George Pan's research while affiliated with Emory University and other places
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Publications (21)
The innate immune system and its components play an important role in the pathogenesis of inflammatory bone destruction. Blockade of inflammatory cytokines does not completely arrest bone erosion, suggesting that other mediators also may be involved in osteolysis. Previously we showed that nucleosides promote osteoclastogenesis and bone-resorption...
Mechanical forces are essential to maintain skeletal integrity, and microgravity exposure leads to bone loss. The underlying molecular mechanisms leading to the changes in osteoblasts and osteoclast differentiation and function remain to be fully elucidated. Because of the infrequency of spaceflights and payload constraints, establishing in vitro a...
We have previously demonstrated that the antagonists of calmodulin (CaM) induce apoptosis of cholangiocarcinoma cells partially through Fas-mediated apoptosis pathways. Recently, CaM has been shown to bind to Fas, which is regulated during Fas or CaM antagonist-mediated apoptosis in Jurkat cells and osteoclasts. Accordingly, the present studies wer...
Prolonged microgravity experienced by astronauts is associated with a decrease in bone mineral density. To investigate the effect of microgravity on differentiation of osteoclasts and osteoblasts, we used a NASA-recommended, ground-based, microgravity-simulating system, the Rotary Cell Culture System (RCCS). Using the RCCS, we demonstrated that mod...
We have previously characterized the role of Fas in tumorigenesis using two cholangiocarcinoma cell lines expressing high (Fas(H)) and low (Fas(L)) levels of Fas. Here we further characterize Fas ligand (FasL) expression and function in these two cell lines. The Fas(L) cells expressed a high level of FasL, whereas the Fas(H) cells expressed a low l...
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95/APO-1; TNFRSF6), a cell surface receptor that regulates apoptosis and its signaling apparatus.
Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequ...
Osteopenia is a common and debilitating side-effect of HAART, yet little is known concerning the effects of HAART on bone metabolism. We reported previously that zidovudine (AZT) stimulates osteoclastogenesis in vitro and causes osteopenia in mice. Here, we confirmed that the AZT-induced osteoclastogenesis is dependent on RANKL in that osteoclastog...
The advent of highly active anti-retroviral therapy (HAART) has dramatically decreased the rate of AIDS-related mortality and significantly extended the life span of patients with AIDS. A variety of metabolic side effects are associated with these therapies, one of which is metabolic bone disease. A higher prevalence of osteopenia and osteoporosis...
Hypoxia produces sex dimorphic immune responses in males and proestrus females. Because Kupffer cells are the major source of proinflammatory cytokines, studies were conducted to discern IL-6 production in mouse Kupffer cells following hypoxia. Hypoxia enhances TLR4 expression in Kupffer cells irrespective of sex. However, MyD88 and Src expression...
One hallmark of AIDS progression is a decline in CD4+ T lymphocytes, though the mechanism is poorly defined. There is ample evidence that increased apoptosis is responsible for some, if not all, of the decline. Prior studies have shown that binding of cellular calmodulin to the envelope glycoprotein (Env) of HIV-1 increases sensitivity to fas-media...
Osteoclast apoptosis is an influential determinant of osteoclast bone-resorbing activity. RANKL, a critical factor for osteoclastogenesis, is also important in osteoclast survival. However, the mechanisms by which RANKL prevents osteoclast apoptosis remain largely unknown.
Fas, a death receptor, mediates apoptosis in multiple types of cells includi...
Members of the tumour necrosis factor receptor family play a pivotal role in cell differentiation, function and apoptosis. However, signalling by many members of the family remains to be elucidated. In the present study, we developed a chimaeric receptor approach for studying signalling by receptors belonging to this family. The chimaeric receptor...
A variety of metabolic complications have been reported to be associated with highly active antiretroviral therapy (HAART), including osteopenia and osteoporosis. In this study, we determine the effects of zidovudine (AZT), a nucleoside reverse transcriptase inhibitor, on osteoclastogenesis in a cultured mouse macrophage preosteoclast cell line (RA...
Calmodulin (CaM) antagonists have been shown to inhibit tumor cell invasion and metastasis and to induce apoptosis in various tumor models, but the molecular mechanism of CaM antagonist-mediated apoptosis is poorly understood. Here, we demonstrate that interferon (IFN)-gamma induces susceptibility to CaM antagonist-mediated apoptosis in human chola...
Human cholangiocarcinoma is a malignancy with no effective therapy and a poor prognosis. Previously, we demonstrated that cultured human cholangiocarcinoma cell lines heterogeneously express Fas on their surface, resulting in 2 subpopulations, Fas-high and Fas-low cells. Fas-low cells are resistant to apoptosis induced by Fas antibody and the calmo...
To evaluate the response of human cholangoicarcinoma cells to TMX treatment through the Fas pathway by pretreatment with IFN-gamma.
Cholangiocarcinoma remains one of the most difficult tumors to treat in clinical medicine. Currently, there are no effective chemotherapy treatments for this disease. Surgery offers the only opportunity for a cure, wit...
Accelerated apoptosis is one mechanism proposed for the loss of CD4+ T-lymphocytes in human immunodeficiency virus type 1 (HIV-1) infection. The HIV-1 envelope glycoprotein, gp160, contains two C-terminal calmodulin-binding domains. Expression of gp160 in Jurkat T-cells results in increased sensitivity to FAS- and ceramide-mediated apoptosis. The p...
We have previously demonstrated that tamoxifen inhibits the growth of human cholangiocarcinoma cells in culture and inhibits tumor growth when cells are injected into nude mice. However, the mechanism of action of tamoxifen remains unknown. Here we demonstrate that tamoxifen and trifluoperazine, both potent calmodulin antagonists, induce apoptosis...
Cholangiocarcinoma continues to have a dismal prognosis with an overall survival rate of less than 10%. An increased understanding
of the molecular oncogenesis of this tumor is needed. Fas/APO-1 (CD95) receptor and Fas ligand have been implicated as key
factors in apoptosis. In this study we have examined the role of the Fas receptor in the growth...
We have previously demonstrated that tamoxifen inhibits the growth of human cholangiocarcinoma cells in culture and inhibits tumor growth when cells are injected into nude mice. However, the mechanism of action of tamoxifen remains unknown. Here we demonstrate that tamoxifen and trifluoperazine, both potent calmodulin antagonists, induce apoptosis...
Recent studies indicate that Fas and Fas ligand are involved in apoptosis of T-cells in HIV-infected patients. We have demonstrated that calcium/calmodulin is involved in Fas-mediated apoptosis in human T-cell lines transfected with HIV recombinant cDNA. In the present study, we examined spontaneous apoptosis of T-cells in vitro in peripheral blood...
Citations
... Similar results were obtained when murine lymphoma EL-4 cells were exposed to TAM (Nagarkatti and Davis, 2003). Further exploring the role of Fas in TAM-induced cell death, Pan et al. (1999) determined that TAM inhibited human cholangiocarcinoma cell viability by 70% in Fasþ cells but only inhibited cell viability by 25% in Fas-cells (Vickers et al., 2002). An inhibitory Fas antibody abrogated this marked increase in cell death (Pan et al., 1999) as did the overexpression of c-FLIP, an endogenous Caspase-8 inhibitor (Pawar et al., 2009). ...
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... A previous study demonstrated that CL is necessary for caspase-8 activation induced by exogenous apoptosis (33). Tamoxifen promotes apoptosis via a caspase-8 dependent mechanism as a calmodulin antagonist [50,51], and our results show that tamoxifen induces apoptosis of breast cancer cells by activating caspase-8. Abnormal CL metabolism caused by TAZ deficiency inhibits the apoptotic response. ...
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... Fas is also expressed in well-differentiated cholangiocarcinoma but expression is diminished or absent from poorly differentiated tumours[34]. Cholangiocarcinoma cell lines display variable levels of Fas, for example the extrahepatic cholangiocarcinoma cell line SkChA-1 includes a mixed population of high and low Fasexpressing cells as determined by mRNA and protein analysis[35,36]. Thus although cholangiocytes constitutively express Fas and this is preserved during neoplastic transformation it can be downregulated as the tumour becomes more genetically unstable[34].stimulation. ...
... According to research by Kin et al., patients experiencing arthritis had increased expression of the NLRP3 inflammasome, which was associated with elevated pro-inflammatory mediators [121] (Figure 7). Another study by Pan et al. found that nucleosides, including nucleoside analogues, may stimulate host immune responses in mice with type II collagen-induced arthritis by interacting with TREM receptors on the skin and NLRP3 inflammasomes [122]. As a result, combining these pro-inflammatory cytokines may result in phenotypic alterations in cells throughout the ossification process [115,123]. ...
... Although there aren't many studies of osteoclast behaviour in simulated microgravity, the amount of research that is out there is unambiguous: it promotes osteoclast function and osteoclastogenesis [84][85][86][87][88][89][90][91]. Osteocytes and osteoblasts can affect osteoclastogenesis by secreting receptor activators of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG). ...
... Trifluoperazine is a phenothiazine, and its primary application is for schizophrenia [58]. It has also been described as modifying P-type ATPase activity [59], inhibiting HIV-associated apoptosis [60], and preventing ROS damage by Fe/H2O2 [61]. Trifluoperazine was proven to be able to decrease the intracellular ROS accumulation and alleviate oxidative damage to cells [62]. ...
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... Particularly, a point mutation at H204 of c-FLIP L reduces CaM binding, resulting in a decreased recruitment of c-FLIP to the DISC and increased CD95-mediated apoptosis of cholangiocarcinoma cells [186]. Other studies show that c-FLIP DED1 can interact with CaM [187,188]. CaM antagonist, trifluoperazine (TFP) inhibits CaM-c-FLIP binding, inducing Dacinostat (LAQ824) ↓ ↓ NA AML [177] Trends in Cancer apoptosis in several cancer cell lines [189][190][191]. The mechanism by which the CaM/c-FLIP complex influences the recruitment of c-FLIP to the DISC is unclear. ...
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... [45] It is also postulated that HIV-infected persons have increased susceptibility to apoptosis because the HIV proteins Tat and Nef induce endothelial cell apoptosis. [46] , [47] Further investigations are necessary to determine whether these apoptotic pathways are associated with lymphocyte or lung parenchymal cells. ...
... Ta1 could enhance the mitogen-triggered maturation of lymphocytes in the peripheral blood and increase the secretion of various T cell lymphokines. [37][38][39] Ta1 could also increase the expression of proteins such as MHC class I, MHC class II, b-2 microglobulin and tumor-specific antigens on the surface of tumor cells, [40] which might lead to tumor suppression. All in all, Ta1 could be useful for the significant survival benefits mainly by boosting the immune function of HCC patients following curative resection. ...
... Both IFN-g and TNF-a promote cell apoptosis. IFN-gamma(IFN-g) modulates the apoptotic pathway by upregulating apoptosis-related genes and overproduction of pro-inflammatory cytokine IFN-g induces the excessive apoptosis of IECs and is involved in Crohn's disease development (49,50). And studies have shown that IFN-g can promote the apoptosis of ovarian granulosa cells (51). ...
