910 research outputs found

    Table1_Integrated transcriptome and cell phenotype analysis suggest involvement of PARP1 cleavage, Hippo/Wnt, TGF-β and MAPK signaling pathways in ovarian cancer cells response to cannabis and PARP1 inhibitor treatment.XLSX

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    Introduction:Cannabis sativa is utilized mainly for palliative care worldwide. Ovarian cancer (OC) is a lethal gynecologic cancer. A particular cannabis extract fraction ('F7′) and the Poly(ADP-Ribose) Polymerase 1 (PARP1) inhibitor niraparib act synergistically to promote OC cell apoptosis. Here we identified genetic pathways that are altered by the synergistic treatment in OC cell lines Caov3 and OVCAR3.Materials and methods: Gene expression profiles were determined by RNA sequencing and quantitative PCR. Microscopy was used to determine actin arrangement, a scratch assay to determine cell migration and flow cytometry to determine apoptosis, cell cycle and aldehyde dehydrogenase (ALDH) activity. Western blotting was used to determine protein levels.Results: Gene expression results suggested variations in gene expression between the two cell lines examined. Multiple genetic pathways, including Hippo/Wnt, TGF-β/Activin and MAPK were enriched with genes differentially expressed by niraparib and/or F7 treatments in both cell lines. Niraparib + F7 treatment led to cell cycle arrest and endoplasmic reticulum (ER) stress, inhibited cell migration, reduced the % of ALDH positive cells in the population and enhanced PARP1 cleavage.Conclusion: The synergistic effect of the niraparib + F7 may result from the treatment affecting multiple genetic pathways involving cell death and reducing mesenchymal characteristics.</p

    Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

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    Acute graft versus host disease (aGvHD) is the major contributor of nonrelapse mortality in alloHSCT. It is associated with an inflammatory immune response manifesting as cytokine storm with ensuing damage to target organs such as liver, gut, and skin. Prevention of aGvHD while retaining the beneficial graft versus leukemia (GvL) effect remains a major challenge. Withania somnifera extract (WSE) is known for its anti-inflammatory, immune-modulatory, and anticancer properties, which are appealing in the context of aGvHD. Herein, we demonstrated that prophylactic and therapeutic use of WSE in experimental model of alloHSCT mitigates aGvHD-associated morbidity and mortality. In the prophylaxis study, a dose of 75 mg/kg of WSE offered greatest protection against death due to aGvHD (hazard ratio [HR] = 0.15 [0.03-0.68], P ≤ .01), whereas 250 mg/kg was most effective for the treatment of aGvHD (HR = 0.16 [0.05-0.5], P ≤ .01). WSE treatment protected liver, gut, and skin from damage by inhibiting cytokine storm and lymphocytic infiltration to aGvHD target organs. In addition, WSE did not compromise the GvL effect, as alloHSCT with or without WSE did not allow the leukemic A20 cells to grow. In fact, WSE showed marginal antileukemic effect in vivo . WSE is currently under clinical investigation for the prevention and treatment of aGvHD

    sj-docx-1-cll-10.1177_09636897241226573 – Supplemental material for Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect

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    Supplemental material, sj-docx-1-cll-10.1177_09636897241226573 for Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect by Saurabh Kumar Gupta, Dievya Gohil, Mohd Bashar Momin, Subhash Yadav, Akanksha Chichra, Sachin Punatar, Anant Gokarn, Sumeet Mirgh, Nishant Jindal, Lingaraj Nayak, Lal Hingorani, Navin Khattry and Vikram Gota in Cell Transplantation</p

    Mitocurcumin utilizes oxidative stress to upregulate JNK/p38 signaling and overcomes Cytarabine resistance in acute myeloid leukemia

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    Acute myeloid leukemia (AML) is a type of blood cancer that is characterized by the rapid growth of abnormal myeloid cells. The goal of AML treatment is to eliminate the leukemic blasts, which is accomplished through intensive chemotherapy. Cytarabine is a key component of the standard induction chemotherapy regimen for AML. However, despite a high remission rate, 70-80% of AML patients relapse and develop resistance to Cytarabine, leading to poor clinical outcomes. Mitocurcumin (MitoC), a derivative of curcumin that enters mitochondria, leading to a drop in mitochondrial membrane potential and mitophagy induction. Further, it activates oxidative stress-mediated JNK/p38 signaling to induce apoptosis. MitoC demonstrated a preferential ability to kill leukemic cells from AML cell lines and patient-derived leukemic blasts. RNA sequencing data suggests perturbation of DNA damage response and cell proliferation pathways in MitoC-treated AML. Elevated reactive oxygen species (ROS) in MitoC-treated AML cells resulted in significant DNA damage and cell cycle arrest. Further, MitoC treatment resulted in ROS-mediated enhanced levels of p21, which leads to suppression of CHK1, RAD51, Cyclin-D and c-Myc oncoproteins, potentially contributing to Cytarabine resistance. Combinatorial treatment of MitoC and Cytarabine has shown synergism, increased apoptosis, and enhanced DNA damage. Using AML xenografts, a significant reduction of hCD45+ cells was observed in AML mice bone marrow treated with MitoC (mean 0.6%; range0.04%-3.56%) compared to control (mean 38.2%; range10.1%-78%), p = 0.03. The data suggest that MitoC exploits stress-induced leukemic oxidative environment to up-regulate JNK/p38 signaling to lead to apoptosis and can potentially overcome Cytarabine resistance via ROS/p21/CHK1 axis.</p

    DataSheet1_Integrated transcriptome and cell phenotype analysis suggest involvement of PARP1 cleavage, Hippo/Wnt, TGF-β and MAPK signaling pathways in ovarian cancer cells response to cannabis and PARP1 inhibitor treatment.docx

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    Introduction:Cannabis sativa is utilized mainly for palliative care worldwide. Ovarian cancer (OC) is a lethal gynecologic cancer. A particular cannabis extract fraction ('F7′) and the Poly(ADP-Ribose) Polymerase 1 (PARP1) inhibitor niraparib act synergistically to promote OC cell apoptosis. Here we identified genetic pathways that are altered by the synergistic treatment in OC cell lines Caov3 and OVCAR3.Materials and methods: Gene expression profiles were determined by RNA sequencing and quantitative PCR. Microscopy was used to determine actin arrangement, a scratch assay to determine cell migration and flow cytometry to determine apoptosis, cell cycle and aldehyde dehydrogenase (ALDH) activity. Western blotting was used to determine protein levels.Results: Gene expression results suggested variations in gene expression between the two cell lines examined. Multiple genetic pathways, including Hippo/Wnt, TGF-β/Activin and MAPK were enriched with genes differentially expressed by niraparib and/or F7 treatments in both cell lines. Niraparib + F7 treatment led to cell cycle arrest and endoplasmic reticulum (ER) stress, inhibited cell migration, reduced the % of ALDH positive cells in the population and enhanced PARP1 cleavage.Conclusion: The synergistic effect of the niraparib + F7 may result from the treatment affecting multiple genetic pathways involving cell death and reducing mesenchymal characteristics.</p

    Mitigating Emotion Dysregulation in Adolescents: The Effectiveness of Vipassana Meditation

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    Introduction. Mood swings, hypersensitivity, stress, and frustration intolerance are only the tip of the iceberg when it comes to the problems adolescents have in properly controlling and regulating their emotions. Their relationships, ability to make decisions, and general happiness may all suffer because of their difficulties with emotional regulation. Vipassana meditation (VM) promotes awareness of the need for change, enhances mental focus, and opens the door to more introspective thought. Methods. The purpose of this research was to examine the impact of vipassana meditation (VM) on adolescents\u27 (n = 60) inability to control their emotions. Participants were randomly assigned in groups: vipassana meditators (those who practise meditation daily) or non-meditators (those who don\u27t practise any form of meditation). A measure of emotional dysregulation, the DERS-36, was administered concurrently to both groups. Results. A statistically significant difference was discovered between the two groups using SPSS-27, suggesting that vipassana meditators have better than non-meditators at keeping their emotions in check. The effect size of vipassana meditation was also investigated, and researchers found it to be 197.136 which indicates a strong impact of vipassana meditation. Overall, vipassana meditation has good impacts 77.9% of variance on the level of emotion dysregulation among adolescents. Discussion. The statistics show that people struggle to keep their feelings in check, suggesting that VM could be helpful. Young people have a better chance of thriving as adults if they are helped when they are struggling.Introduction. Mood swings, hypersensitivity, stress, and frustration intolerance are only the tip of the iceberg when it comes to the problems adolescents have in properly controlling and regulating their emotions. Their relationships, ability to make decisions, and general happiness may all suffer because of their difficulties with emotional regulation. Vipassana meditation (VM) promotes awareness of the need for change, enhances mental focus, and opens the door to more introspective thought. Methods. The purpose of this research was to examine the impact of vipassana meditation (VM) on adolescents\u27 (n = 60) inability to control their emotions. Participants were randomly assigned in groups: vipassana meditators (those who practise meditation daily) or non-meditators (those who don\u27t practise any form of meditation). A measure of emotional dysregulation, the DERS-36, was administered concurrently to both groups. Results. A statistically significant difference was discovered between the two groups using SPSS-27, suggesting that vipassana meditators have better than non-meditators at keeping their emotions in check. The effect size of vipassana meditation was also investigated, and researchers found it to be 197.136 which indicates a strong impact of vipassana meditation. Overall, vipassana meditation has good impacts 77.9% of variance on the level of emotion dysregulation among adolescents. Discussion. The statistics show that people struggle to keep their feelings in check, suggesting that VM could be helpful. Young people have a better chance of thriving as adults if they are helped when they are struggling

    IMPROVED PROCESS FOR THE PREPARATION OF LURBINECTEDIN

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    The present disclosure relates to an improved process for the preparation of Lurbinectedin of formula-1which is structurally shown as below: Formula-
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