This document discusses research into the effects of black cohosh (Cimicifuga racemosa) on breast cancer cells. It finds that extracts of black cohosh inhibit the growth of both estrogen-dependent and estrogen-independent breast cancer cell lines. The active compounds in black cohosh, such as actein and cinnamic acid esters, induce apoptosis in breast cancer cells through multiple pathways including interaction with Na-K-ATPase, HER2 receptors, and reduction of reactive oxygen species. Synergy between compounds contributes to the anti-cancer activity of black cohosh.
Inhibition of glutathione by buthionine sulfoximine enhanced the anti-cancer ...Ashujit
Multiple myeloma (MM) is an incurable blood cancer. Melphalan is an alkylating agent given prior to stem cell transplantation to MM patients. Increased glutathione confers resistance to melphalan. This study investigate the effect of inhibition of glutathione by BSO in preclinical models of MM. Pretreatment with BSO enhanced the anti-cancer effect of melphalan in cell lines and animal models. BSO and melphalan combination was well tolerated by animals and enhanced the survival as compared to controls, BSO and melphalan alone. BSO enhanced depth and duration of responses induced by melphalan. In the combination group, majority of treated animals achieved complete response (CR) and more than 20% had maintained CR. Also, the survival of animals was doubled after combination treatment as compared to BSO or melphalan alone. Mechanistic investigation demonstrated that BSO enhanced melphalan induced DNA damage, caspase cleavage and apoptosis. The combination also achieved multi-logs of cells kills in nine human multiple myeloma cell lines and primary MM cells isolated from blood and bone marrows. Interestingly, the effect of BSO and melphalan combination was abolished when cells were treated with N-acetyl cysteine and sodium thiosulfate but not with vitamin C and vitamin E. This observation suggests that effect of BSO is primarily driven by its ability to deplete glutathione and therefore preventing melphalan detoxification. Together, this study provides framework for testing the combination in a Phase I trial.
This study characterized differences between parental breast cancer cells and their exemestane-resistant counterparts. The resistant cells exhibited altered morphology, increased cancer stem cells, and expressed different proteins associated with more abnormal and aggressive subtypes. They also had an altered miRNA profile and increased dependence on growth factor pathways. Inhibition of mTOR decreased cell viability in resistant cells but not cancer stem cell formation. Certain miRNAs, such as 181a, may play a role in resistance by regulating these cellular and molecular changes, and could be potential therapeutic targets for exemestane resistance.
1) The document discusses response rates and outcomes for patients with chronic myeloid leukemia (CML) treated with various tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, nilotinib, and bosutinib.
2) It reports that achieving a major cytogenetic response or deeper molecular response (e.g. MMR) at certain timepoints (e.g. 12 months) on imatinib is associated with improved progression-free and overall survival.
3) For patients who become resistant or intolerant to imatinib, the second-generation TKIs dasatinib, nilotinib and bosutinib have response rates ranging from
1. The document presents the discovery of JSI-124, a selective inhibitor of the JAK/STAT3 pathway, which was identified from screening a library of compounds for inhibition of STAT3 phosphorylation in cancer cells.
2. JSI-124 was found to reduce phospho-STAT3 levels in multiple human cancer cell lines and block STAT3 DNA binding and gene transcription, inhibiting tumor growth.
3. JSI-124 selectively targeted STAT3 signaling over other pathways and showed potent antitumor activity against human tumor xenografts in mouse models, demonstrating its potential as an anticancer therapeutic targeting the STAT3 pathway.
This document examines the effects of two DNA intercalators, mitoxantrone and WP631, on the expression of COL1A1, the gene encoding the alpha 1 chain of type I collagen, in cultured human dermal fibroblasts. The study finds that both drugs potently inhibit COL1A1 production and mRNA levels in a dose-dependent manner without causing cytotoxicity or apoptosis. This inhibition occurs through an abrogation of COL1A1 transcriptional activity mediated by competition of the drugs with the Sp1 transcription factor for DNA binding. Both drugs are also shown to inhibit TGF-β-induced stimulation of COL1A1 transcription. WP631 exhibits greater potency than mitoxantrone, inhibiting COL
1) The study found higher levels of MT1-MMP and lower levels of RECK, an MT1-MMP inhibitor, on circulating human CD34+ progenitor cells compared to those in bone marrow. MT1-MMP levels correlated with successful mobilization of CD34+ cells in healthy donors and patients receiving G-CSF treatment.
2) Treatment with G-CSF further increased MT1-MMP and decreased RECK expression on human and mouse hematopoietic cells in a PI3K/Akt-dependent manner. Blocking MT1-MMP impaired chemotaxis and homing of mobilized human CD34+ progenitors.
3) Mobilization of human progen
OSU-03012 sensitizes breast cancers to lapatinib-induced cell killing: a role...Enrique Moreno Gonzalez
Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms
associated with enhancing the activity of lapatinib via combination with other therapies.
This document describes a study examining gene expression changes in breast epithelial cells and fibroblasts when co-cultured together. Non-malignant (MCF10A) and breast cancer (MDA-MB231) epithelial cell lines were co-cultured with fibroblasts isolated from either benign breast tissues (NAF) or breast carcinoma tissues (CAF) using a transwell system. Gene expression profiles of each cell type were compared between co-culture and monoculture conditions. While epithelial cells showed large changes in gene expression when co-cultured, fibroblasts were less affected. Specific gene expression changes were observed for each epithelial cell - fibroblast combination that could impact processes like cell polarity, membrane biogenesis, growth control
Inhibition of glutathione by buthionine sulfoximine enhanced the anti-cancer ...Ashujit
Multiple myeloma (MM) is an incurable blood cancer. Melphalan is an alkylating agent given prior to stem cell transplantation to MM patients. Increased glutathione confers resistance to melphalan. This study investigate the effect of inhibition of glutathione by BSO in preclinical models of MM. Pretreatment with BSO enhanced the anti-cancer effect of melphalan in cell lines and animal models. BSO and melphalan combination was well tolerated by animals and enhanced the survival as compared to controls, BSO and melphalan alone. BSO enhanced depth and duration of responses induced by melphalan. In the combination group, majority of treated animals achieved complete response (CR) and more than 20% had maintained CR. Also, the survival of animals was doubled after combination treatment as compared to BSO or melphalan alone. Mechanistic investigation demonstrated that BSO enhanced melphalan induced DNA damage, caspase cleavage and apoptosis. The combination also achieved multi-logs of cells kills in nine human multiple myeloma cell lines and primary MM cells isolated from blood and bone marrows. Interestingly, the effect of BSO and melphalan combination was abolished when cells were treated with N-acetyl cysteine and sodium thiosulfate but not with vitamin C and vitamin E. This observation suggests that effect of BSO is primarily driven by its ability to deplete glutathione and therefore preventing melphalan detoxification. Together, this study provides framework for testing the combination in a Phase I trial.
This study characterized differences between parental breast cancer cells and their exemestane-resistant counterparts. The resistant cells exhibited altered morphology, increased cancer stem cells, and expressed different proteins associated with more abnormal and aggressive subtypes. They also had an altered miRNA profile and increased dependence on growth factor pathways. Inhibition of mTOR decreased cell viability in resistant cells but not cancer stem cell formation. Certain miRNAs, such as 181a, may play a role in resistance by regulating these cellular and molecular changes, and could be potential therapeutic targets for exemestane resistance.
1) The document discusses response rates and outcomes for patients with chronic myeloid leukemia (CML) treated with various tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, nilotinib, and bosutinib.
2) It reports that achieving a major cytogenetic response or deeper molecular response (e.g. MMR) at certain timepoints (e.g. 12 months) on imatinib is associated with improved progression-free and overall survival.
3) For patients who become resistant or intolerant to imatinib, the second-generation TKIs dasatinib, nilotinib and bosutinib have response rates ranging from
1. The document presents the discovery of JSI-124, a selective inhibitor of the JAK/STAT3 pathway, which was identified from screening a library of compounds for inhibition of STAT3 phosphorylation in cancer cells.
2. JSI-124 was found to reduce phospho-STAT3 levels in multiple human cancer cell lines and block STAT3 DNA binding and gene transcription, inhibiting tumor growth.
3. JSI-124 selectively targeted STAT3 signaling over other pathways and showed potent antitumor activity against human tumor xenografts in mouse models, demonstrating its potential as an anticancer therapeutic targeting the STAT3 pathway.
This document examines the effects of two DNA intercalators, mitoxantrone and WP631, on the expression of COL1A1, the gene encoding the alpha 1 chain of type I collagen, in cultured human dermal fibroblasts. The study finds that both drugs potently inhibit COL1A1 production and mRNA levels in a dose-dependent manner without causing cytotoxicity or apoptosis. This inhibition occurs through an abrogation of COL1A1 transcriptional activity mediated by competition of the drugs with the Sp1 transcription factor for DNA binding. Both drugs are also shown to inhibit TGF-β-induced stimulation of COL1A1 transcription. WP631 exhibits greater potency than mitoxantrone, inhibiting COL
1) The study found higher levels of MT1-MMP and lower levels of RECK, an MT1-MMP inhibitor, on circulating human CD34+ progenitor cells compared to those in bone marrow. MT1-MMP levels correlated with successful mobilization of CD34+ cells in healthy donors and patients receiving G-CSF treatment.
2) Treatment with G-CSF further increased MT1-MMP and decreased RECK expression on human and mouse hematopoietic cells in a PI3K/Akt-dependent manner. Blocking MT1-MMP impaired chemotaxis and homing of mobilized human CD34+ progenitors.
3) Mobilization of human progen
OSU-03012 sensitizes breast cancers to lapatinib-induced cell killing: a role...Enrique Moreno Gonzalez
Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms
associated with enhancing the activity of lapatinib via combination with other therapies.
This document describes a study examining gene expression changes in breast epithelial cells and fibroblasts when co-cultured together. Non-malignant (MCF10A) and breast cancer (MDA-MB231) epithelial cell lines were co-cultured with fibroblasts isolated from either benign breast tissues (NAF) or breast carcinoma tissues (CAF) using a transwell system. Gene expression profiles of each cell type were compared between co-culture and monoculture conditions. While epithelial cells showed large changes in gene expression when co-cultured, fibroblasts were less affected. Specific gene expression changes were observed for each epithelial cell - fibroblast combination that could impact processes like cell polarity, membrane biogenesis, growth control
This document compares the efficacy of 5 different FGFR inhibitors - AZD4547, BGJ398, JNJ42756493, PD173074 and TKI258 - at inhibiting FGFR1 signaling and cell proliferation in solid tumor cell lines and leukemia cell lines that overexpress FGFR1. It finds that the pan-FGFR inhibitors AZD4547, BGJ398 and JNJ42756493 more potently suppress FGFR1 phosphorylation and downstream signaling, cause more cell cycle arrest, and have lower GI50 values, indicating they more efficiently inhibit cell growth. It also shows that BGJ398 treatment significantly suppresses leukemia progression in a xenograft model of primary human AML overexpressing FGFR1, supporting
This document summarizes outcomes from the first 100 patients who received haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and melphalan-based conditioning at MD Anderson Cancer Center. Key findings include:
- Patients had various hematologic malignancies and received transplants between 2010-2014.
- Conditioning included fludarabine, melphalan, and post-transplant cyclophosphamide.
- Outcomes were promising with 95% donor engraftment, 31% grade 2-4 acute GVHD, and 1-year non-relapse mortality of 16%.
- Overall survival at 1 year was 66% with disease relapse as the main cause
Extreme fetal growth, either restricted (IUGR) or large (LGA), is associated with epigenetic changes in hematopoietic stem/progenitor cells that may increase risk of adult diseases. The study found global shifts towards DNA hypermethylation in these cells from infants with IUGR or LGA compared to controls. There was a sexually dimorphic response, with IUGR associated with greater epigenetic dysregulation in males and LGA predominantly affecting females. The differentially methylated loci were enriched near genes involved in glucose homeostasis and stem cell function.
This study found that overexpression of vascular endothelial growth factor (VEGF) by estrogen-dependent MCF-7 breast cancer cells promoted estrogen-independent tumor growth in mice. MCF-7 cells were engineered to overexpress VEGF121 or VEGF165. When implanted in ovariectomized mice, the VEGF-overexpressing MCF-7 tumors grew similarly to, or greater than, parental MCF-7 tumors in mice supplemented with estrogen. Overexpression of VEGF stimulated angiogenesis and proliferation in the MCF-7 tumors through both autocrine and paracrine mechanisms, allowing the tumors to grow independently of estrogen. This suggests that upregulation of VEGF contributes to breast cancers acquiring estrogen-independent growth.
This document reviews different types of hemopoietic growth factors called colony stimulating factors (CSFs), including their synthesis, effects on cells, and potential clinical applications and side effects. It discusses granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF), macrophage CSF (M-CSF), and multi-CSF, and their roles in stimulating various blood cell types. It also reviews early clinical trials using G-CSF and potential future directions using GM-CSF to treat cancers.
Variant G6PD levels promote tumor cell proliferation or apoptosis via the STA...Enrique Moreno Gonzalez
Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown.
This document discusses hematopoietic growth factors (HGFs), which regulate blood cell production. It focuses on erythropoietin and myeloid growth factors, describing their clinical uses, dosages, and risks. Erythropoietin is used to treat chemotherapy-induced anemia but may increase thromboembolic risks and possibly promote tumor growth. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are used to prevent or treat febrile neutropenia from chemotherapy.
Immunosupression - A back bone in the success of liver transplantationBhavin Vasavada
Immunosuppression after liver transplantation primarily involves calcineurin inhibitors like cyclosporine and tacrolimus. Steroids are also used for initial immunosuppression but are tapered off if possible due to side effects. Other common adjunct immunosuppressants include mycophenolate mofetil, which prevents lymphocyte proliferation, and sirolimus, an mTOR inhibitor. Induction therapy with antibodies may also be used to prevent early rejection. Close monitoring of drug levels is needed due to side effects and interactions between these powerful immunosuppressive agents.
Three key points:
1. A kinome-centered synthetic lethality screen identified that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors.
2. MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance.
3. Drugs targeting both EGFR and ERBB2, each capable of forming hetero-dimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM.
Proteomics Exploration of Chronic Lymphocytic Leukemia_Crimson PublishersCrimsonpublishersCancer
Chronic Lymphocytic Leukemia (CLL) is an adult heme malignancy characterized by the presence of mature-appearing CD5+ B cells in the blood, bone marrow, and secondary lymphoid organs [1]. In the United States, there will be an estimate of 20,720 new cases and 3,930 deaths according to the American Cancer Society statistics. Symptoms include swollen lymph nodes, frequent infections, and fatigue which negatively impacts the quality of life of people affected [1]. CLL is heterogeneous in its progression and clinical outcomes. Factors that contribute to the heterogeneity include the immunoglobulin heavy chain (IGHV) status and chromosomal aberrations [2,3]. There are two subtypes of CLL: Unmutated(U-CLL) and Mutated CLL(M-CLL). 40% and 60% of patients are diagnosed with unmutated and mutated CLL. U-CLL is characterized by the presence of CLL cells that have less than two percent of their IGHV mutated, whereas M-CLL cells have more than two percent mutated [4]. U-CLL is the more aggressive phenotype [2]. These cells have increased responsiveness to antigens that bind the B cell receptor (BCR) versus M-CLL cells [5]. M-CLL is the more indolent phenotype. Increased BCR signaling results in increased cell survival and proliferation [5].
1. The document investigates the role of adipocytes in stress hematopoiesis and the molecular mechanisms by which fatty bone marrow inhibits hematopoiesis.
2. It finds that the PPARγ agonist rosiglitazone delays hematopoietic recovery after chemotherapy by promoting adipogenesis rather than directly affecting hematopoietic stem/progenitor cells.
3. Adipocytes are shown to impair the proliferation and differentiation of hematopoietic stem/progenitor cells, potentially through adiponectin receptor-AMPK signaling, as the effect can be partially reversed by an anti-adiponectin antibody.
Rosehip extracts were found to significantly decrease cell proliferation in three human glioblastoma cell lines (A-172, U-251 MG, and U-1242 MG) in a dose-dependent manner. The extracts were shown to be equally or more effective at decreasing cell proliferation than inhibitors of the MAPK and AKT signaling pathways. Pretreatment with rosehip extracts selectively decreased phosphorylation of AKT, MAPK, and p70S6K, suggesting the extracts prevent glioblastoma cell proliferation by blocking both the MAPK and AKT signaling pathways. Additionally, rosehip extracts increased the efficacy of temozolomide against glioblastoma cells and demonstrated greater inhibition of cell proliferation than temozolomide alone or
ADAR2 editing activity in newly diagnosed versus relapsed pediatric high-grad...Enrique Moreno Gonzalez
High-grade (WHO grade III and IV) astrocytomas are aggressive malignant brain tumors affecting humans with a high risk of recurrence in both children and adults. To date, limited information is available on the genetic and molecular alterations important in the onset and progression of pediatric high-grade astrocytomas and, even less, on the prognostic factors that influence long-term outcome in children with recurrence. A-to-I RNA editing is an essential post-transcriptional mechanism that can alter the nucleotide sequence of several RNAs and is
mediated by the ADAR enzymes. ADAR2 editing activity is particularly important in mammalian brain and is impaired in both adult and pediatric high-grade astrocytomas.
Moreover, we have recently shown that the recovered ADAR2 activity in high-grade astrocytomas inhibits in vivo tumor growth. The aim of the present study is to investigate whether changes may occur in ADAR2-mediated RNA editing profiles of relapsed highgrade astrocytomas compared to their respective specimens collected at diagnosis, in four pediatric patients.
Diagnosing PM/DM is challenging due to rarity of the disease, their similar clinical presentation and the possibility of overlap syndromes. A comprehensive strategy for serological testing comprises of parallel determination of both MSA and MAA thereby reducing the time to diagnosis. Current immunoassays techniques (Immunoblot) targeting MAA & MSAs have –
The ability to include many parameters simultaneously which ensures higher detection rate; Become readily accessible & hence an opportunity for laboratories to contribute significantly in the disease diagnosis. MSA are highly specific for PM/DM, and many of them are also associated with a unique clinical subset of PM/DM, making them useful clinical diagnostic/prognostic biomarkers & continue to evolve.
1) Human growth hormone (HGH) treatment increased survival motor neuron (SMN) protein levels in human neuronal cells in a dose-dependent manner by activating the STAT5 signaling pathway.
2) Systemic administration of HGH to spinal muscular atrophy (SMA) mouse models induced higher levels of SMN protein in the brain and spinal cord.
3) HGH treatment improved disease phenotypes and increased survival in two severe SMA mouse models, confirming that activating the STAT5 pathway may be a promising therapeutic strategy for SMA.
1) The document reports that 6 out of 16 melanoma tumor samples analyzed acquired expression of EGFR after developing resistance to BRAF or MEK inhibitor drugs.
2) Using a shRNA library targeting chromatin regulators, the researchers found that suppression of SOX10 in melanoma cells leads to activation of TGF-β signaling and upregulation of EGFR and PDGFRB, conferring resistance to BRAF and MEK inhibitors.
3) Expression of EGFR in melanoma cells or treatment with TGF-β results in a slow-growth phenotype with cellular hallmarks of senescence. However, EGFR expression or TGF-β exposure becomes advantageous for proliferation in the presence of BRAF or
Mesenchymal stem cells have immunomodulatory properties and may provide benefits in kidney transplantation. A randomized controlled trial compared induction therapy with autologous mesenchymal stem cells to anti-IL-2 receptor antibody induction in living-related kidney transplant recipients. Patients receiving mesenchymal stem cells had lower rates of acute rejection and opportunistic infection within the first year, as well as better kidney function. No safety issues or compromises in graft survival were observed with mesenchymal stem cell treatment.
This document discusses the role of epigenetics in type 2 diabetes (T2D). It describes how environmental factors like undernutrition can induce chronic metabolic and hormonal changes through epigenetic mechanisms like DNA methylation and histone modification, enhancing the risk of T2D later in life. Specific genes involved in insulin production and secretion like INS and PPARGC1A show changes in DNA methylation and histone markers in pancreatic cells and tissues of T2D patients. Factors like obesity, diet, exercise and aging can also influence epigenetic changes linked to T2D risk and complications through various mechanisms. While research is still ongoing, epigenetics appears to play an important part in the development and pathology of
This study investigated the effects of artesunate on drug resistance in lung carcinoma cell lines. The results showed that:
1) Artesunate attenuated the viability of drug-resistant lung carcinoma cell lines A549/DDP and SBC-3/ADM and suppressed the multidrug resistance protein BCRP.
2) Artesunate treatment upregulated miR-493-5p expression and downregulated the target gene BRCA1 in the drug-resistant cell lines.
3) Silencing miR-493-5p reversed the anti-drug resistance effects of artesunate by increasing cell viability and BCRP expression and upregulating the BRCA1 pathway.
This document discusses FLT3-ITD mutations in acute myeloid leukemia (AML) and the use of FLT3 tyrosine kinase inhibitors (TKIs) in the setting of allogeneic stem cell transplantation for AML. FLT3-ITD mutations occur in around 25% of AML cases and are associated with an inferior prognosis. TKIs like sorafenib and quizartinib have shown efficacy in relapsed/refractory FLT3-ITD positive AML, particularly after allogeneic stem cell transplantation. Ongoing clinical trials are investigating the use of TKIs as maintenance therapy before and after transplantation to improve outcomes for AML patients with FLT
Black cohosh is an herbal remedy used to treat menopausal symptoms like hot flashes, but its efficacy is unclear due to limitations of studies. While some studies found it reduced hot flashes and menopausal scores, others found no effect. It may act as a selective estrogen receptor modulator, but its mechanism is uncertain. Side effects include liver toxicity in some cases as well as gastrointestinal issues, headaches, and hypotension. More research is needed to definitively assess its safety and effectiveness.
Black cohosh is an herbal remedy used to treat menopausal symptoms like hot flashes. In vitro studies show it may inhibit breast cancer cells and improve bone health by interacting with estrogen receptors, and components bind to opioid receptors in the brain linked to menopausal symptoms. However, clinical evidence for its efficacy is mixed and long term safety is unclear. Pharmacists should counsel patients on proper use and discrepancies in the data when recommending black cohosh.
This document compares the efficacy of 5 different FGFR inhibitors - AZD4547, BGJ398, JNJ42756493, PD173074 and TKI258 - at inhibiting FGFR1 signaling and cell proliferation in solid tumor cell lines and leukemia cell lines that overexpress FGFR1. It finds that the pan-FGFR inhibitors AZD4547, BGJ398 and JNJ42756493 more potently suppress FGFR1 phosphorylation and downstream signaling, cause more cell cycle arrest, and have lower GI50 values, indicating they more efficiently inhibit cell growth. It also shows that BGJ398 treatment significantly suppresses leukemia progression in a xenograft model of primary human AML overexpressing FGFR1, supporting
This document summarizes outcomes from the first 100 patients who received haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and melphalan-based conditioning at MD Anderson Cancer Center. Key findings include:
- Patients had various hematologic malignancies and received transplants between 2010-2014.
- Conditioning included fludarabine, melphalan, and post-transplant cyclophosphamide.
- Outcomes were promising with 95% donor engraftment, 31% grade 2-4 acute GVHD, and 1-year non-relapse mortality of 16%.
- Overall survival at 1 year was 66% with disease relapse as the main cause
Extreme fetal growth, either restricted (IUGR) or large (LGA), is associated with epigenetic changes in hematopoietic stem/progenitor cells that may increase risk of adult diseases. The study found global shifts towards DNA hypermethylation in these cells from infants with IUGR or LGA compared to controls. There was a sexually dimorphic response, with IUGR associated with greater epigenetic dysregulation in males and LGA predominantly affecting females. The differentially methylated loci were enriched near genes involved in glucose homeostasis and stem cell function.
This study found that overexpression of vascular endothelial growth factor (VEGF) by estrogen-dependent MCF-7 breast cancer cells promoted estrogen-independent tumor growth in mice. MCF-7 cells were engineered to overexpress VEGF121 or VEGF165. When implanted in ovariectomized mice, the VEGF-overexpressing MCF-7 tumors grew similarly to, or greater than, parental MCF-7 tumors in mice supplemented with estrogen. Overexpression of VEGF stimulated angiogenesis and proliferation in the MCF-7 tumors through both autocrine and paracrine mechanisms, allowing the tumors to grow independently of estrogen. This suggests that upregulation of VEGF contributes to breast cancers acquiring estrogen-independent growth.
This document reviews different types of hemopoietic growth factors called colony stimulating factors (CSFs), including their synthesis, effects on cells, and potential clinical applications and side effects. It discusses granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF), macrophage CSF (M-CSF), and multi-CSF, and their roles in stimulating various blood cell types. It also reviews early clinical trials using G-CSF and potential future directions using GM-CSF to treat cancers.
Variant G6PD levels promote tumor cell proliferation or apoptosis via the STA...Enrique Moreno Gonzalez
Glucose-6-phosphate dehydrogenase (G6PD), elevated in tumor cells, catalyzes the first reaction in the pentose-phosphate pathway. The regulation mechanism of G6PD and pathological change in human melanoma growth remains unknown.
This document discusses hematopoietic growth factors (HGFs), which regulate blood cell production. It focuses on erythropoietin and myeloid growth factors, describing their clinical uses, dosages, and risks. Erythropoietin is used to treat chemotherapy-induced anemia but may increase thromboembolic risks and possibly promote tumor growth. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are used to prevent or treat febrile neutropenia from chemotherapy.
Immunosupression - A back bone in the success of liver transplantationBhavin Vasavada
Immunosuppression after liver transplantation primarily involves calcineurin inhibitors like cyclosporine and tacrolimus. Steroids are also used for initial immunosuppression but are tapered off if possible due to side effects. Other common adjunct immunosuppressants include mycophenolate mofetil, which prevents lymphocyte proliferation, and sirolimus, an mTOR inhibitor. Induction therapy with antibodies may also be used to prevent early rejection. Close monitoring of drug levels is needed due to side effects and interactions between these powerful immunosuppressive agents.
Three key points:
1. A kinome-centered synthetic lethality screen identified that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors.
2. MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance.
3. Drugs targeting both EGFR and ERBB2, each capable of forming hetero-dimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM.
Proteomics Exploration of Chronic Lymphocytic Leukemia_Crimson PublishersCrimsonpublishersCancer
Chronic Lymphocytic Leukemia (CLL) is an adult heme malignancy characterized by the presence of mature-appearing CD5+ B cells in the blood, bone marrow, and secondary lymphoid organs [1]. In the United States, there will be an estimate of 20,720 new cases and 3,930 deaths according to the American Cancer Society statistics. Symptoms include swollen lymph nodes, frequent infections, and fatigue which negatively impacts the quality of life of people affected [1]. CLL is heterogeneous in its progression and clinical outcomes. Factors that contribute to the heterogeneity include the immunoglobulin heavy chain (IGHV) status and chromosomal aberrations [2,3]. There are two subtypes of CLL: Unmutated(U-CLL) and Mutated CLL(M-CLL). 40% and 60% of patients are diagnosed with unmutated and mutated CLL. U-CLL is characterized by the presence of CLL cells that have less than two percent of their IGHV mutated, whereas M-CLL cells have more than two percent mutated [4]. U-CLL is the more aggressive phenotype [2]. These cells have increased responsiveness to antigens that bind the B cell receptor (BCR) versus M-CLL cells [5]. M-CLL is the more indolent phenotype. Increased BCR signaling results in increased cell survival and proliferation [5].
1. The document investigates the role of adipocytes in stress hematopoiesis and the molecular mechanisms by which fatty bone marrow inhibits hematopoiesis.
2. It finds that the PPARγ agonist rosiglitazone delays hematopoietic recovery after chemotherapy by promoting adipogenesis rather than directly affecting hematopoietic stem/progenitor cells.
3. Adipocytes are shown to impair the proliferation and differentiation of hematopoietic stem/progenitor cells, potentially through adiponectin receptor-AMPK signaling, as the effect can be partially reversed by an anti-adiponectin antibody.
Rosehip extracts were found to significantly decrease cell proliferation in three human glioblastoma cell lines (A-172, U-251 MG, and U-1242 MG) in a dose-dependent manner. The extracts were shown to be equally or more effective at decreasing cell proliferation than inhibitors of the MAPK and AKT signaling pathways. Pretreatment with rosehip extracts selectively decreased phosphorylation of AKT, MAPK, and p70S6K, suggesting the extracts prevent glioblastoma cell proliferation by blocking both the MAPK and AKT signaling pathways. Additionally, rosehip extracts increased the efficacy of temozolomide against glioblastoma cells and demonstrated greater inhibition of cell proliferation than temozolomide alone or
ADAR2 editing activity in newly diagnosed versus relapsed pediatric high-grad...Enrique Moreno Gonzalez
High-grade (WHO grade III and IV) astrocytomas are aggressive malignant brain tumors affecting humans with a high risk of recurrence in both children and adults. To date, limited information is available on the genetic and molecular alterations important in the onset and progression of pediatric high-grade astrocytomas and, even less, on the prognostic factors that influence long-term outcome in children with recurrence. A-to-I RNA editing is an essential post-transcriptional mechanism that can alter the nucleotide sequence of several RNAs and is
mediated by the ADAR enzymes. ADAR2 editing activity is particularly important in mammalian brain and is impaired in both adult and pediatric high-grade astrocytomas.
Moreover, we have recently shown that the recovered ADAR2 activity in high-grade astrocytomas inhibits in vivo tumor growth. The aim of the present study is to investigate whether changes may occur in ADAR2-mediated RNA editing profiles of relapsed highgrade astrocytomas compared to their respective specimens collected at diagnosis, in four pediatric patients.
Diagnosing PM/DM is challenging due to rarity of the disease, their similar clinical presentation and the possibility of overlap syndromes. A comprehensive strategy for serological testing comprises of parallel determination of both MSA and MAA thereby reducing the time to diagnosis. Current immunoassays techniques (Immunoblot) targeting MAA & MSAs have –
The ability to include many parameters simultaneously which ensures higher detection rate; Become readily accessible & hence an opportunity for laboratories to contribute significantly in the disease diagnosis. MSA are highly specific for PM/DM, and many of them are also associated with a unique clinical subset of PM/DM, making them useful clinical diagnostic/prognostic biomarkers & continue to evolve.
1) Human growth hormone (HGH) treatment increased survival motor neuron (SMN) protein levels in human neuronal cells in a dose-dependent manner by activating the STAT5 signaling pathway.
2) Systemic administration of HGH to spinal muscular atrophy (SMA) mouse models induced higher levels of SMN protein in the brain and spinal cord.
3) HGH treatment improved disease phenotypes and increased survival in two severe SMA mouse models, confirming that activating the STAT5 pathway may be a promising therapeutic strategy for SMA.
1) The document reports that 6 out of 16 melanoma tumor samples analyzed acquired expression of EGFR after developing resistance to BRAF or MEK inhibitor drugs.
2) Using a shRNA library targeting chromatin regulators, the researchers found that suppression of SOX10 in melanoma cells leads to activation of TGF-β signaling and upregulation of EGFR and PDGFRB, conferring resistance to BRAF and MEK inhibitors.
3) Expression of EGFR in melanoma cells or treatment with TGF-β results in a slow-growth phenotype with cellular hallmarks of senescence. However, EGFR expression or TGF-β exposure becomes advantageous for proliferation in the presence of BRAF or
Mesenchymal stem cells have immunomodulatory properties and may provide benefits in kidney transplantation. A randomized controlled trial compared induction therapy with autologous mesenchymal stem cells to anti-IL-2 receptor antibody induction in living-related kidney transplant recipients. Patients receiving mesenchymal stem cells had lower rates of acute rejection and opportunistic infection within the first year, as well as better kidney function. No safety issues or compromises in graft survival were observed with mesenchymal stem cell treatment.
This document discusses the role of epigenetics in type 2 diabetes (T2D). It describes how environmental factors like undernutrition can induce chronic metabolic and hormonal changes through epigenetic mechanisms like DNA methylation and histone modification, enhancing the risk of T2D later in life. Specific genes involved in insulin production and secretion like INS and PPARGC1A show changes in DNA methylation and histone markers in pancreatic cells and tissues of T2D patients. Factors like obesity, diet, exercise and aging can also influence epigenetic changes linked to T2D risk and complications through various mechanisms. While research is still ongoing, epigenetics appears to play an important part in the development and pathology of
This study investigated the effects of artesunate on drug resistance in lung carcinoma cell lines. The results showed that:
1) Artesunate attenuated the viability of drug-resistant lung carcinoma cell lines A549/DDP and SBC-3/ADM and suppressed the multidrug resistance protein BCRP.
2) Artesunate treatment upregulated miR-493-5p expression and downregulated the target gene BRCA1 in the drug-resistant cell lines.
3) Silencing miR-493-5p reversed the anti-drug resistance effects of artesunate by increasing cell viability and BCRP expression and upregulating the BRCA1 pathway.
This document discusses FLT3-ITD mutations in acute myeloid leukemia (AML) and the use of FLT3 tyrosine kinase inhibitors (TKIs) in the setting of allogeneic stem cell transplantation for AML. FLT3-ITD mutations occur in around 25% of AML cases and are associated with an inferior prognosis. TKIs like sorafenib and quizartinib have shown efficacy in relapsed/refractory FLT3-ITD positive AML, particularly after allogeneic stem cell transplantation. Ongoing clinical trials are investigating the use of TKIs as maintenance therapy before and after transplantation to improve outcomes for AML patients with FLT
Black cohosh is an herbal remedy used to treat menopausal symptoms like hot flashes, but its efficacy is unclear due to limitations of studies. While some studies found it reduced hot flashes and menopausal scores, others found no effect. It may act as a selective estrogen receptor modulator, but its mechanism is uncertain. Side effects include liver toxicity in some cases as well as gastrointestinal issues, headaches, and hypotension. More research is needed to definitively assess its safety and effectiveness.
Black cohosh is an herbal remedy used to treat menopausal symptoms like hot flashes. In vitro studies show it may inhibit breast cancer cells and improve bone health by interacting with estrogen receptors, and components bind to opioid receptors in the brain linked to menopausal symptoms. However, clinical evidence for its efficacy is mixed and long term safety is unclear. Pharmacists should counsel patients on proper use and discrepancies in the data when recommending black cohosh.
Black cohosh is an herbal remedy used to treat menopausal symptoms like hot flashes. However, clinical data on its efficacy is mixed and safety studies are limited. Several cases reported potential liver toxicity from black cohosh use. Common side effects include GI issues, nausea, vomiting, and hypotension. More research is needed to definitively understand black cohosh's safety and effectiveness for managing menopausal symptoms.
This document provides a weekly update of US patent litigation cases from December 9-16, 2011. It lists 7 patent infringement lawsuits filed in various US district courts during this period. The plaintiffs, defendants, causes of action, and counsel information are provided for each case. The cases involve technologies such as golf equipment, digital media, pharmaceuticals, medical devices, and semiconductors. Plaintiff and defendant counsel contact information is also provided.
The human genome project, which has been under way for several years now, represents an attempt to build a complete genetic profile of the human race. Already researchers claim to have identified the gene responsible for a number of abnormalities, from cystic fibrosis to, most recently, aggression. Should this be regarded as an exciting enterprise that deserves the support of therapists of all persuasions? Or is it an extreme expression of hubris, a hazardous undertaking with unforeseeable and possibly disastrous consequences for human health and liberty. The result of this misperception is that, inevitably, genetic mapping will lead to genetic manipulation – indeed that is the avowed aim of geneticists. Whatever the good intentions of researchers, the medical -industrial establishment a tacit alliance of doctors, drug companies ,insurance, and other interested parties, influenced to varying degrees by consideration of money or power –will ensure that the pressures on ‘genetic defectives’ to undergo therapy will be irresistible. This will give rise to a society where the individual will relinquish all control over his or her own health, and where virtually everyone, from gestation onward, will become a “patient” under the control of the medical- industrial complex.
What does all this have to do with Phytotherapy(Herbal Medicine)? The natural therapies-among which the phytotherapy, in global terms, is paramount-in general reflect the philosophical view that nature in totality , is the expression of a universal harmony and equilibrium , the rupture of which gives rise to numerous ill effects, among them environmental devastation in the biosphere and ill-health in the individual.
Phytotherapy, by contrast, aims not to cure disease by a technological fix, but to bring about a restoration of homoeostasis through remedies that assist , but stop short of violence to, the organism’s intrinsic healing powers.
The eminent French doctor J.C Lapaz maintains that 90% of both common and serious illnesses could be treated with phytotherapy.It is therefore the lecturer believe that widening the scope of natural medicine in this way presents as worthy as a challenge to science as the human genome project, and one whose success would be crowned with immeasurably greater benefits to humanity and prevention of diseases.
Dokumen ini membahas rancangan sistem otomatisasi pengisian air minum ke kemasan menggunakan mikrokontroler AT8535 yang terdiri dari rotary conveyor, cup feeder, dan cup sealer untuk mendeteksi dan mengisi empat kemasan secara otomatis. Sistem ini dirancang untuk meningkatkan efisiensi proses produksi di industri.
Rangkaian ini menggunakan sensor aluminium foil yang dapat mendeteksi air dan memberikan sinyal. Air akan menghantarkan arus listrik pada sensor sehingga memberikan output sinyal pada speaker. Namun, outputnya berupa gelombang pulsa yang tidak stabil karena pengganti speaker (buzzer) tidak sesuai. Rangkaian ini dirancang untuk mendeteksi turunnya hujan dengan menggunakan komponen resistor dan elektroda sebagai pendeteksinya. Ketika air meny
Irwin's Study is a tuition centre founded in 2009 that specializes in General Paper (GP) tuition. It was founded by Irwin, who has studied at Oxford University, the London School of Economics, and Raffles Institution. Irwin's Study provides GP classes in an interactive environment without ridicule for O-Level, A-Level, and JC students. It is also involved in charity work with the Singapore Cancer Society.
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P. Teja is seeking a position where they can contribute their skills and abilities to an organization's growth. They have a B.Tech in computer science from Bhoj Reddy Engineering College for Women with a 63.6% percentage. Their technical skills include programming languages like C, C++, and Java as well as HTML, MS Office, and operating systems like Windows. They completed an academic project on dynamic personalized recommendation on sparse data using technologies like ASP.NET, HTML, SQL Server, and IIS. P. Teja's strengths include good communication skills, a zeal to learn new things innovatively, and an ability to find multiple solutions to problems.
Black cohosh has been shown to inhibit the growth of both estrogen-dependent and estrogen-independent breast cancer cell lines. It appears to exert these effects through multiple mechanisms, including weak antagonism of estrogen receptors, induction of apoptosis through caspase activation, and cell cycle arrest. Extracts of black cohosh inhibited proliferation in a dose-dependent manner and induced apoptosis in breast cancer cells through both genomic and non-genomic mechanisms due to its various active components.
Laura Karanja presented on the international regulatory framework for genetic resources and intellectual property protections relevant to KALRO. The presentation covered:
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Packet Tracer 6.2 new features.
Original PPT file available on https://www.netacad.com/documents/300006/233106968/Packet+Tracer+6.2+New+Features.pptx/2c7a445c-bc47-44e4-a648-45141426d1a2?version=1.1
1. Researchers at KALRO Njoro have developed 5 new sweetpotato varieties that are tolerant to high altitudes between 1700-2300 masl, have improved yields of 15-46 tons/ha, and resistance to viruses and weevils.
2. The varieties were tested on-farm through participatory selection and evaluation with farmers. They have good agronomic traits, higher beta-carotene and dry matter content, and are adapted across locations.
3. The new varieties help address food security and nutrition in highland areas, and have potential to supplement maize due to emerging disease issues. Their promotion and adoption will expand sweetpotato production and incomes.
Annals of Mutagenesis is an open access, peer reviewed, scholarly journal dedicated to publish articles covering all areas of Mutagenesis.
The journal aims to promote research communications and provide a forum for doctors, researchers, physicians and healthcare professionals to find most recent advances in all areas of Mutagenesis. Annals of Mutagenesis accepts original research articles, reviews, mini reviews, case reports and rapid communication covering all aspects of mutagenesis.
Annals of Mutagenesis strongly supports the scientific up gradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Propolis with its active component CAPE (Caffeic Acid Phenethyl Ester) stops breast cancer cell growth. These results of CAPE are present in the naturopathic formulation
of propolis, a widely available natural substance with an extended safety record, making it a naturally-occurring and readily available epigenetic agent with great potential in breast cancer and oncology in general. The ability to link the biological effects of a naturopathic remedy to the pharmacologic effects seen with an exciting class of drugs in the treatment of cancer opens the door to a host of new therapeutic opportunities for patients.
This document describes a study investigating the role of the protein Morgana in breast cancer metastasis. The study found that knocking down Morgana impaired migration, invasion, and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, Morgana was found to increase the transcriptional activity of NF-κB, leading to increased expression of metastasis-promoting genes like MMP-9. Overexpressing Morgana had the opposite effect of increasing NF-κB target gene expression. Therefore, Morgana appears to promote breast cancer metastasis by activating the NF-κB pathway and increasing expression of pro-metastatic genes.
This document reviews current understanding of cellular receptor signaling pathways that interact with estrogen receptors and their role in resistance to endocrine therapy for breast cancer. It discusses how growth factor pathways like HER2, IGF1R, and FGFR interact with and modify estrogen receptor activity through various mechanisms. This crosstalk can lead to downregulation of estrogen receptors, decreased response to estrogen, and development of resistance. The document also reviews clinical trials examining combination therapies that target these pathways in addition to endocrine therapy, with the aim of reducing or reversing resistance.
This research article investigates the effects of the natural flavonoid luteolin on colon cancer cells. The researchers found that physiological concentrations of luteolin induce apoptosis in colon cancer cells by increasing levels of the sphingolipid ceramide. Luteolin inhibits the conversion of ceramide to more complex sphingolipids and disrupts the transport of ceramide between organelles. These effects are mediated by luteolin's ability to inhibit the enzymes sphingosine kinase 2 and Akt, thereby reducing levels of the molecule sphingosine-1-phosphate which normally promotes cell survival. Overall, the study reveals that luteolin exerts anticancer effects by targeting the balance between ceramide and sphingosine-1-
1) Cancer is caused by uncontrolled cell growth that can spread to other parts of the body. Herbal drugs provide an alternative to chemotherapy to treat cancer while avoiding harmful side effects.
2) Many herbal compounds have been shown to be effective against cancer through mechanisms like antioxidant effects, immune boosting, inducing apoptosis, and inhibiting angiogenesis.
3) Specific herbal compounds and plants discussed that have anti-cancer properties include polyphenols, citrus flavonoids, tannins, curcumin, gallacatechins, saponins, brassinosteroids, alkaloids, bromelain, cardiac glycosides, and dietary fiber. Combinations of herbal compounds may enhance their anti
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3. Microarray analysis identified several differentially expressed genes involved in cell proliferation, survival, and metastasis that may underpin the combination's mode
Evaluation of the changes in the gene CYP3A4 expression in HepG2 cells under ...Angela Farngren
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Molecular mechanisms of action and potential biomarkers of growth inhibition ...Enrique Moreno Gonzalez
Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines.
Breast cancer is the most common female malignancy and is
responsible for about 14% of cancer-related deaths in women
[1]. Triple-negative breast cancer (TNBC), characterized by the
absence of expression of Estrogen Receptor (ER), Progesterone
Receptor (PR), and human epidermal growth factor receptor 2
(HER2), is the most aggressive and deadly subtype of breast cancer
Effectiveness of Resveratrol on Metastasis: A Reviewiosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
This document summarizes a research article that studied the role of the heparan sulfate sulfotransferase 3-OST3A in breast cancer. The key findings were:
1) 3-OST3A expression was epigenetically repressed in most breast cancer cell lines through DNA methylation and histone modifications, except in HER2+ SKBR3 cells.
2) Gain and loss of function experiments showed 3-OST3A had profound effects on cell behavior, acting as a tumor suppressor in luminal MCF-7 and triple negative MDA-MB-231 cells but as an oncogene in HER2+ SKBR3 cells.
3) In a clinical study
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2) Experiments showed that prodigiosin triggers accumulation of the tumor suppressor protein p53, but induction of NAG-1 was independent of p53.
3) Prodigiosin causes inhibition of AKT and activation of glycogen synthase kinase-3B (GSK-3B). Induction of NAG-1 and apoptosis correlated with GSK-3B activation. Inhibiting GSK-3B reduced apoptosis, suggesting GSK-3B plays a key role in the proap
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1. Black cohosh (Cimicifuga
racemosa): A potential remedy for
breast cancer
Black cohosh-A gift from Native Americans
Black cohosh(Cinicifuga racemosa) is a herbaceous perennial plant. Native to North
America, the root and rhizomes of black cohoshwere used by Native American women for
menstrual cramps, difficult childbirth and complicated menopause, as well as other
conditions likedysmeorrhea, colic and rheumatism. Native Americans subsequently
introduced the herb to the American colonists, who used it for women’s complaints, as well
as illness like bronchiitis, nervous disorders and inflammation. Today, black cohoshis
widely used in various pharmaceutical preparations. It is widely used in the U.S. and Europe
against menopausal symptoms, suchas hot flashes, sweats, irritability and vaginal dryness.
The action of black cohoshis attributed to synergy of its active components. The main active
compounds ofthe herb’s root are believed to be the triterpene glycosides (TTGs), including
actein and cimifungoside. Other possible biologically active compounds include the
isoflavone formononetin, the TTGs 27-deoxyactein and racemoside, as well as the aromatic
(CAEs), sugars and long-chain fatty acids.
One aim of this research was to examine the effects of the various black cohoshcompounds
on the growth of human breast cancer cells, including inhibition effect, cell cycle progression
and expression proteins involved in cell cycle control. Another aim of the research was to
identify new approaches to breast cancer prevention and therapy, leading to following
studies concerning the use of herbology in cancer treatment.
Cimicifuga racemosa structure of the triterpene glycoside actein:
2. Basic structure of cinnamic acid esters:
Methodology:
This research was library-based, and took place at the library of the University of East
London (on Stratford campus). It included the collection and analysis of data from 29
different scientific articles concerning the anti-breast-cancer activity and properties of black
cohosh(Cimicifuga racemosa) and its different compounds. Thearticles for the research
were obtained through PubMed and Google Scholar.
Results:
Ethanolic and isopropanolic extracts of black cohoshrhizomes inhibited the growth of both
estrogen-dependent MCF-7 and estrogen-independent MDA-MB human breast cancer cells.
Black cohoshalso showed no estrogenic activity in MCF-7, but antagonised these activities.
In addition, estrogen-receptor-negative (ER-) were significantly more sensitive than ER+
cells. There was dose-dependentanti-proliferative action of black cohoshin breast cancer
cells, probably evoked by genomic (ER and non-ER mediated) mechanisms, due to the
various properties of different components of the herb. Also, it was found that black cohosh
doesn’tbind to ER-alpha or beta. However, there were no differences in sensitivity of MCF-
7 and MDA-MB cell lines to either TTGs or CAEs, according to IC50 values. In both cell
types, the herb had no significant effect on the conversion of androstenedione to estradiol at
any dose, and only the highest doses inhibited the conversion of estrone to estradiol.
Black cohoshwas also found to initiate cytotoxicity through induction of apoptosis. An
ethanolic extract of the plant was found to inhibit the activity of cyclin D1 promoter and
increase the activity of P21cip1 promoter in ER- human breast cancer cells. Ethyl acetate
fraction of black cohoshinhibited growth of MCF-7 (ER+, Her2 low) cells and induced cell
cycle arrest at G1 after treatment with 30 micrograms/mL, and at G2/M after treatment with
60 micrograms/mL. This suggests that the fraction contains a mixture of components, with
the more active/abundant component causing G1 arrest, and the less active causing G2/M
arrest. Therefore, it is possible that at high concentrations the fraction affects proteins
regulating later phases in the cell cycle. CAEs turned out to be the more potent inhibitors of
proliferation and apoptosis inducers in MCF-7 cells.
Black cohoshhas as anti-proliferative effect, therefore genes involved in proliferation control
are significantly over-expressed. Transcripts related to cell cycle regulation and DNA
replication are regulated in a manner supporting cell cycle arrest. Genes, whose products are
involved in the transition from G1 to S-phase, appears to be down-regulated, such as cyclins
(CCNA2, CCNE2, CCNF), cdk2 and transcription regulators (E2F2, PCNA, SKP2), whereas
3. transcription of inhibitory genes cyclin G2 (CCNG2), GADD45A (growth arrest and DNA-
damage-inducible) and P21cip1 was increased.
Since actein was found to alter the expression of genes involved in calcium metabolism and
the Na-K-ATPase affects calcium metabolism, the ability of actein to inhibit the activity of
the ATPase and activate related down-stream pathways is possible. Na-K-ATPase mediates
many stress responses and proliferation pathways that are affected by actein. Actein may act
through interaction with the Na-K-ATPase promoters in the cell membrane and induction of
clustering of ATPasewith neighbouring proteins in micro-domains.
Some CAEs are also potential inhibitors of EGFR and Her2 proteins, which have a proven
connection with breast cancer. It had also been shown that CAEs have selective anti-
proliferative activity towards cancer cells. Among the compounds isolated from black
cohoshwith anti-oxidant behaviour, methyl caffeate has the highest potency in protecting
DNA against single-strand cleavage. Also, both caffeic and ferulic acids protectDNA by
reducing reactive oxygen species.
Functional categoriesof genesregulatedinMCF-7cellsafter24 h incubationwithblackcohoshextract.Geneswere
groupedin5 large groups(Apoptosis,Proliferation,General Growth,Signaling& Transport,Metabolism),some
consistingof subgroups.Genesthatare notclearlyassociatedwiththese groupsare summarizedinthe category
others.The categorystressresponse containsgenesalsogroupedintoone of the 6 mainclasses.Each bar represents
the numberof genesthat were up- (dark) ordownregulated(white) inthe respective group.
4. . Effectof iCR, TTG and CAE on tumor cell growth.MCF-7 and MDA-MB 231 cellswere treatedfor24 h withor
withoutsubstancesatthe indicatedconcentrations.Attachedcellswerestainedwithcrystal violetandthe
absorbance of the cell lysate wasmeasuredat540 nm.Data are expressedasmean±SDof triplicate wellsfromtwo
independentexperiments.*p<0.05 vs.untreatedcontrol.
5. Discussion:
From the aspectof general function of black cohosh, the herb seems to have anti-
cancer properties, since both ethanolic and isopropanolic extracts of black cohosh
rhizomes inhibit growth of both estrogen-dependent MCF-7 and estrogen-
independent MDA-MB cell lines. In addition, MDA-MB-231 cells showed a
higher sensitivity to the cytotoxic effects of black cohoshthan MCF-7 cells.
It also seems, for this reason, that the activity of black cohoshon breast cancer
cells is mainly non- estrogenic. This is also supported by the fact that there was no
significant effect on the conversion of estrone to estradiol.
It is far more likely that black cohosh, especially its actein fraction, causes
cytotoxic effects on breast cancer cells through apoptosis induction through the
Her2 receptor, as well as the Na-K-ATPase enzyme. Action via binding to Her2 is
likely, since the Her2+ MDA-MB cell lines are more sensitive to the cytotoxic
effect than MCF-7 (Her2 low) cells. Also, MCF-7 cells transfected for Her2 are
more sensitive than normal MCF-7 cells to actein.
Actein also seems to act via activation of Na-K-ATPase, due to actein’s effect on
calcium metabolism related genes, which are also related to ATPase activation.
This makes sense also due to actein’s role in alteration of actin filaments’
distribution, through which apoptosis is induces. Inhibition of ATPase has also
been shown to be related to a compound’s lipid-affinity, and actein has steroid-like
sterol composition, that makes it lipophilic enough for this role.
Unlike TTGs, CAEs do seem to inhibit EGFR, in addition to Her2. It most likely
acts through reduction of DNA damage by protection from reactive oxygen
species.
Synergy between different black cohoshcompounds is likely, since it has been
shown to inhibit breast cancer through several pathways. Probably the binding of
actein to ATPase makes the cell membrane more penetrable through structure
alteration, which allows CAE access. Then, the CAEs can act against the reactive
oxygen species, and also inhibit EGFRs. By binding to ATPase and Her2, actein
also has anti-cancer activity in its own right, but also increases the effectiveness of
CAEs.
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