.

BACKGROUND: Ovarian cancer has the highest mortality rate among gynecological malignancies. Despite recent advances in treatment, most patients still suffer from poor prognosis. Curcumin has shown highly cytotoxic effects against different types of cancer. However, its poor bioavailability restricts its clinical application. Gemini Curcumin (Gemini-Cur) has been developed to overcome this limitation. OBJECTIVE: Here, we aimed to unravel the inhibitory effect of Gemini-Cur in ovarian cancer. METHODS: OVCAR-3 cells were treated with free curcumin and Gemni-Cur in a time- and dose-dependent manner. Then, the anticancer activity was investigated by uptake kinetics, cellular viability and apoptotic assays. Furthermore, we evaluated the BAX/Bcl-2 expression ratio by real-time PCR and western blotting. RESULTS: Our data showed that gemini surfactant nanoparticles enhance the cellular uptake of curcumin compared to free curcumin (p<0.01). Regarding the growth inhibitory effect of nano-curcumin, the results demonstrated that Gemini-Cur suppresses the proliferation of OVCAR-3 cells through induction of apoptosis (p<0.001). CONCLUSION: The results illustrate that Gemini-Cur nanoparticles have a great potential for developing novel therapeutics against ovarian cancer.

Down-regulation of Survivin and Bcl-2 concomitant with the activation of caspase-3 as a mechanism of apoptotic death in KG1a and K562 cells upon exposure to a derivative from ciprofloxacin family.

Ciprofloxacin derivatives belong to a family of antibiotics called fluoroquinolones. Recently, these compounds have been recommended for the treatment of cancer. In the present study, we assessed the cytotoxicity of several new synthetic ciprofloxacin derivatives and the apoptosis-inducing activity of the most efficient derivative in two human myeloid leukemia K562 and KG1-a cell lines. Among the prepared ciprofloxacin derivatives, 1-cyclopropyl-7-(4-(2-((3,7-dimethyloct-6-en-1-yl)oxy)-2-oxoethyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4dihydroquinoline-3-carboxylic acid (4-DMOCP) was more active compound with IC50 of 19.56 and 22.13 µM for K562 and KG1-a, respectively. Apoptotic activity of the 4-DMOCP was examined morphologically through Hoechst 33258 staining, Annexin V/PI double staining, and caspase-3 activity assays. Changes in the expression level of some apoptosis-related genes and protein, including Bcl-2, Bax, Survivin, p53, Caspase-8 and Caspase-9 were evaluated by the real-time quantitative PCR (qRT PCR) and western blotting. The qRT PCR analysis showed that 4-DMOCP induces apoptosis in both cell lines via the down-regulation of Survivin and Bcl2, up-regulation of caspase-8 and -9, as well as a time-dependent increase in the Bax/Bcl2 transcripts. The mRNA level of p53 was also increased in both cell lines. In addition, western blot analysis revealed that treatment with the compound, down-regulated the protein expression levels of Bcl2 and Survivin and up-regulated the protein level of Bax in both cell lines. These findings suggest that these new compounds can be good candidates for the treatment of acute and chronic myeloid leukemia.