Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic syst... more Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymor-phonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (trigger-ing receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signal-ing. After TREM crosslinking, DAP12’s tyrosines in its ITAMmotif get phosphorylated induc-ing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling p...
Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke ext... more Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke extract (CSE) on bone marrow hematopoiesis remain unknown. The objective of this study was to elucidate the direct effects of cigarette smoke on human bone marrow hematopoiesis and characterize the inflammatory process known to result from cigarette smoking. Bone marrow mononuclear cells (BMCs) from healthy individuals when exposed to CSE had significantly diminished CFU-E, BFU-E and CFU-GM. We found increased nuclear translocation of the NF-kB p65 subunit and, independently, enhanced activation of AKT and ERK1/2. Exposure of BMCs to CSE induced IL-8 and TGF-b1 production, which was dependent on NF-kB and ERK1/2, but not on AKT. CSE treatment had no effect on the release of TNF-a, IL-10, or VEGF. Finally, CSE also had a significant induction of TLR2, TLR3 and TLR4, out of which, the up-regulation of TLR2 and TLR3 was found to be dependent on ERK1/2 and NF-kB activation, but not AKT. These r...
788 Understanding the pathophysiology of myelodysplastic syndrome (MDS) is limited by a complex m... more 788 Understanding the pathophysiology of myelodysplastic syndrome (MDS) is limited by a complex molecular mechanism and lack of an adequate animal model that recapitulates the role of inflammation in the abnormal hematopoiesis. We recently showed that patients with MDS have expansion of inflammation-related hematopoietic suppressive cells called immature myeloid-derived suppressor cells (MDSC) that display direct cytotoxic and suppressive effects on autologous hematopoietic progenitor cells (HPCs). Expansion of bone marrow (BM) MDSCs contributed to the production of inflammatory cytokines and reduced HPC survival underlying BM failure in lower risk patients. Here we provide evidence that MDSC activation, expansion and development is driven by overexpression of inflammatory-related signaling molecules, myeloid-related protein 8 (MRP8, encoded by S100A8) and MRP14 (encoded by S100A9). Both MRP proteins serve as the native endogenous ligands for Toll-like receptor 4 (TLR4), which is an...
Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic syst... more Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12's tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling ...
This study evaluated the antitumor effects of icariside II (IS), isolated from Herba Epimedii, on... more This study evaluated the antitumor effects of icariside II (IS), isolated from Herba Epimedii, on in vitro and in vivo models of melanoma and determined its mechanism of apoptosis. Mouse (B16) and human (A375, SK-MEL-5) melanoma cell lines were treated with IS at different concentrations (0-100 μM). Cell viability and proliferation was detected by WST-1 assay and with the xCELLigence system, respectively. Apoptosis was measured by the annexin-V/PI flow cytometric assay. Western blot was used to measure cleaved caspase 3, survivin, P-STAT3, P-ERK and P-AKT. B16 and A375 cells were injected subcutaneously into C57BL/6J and BALB/c-nu mice, respectively. After 1 wk, IS solution at (50 mg/kg, 100 mg/kg) was administered by intraperitoneal injection 3 times for a week. Tumor size was measured with an electronic digital caliper. IS inhibited the proliferation of melanoma cells in a dose- and time-dependent manner. Treatment of A375 cells with IS resulted in an increased number of apoptotic cells ranging from 5.6% to 26.3% mirrored by increases in cleaved caspase-3 and a decrease in survivin expression. IS significantly inhibited the activation of the JAK-STAT3 and MAPK pathways but promoted an unsustained activation peak of the PI3K-AKT pathway. IS administration (50 mg/kg) resulted in a 47.5% decreased tumor volume in A375 bearing mice. Furthermore, IS administration (50 mg/kg, 100 mg/kg) resulted in 41% and 49% decreased tumor volume in B16 bearing mice, respectively. IS dramatically inhibited the proliferation of melanoma cells in vivo and in vitro through the regulation of apoptosis. These effects demonstrate the ability of IS to effectively overcome the survival signals of tumor cells, which support further preclinical evaluation of IS in cancer as a new potential chemotherapeutic agent.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic syst... more Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymor-phonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (trigger-ing receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signal-ing. After TREM crosslinking, DAP12’s tyrosines in its ITAMmotif get phosphorylated induc-ing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling p...
Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke ext... more Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke extract (CSE) on bone marrow hematopoiesis remain unknown. The objective of this study was to elucidate the direct effects of cigarette smoke on human bone marrow hematopoiesis and characterize the inflammatory process known to result from cigarette smoking. Bone marrow mononuclear cells (BMCs) from healthy individuals when exposed to CSE had significantly diminished CFU-E, BFU-E and CFU-GM. We found increased nuclear translocation of the NF-kB p65 subunit and, independently, enhanced activation of AKT and ERK1/2. Exposure of BMCs to CSE induced IL-8 and TGF-b1 production, which was dependent on NF-kB and ERK1/2, but not on AKT. CSE treatment had no effect on the release of TNF-a, IL-10, or VEGF. Finally, CSE also had a significant induction of TLR2, TLR3 and TLR4, out of which, the up-regulation of TLR2 and TLR3 was found to be dependent on ERK1/2 and NF-kB activation, but not AKT. These r...
788 Understanding the pathophysiology of myelodysplastic syndrome (MDS) is limited by a complex m... more 788 Understanding the pathophysiology of myelodysplastic syndrome (MDS) is limited by a complex molecular mechanism and lack of an adequate animal model that recapitulates the role of inflammation in the abnormal hematopoiesis. We recently showed that patients with MDS have expansion of inflammation-related hematopoietic suppressive cells called immature myeloid-derived suppressor cells (MDSC) that display direct cytotoxic and suppressive effects on autologous hematopoietic progenitor cells (HPCs). Expansion of bone marrow (BM) MDSCs contributed to the production of inflammatory cytokines and reduced HPC survival underlying BM failure in lower risk patients. Here we provide evidence that MDSC activation, expansion and development is driven by overexpression of inflammatory-related signaling molecules, myeloid-related protein 8 (MRP8, encoded by S100A8) and MRP14 (encoded by S100A9). Both MRP proteins serve as the native endogenous ligands for Toll-like receptor 4 (TLR4), which is an...
Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic syst... more Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12's tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling ...
This study evaluated the antitumor effects of icariside II (IS), isolated from Herba Epimedii, on... more This study evaluated the antitumor effects of icariside II (IS), isolated from Herba Epimedii, on in vitro and in vivo models of melanoma and determined its mechanism of apoptosis. Mouse (B16) and human (A375, SK-MEL-5) melanoma cell lines were treated with IS at different concentrations (0-100 μM). Cell viability and proliferation was detected by WST-1 assay and with the xCELLigence system, respectively. Apoptosis was measured by the annexin-V/PI flow cytometric assay. Western blot was used to measure cleaved caspase 3, survivin, P-STAT3, P-ERK and P-AKT. B16 and A375 cells were injected subcutaneously into C57BL/6J and BALB/c-nu mice, respectively. After 1 wk, IS solution at (50 mg/kg, 100 mg/kg) was administered by intraperitoneal injection 3 times for a week. Tumor size was measured with an electronic digital caliper. IS inhibited the proliferation of melanoma cells in a dose- and time-dependent manner. Treatment of A375 cells with IS resulted in an increased number of apoptotic cells ranging from 5.6% to 26.3% mirrored by increases in cleaved caspase-3 and a decrease in survivin expression. IS significantly inhibited the activation of the JAK-STAT3 and MAPK pathways but promoted an unsustained activation peak of the PI3K-AKT pathway. IS administration (50 mg/kg) resulted in a 47.5% decreased tumor volume in A375 bearing mice. Furthermore, IS administration (50 mg/kg, 100 mg/kg) resulted in 41% and 49% decreased tumor volume in B16 bearing mice, respectively. IS dramatically inhibited the proliferation of melanoma cells in vivo and in vitro through the regulation of apoptosis. These effects demonstrate the ability of IS to effectively overcome the survival signals of tumor cells, which support further preclinical evaluation of IS in cancer as a new potential chemotherapeutic agent.
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