BACKGROUND: Previous studies have suggested that the hippocampus is one of the neurotoxic target sites for lead. However, the molecular mechanisms of action, including the effect of lead on cell-cycle arrest, remain ...BACKGROUND: Previous studies have suggested that the hippocampus is one of the neurotoxic target sites for lead. However, the molecular mechanisms of action, including the effect of lead on cell-cycle arrest, remain poorly understood. OBJECTIVE: To investigate the effects of different lead concentrations on cell-cycle arrest, DNA damage, and cyclin D1 expression in primary cultured rat hippocampal neurons. DESIGN, TIME AND SETTING: A randomized, controlled, in vitro experiment was performed at the China Medical University between July 2008 and May 2009. MATERIALS: Antibodies specific to cyclin D1 and actin were synthesized and purified by Santa Cruz Biotechnology, USA. FACStar flow cytometer was purchased from Becton Dickinson, San Jose, California, USA. METHODS: Wistar rat hippocampal neurons were primary cultured for 7 days. Neurons in the control group were treated with 0.01 mol/L phosphate buffered saline. Neurons in the 0.2, 1.0, and 10 umol/L lead acetate groups were subjected to 0.2, 1.0, and 10 umol/L lead acetate. Subsequently hippocampal neurons in each group were cultured for 24 hours. MAIN OUTCOME MEASURES: The effects of lead on cell cycle were measured by flow cytometry, DNA damage was measured using the comet assay, and cyclin D1 expression was measured using Western blot analysis. RESULTS: Treatment of hippocampal neurons with 0.2 umol/L lead acetate did not significantly alter cell cycle phase distribution, i.e., sub-G1, S, G0/G1, G2/M, whereas treatment with 1.0 and 10 umol/L lead acetate significantly increased the percentage of S and sub-G1 phase cells (P 〈 0.05). Olive tail moment in all lead-treated groups and the percentage of DNA in the tail in 1.0 umol/L and 10 umol/L lead acetate groups were significantly greater compared with the control group (P 〈 0.05). In addition, the percentage of tail DNA was greater in the 0.2 umol/L lead acetate group compared with the control group (P 〉 0.05). Following incubation with 0.2, 1.0, and 10 umol/L lead acetate for 24 hours, cyclin D1 expression gradually decreased with exposure to increasing lead acetate concentrations (1.0-10 umol/L). CONCLUSION: Lead exposure to primary cultured rat hippocampal neurons resulted in dose-dependently disturbed cellular homeostasis, including DNA damage, reduced cyclin D1 expression, and stagnation of cell-cycle progression.展开更多
<strong>Introduction</strong>.<span><span><span style="font-family:;" "=""><span style="font-family:Verdana;"> The molecular biological mechanism ...<strong>Introduction</strong>.<span><span><span style="font-family:;" "=""><span style="font-family:Verdana;"> The molecular biological mechanism of the increased incidence of the various types of cancer in obesity or type 2 diabetes in rodents or humans has largely been resolved in recent years. By contrast, the molecular biological mechanism of the decreased, not increased, incidence of the various types of cancer in the homozygous long-lived Ames dwarf mice still remains unresolved. </span><b><span style="font-family:Verdana;">Objective.</span></b><span style="font-family:Verdana;"> The first objective of the present study was to investigate whether the decrease in the incidence of cancer in the homozygous long-lived Ames dwarf mice is due to the increase, not decrease, in the expression of p27Kip1, a cell cycle repressor protein. The second objective was to investigate whether the decrease in the incidence of cancer in the homozygous long-lived Ames dwarf mice is due to the decrease, not increase, in the levels of glucose or insulin. </span><b><span style="font-family:Verdana;">Methods.</span></b><span style="font-family:Verdana;"> To achieve these objectives, we first performed western immunoblot analysis of the hepatic expression of p27Kip1 protein. We then performed, using a human breast cancer cell line </span><i><span style="font-family:Verdana;">in</span></i> <i><span style="font-family:Verdana;">vitro</span></i><span style="font-family:Verdana;">, the luciferase reporter plasmid assay to determine whether the translation initiation activity of the p27Kip1 mRNA is increased when the concentrations of either glucose or insulin are decreased. </span><b><span style="font-family:Verdana;">Results and Conclusion. </span></b><span style="font-family:Verdana;">The results of the first objective indicated that the hepatic expression of p27Kip1 protein was up-regulated in the homozygous long-lived Ames dwarf mice as expected. We also found that the lower concentrations of glucose or insulin increased the translation initiation activity of the p27Kip1 mRNA.</span></span></span></span>展开更多
Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular pro...Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cellcycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors, p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase (CDK) 4 and CDK6 with cyclin DI, is frequently inactivated in HCC via CpG methylation of its promoter region, p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients, p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC.展开更多
Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtaine...Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtained from the root of Sanguinaria canadensis, and from other poppy Fumaria species, with recognized anti-microbial, anti-oxidant and anti-inflammatory properties. Recently, increasing evidence that sanguinarine exibits anticancer potential through its capability of inducing apoptosis and/or antiproliferative effects on tumor cells, has been proved. Moreover, its antitumor seems to be due not only to its pro-apoptotic and inhibitory effects on tumor growth, but also to its antiangiogenic and anti-invasive properties. Although the precise mechanisms underlying the antitumor activity of this compound remain not fully understood, in this review we will focus on the most recent findings about the cellular and molecular pathways affected by sanguinarine, together with the rationale of its potential application in clinic. The complex of data currently available suggest the potential application of sanguinarine as an adjuvant in the therapy of cancer, but further pre-clinical studies are needed before such an antitumor strategy can be effectively translated in the clinical practice.展开更多
Objective:The morbidity of malignant melanoma keeps increasing annually.It has high risks of metastasis,drug resistance,and poor prognosis in clinics.Moreover,the available medicines used commonly,such as dacarbazine,...Objective:The morbidity of malignant melanoma keeps increasing annually.It has high risks of metastasis,drug resistance,and poor prognosis in clinics.Moreover,the available medicines used commonly,such as dacarbazine,temozolomide,the v-Raf murine sarcoma viral oncogene homolog B1(BRAF)inhibitor vemurafenib,and the programmed cell death protein 1 inhibitor pembrolizumab,have some limitations at some extent.Therefore,a more effective therapeutic strategy is still urgently necessary.Methods:In this study,Brucea javanica(L.)Merr.globulins were hydrolyzed with pepsin,then ultra-filtrated to collect small molecular peptides(≤3 kDa).The peptides were then analyzed by antiproliferative assay,cell-cycle distribution,apoptosis assay,and in vitro wound-scratch assay.Finally,western blotting was conducted to elucidate the underlying anti-melanoma mechanism.Results:The small molecular peptide from B.javanica significantly inhibited malignant melanoma cell proliferation with the IC_(50) of 2.72 mg/mL for 72 h.Further analysis indicated that B.javanica peptides arrested cell cycle at the S and G2/M phases and induced apoptosis by upregulating p21,p53,Bax,caspase-3,and cleaved PARP while downregulating Bcl-2 expression.The inhibitory migration effects were also confirmed by wound-healing assay.Conclusion:The small molecular biopeptides from B.javanica may be a promising bioactive agent candidate for melanoma treatment.展开更多
Recent progresses in the protein regulatory network of budding yeast Saccharomyces cerevisiae have provided a global picture of its protein network for further dynamical research. We simplify and modularize the protei...Recent progresses in the protein regulatory network of budding yeast Saccharomyces cerevisiae have provided a global picture of its protein network for further dynamical research. We simplify and modularize the protein regulatory networks in yeast nucleus, and study the dynamical properties of the core 37-node network by a Boolean network model, especially the evolution steps and final fixed points. Our simulation results show that the number of fixed points N(k) for a given size of the attraction basin k obeys a power-law distribution N(k) χ k^-2.024. The yeast network is more similar to a scale-free network than a random network in the above dynamical properties.展开更多
The effects of tumor necrosis factor-α(TNF) on protein metabolism and cell-cycle kinetics were investigated in malignant tumor. Sprague-Dawley rats, subcutaneously inoculated with Walker 256 carcinosarcoma,were injec...The effects of tumor necrosis factor-α(TNF) on protein metabolism and cell-cycle kinetics were investigated in malignant tumor. Sprague-Dawley rats, subcutaneously inoculated with Walker 256 carcinosarcoma,were injected intraperitoneally with recombinant human TNF at a dose of 4-75×106 U/kg for 3 consecutive days.Tumor protein metabolism and cell-cycle kinetics were analyzed. The results showed a significant decrease in tumor volume and weight in comparison with control.TNF resulted in significant decrease in tumor Protein fractional synthesis rate, Protein synthesis and fractional growth rate, but no change of tumor protein fractional degradation rate. TNF also resulted in remarkable decline in labelling index and GI phase increase of tumor cells, 6 hours after bromodeoxyuridine injection, by cytometry. The results indicated that TNF inhibits tumor growth as a result of decreases in tumor cell DNA and protein syntheses.展开更多
Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycl...Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aimed to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human ovarian cancer SK-OV-3 cells. The results suggested that YSY-01A significantly (P〈0.05) inhibited cellular proliferation of SK-OV-3 cells in a concentration-dependent and time-dependent manner. Furthermore, YSY-01A induced a G2/M cell cycle arrest of SK-OV-3 cells. Further investigation revealed that YSY-01A significantly (P〈0.05) changed the expression levels of a series of cell cycle related protein, such as cyclin B1, cdc2, and p-cdc2 (T14). Meanwhile, YSY-01A could inhibit the TNF-a-induced NF-kB nuclear translocation and lead to the increase of 1kBa as well as the decrease of IKK and Gadd45a In conclusion, YSY-01A showed remarkable anti-cancer activity on SK-OV-3 cells, and its molecular mechanisms were related to G2/M cell cycle arrest.展开更多
Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycl...Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aims to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human colorectal adenocarcinoma cells HT-29. The results suggested that YSY-01A significantly (P0.05) inhibited cellular proliferation of HT-29 cells in a time and concentration-dependent manner. Furthermore, YSY-01A suppressed the G 2 /M transition of HT-29 cells, whereas the mitotic inhibitor paclitaxel induced M phase accumulation. Further investigation revealed that YSY-01A significantly (P0.05) up-regulated the expression levels of a series of cell cycle related protein, such as cyclin B1, Wee1, p-cdc2 (Tyr15), p53, p21, and p27. The HT-29 cells only exhibited typical cytotoxic symptom when YSY-01A concentration reached 0.5 μM (P0.05), which was above the dose we used in the mechanism research. In conclusion, YSY-01A showed remarkable anti-cancer activity on HT-29 cells, and its molecular mechanisms are related to G 2 /M cell cycle transition arrest.展开更多
Objective: Heat stress (HS) is an important environmental stressor that adversely influences livestock during the summer. The aim of this study was to investigate whether magnolol protects against HS-induced intest...Objective: Heat stress (HS) is an important environmental stressor that adversely influences livestock during the summer. The aim of this study was to investigate whether magnolol protects against HS-induced intestinal epithelial cell injury. Materials and methods: An intestinal epithelial cell line (IEC-6) was subjected to HS at 42℃, with and without magnolol pretreatment. Cell injury was detected by monitoring lactate dehydrogenase (LDH) release. MTS (3-(4,5-dimethyithiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay was used to as- sess cell proliferation and viability, including identifying effective concentrations of magnolol. Flow cytometry confirmed Gl-phase cell-cycle arrest and its alleviation by magnolol. Active DNA synthesis was measured by incorporation of nucleic acid 5-ethynyl-2'-deoxyuridine (EdU). Gl-phase cell-cycle-related gene expression was assessed by real-time reverse transcription polymerase chain reaction (RT-PCR) and levels of Gl-phase-related proteins by Western blotting Results: HS induced IEC-6 cell injury and decreased cell viability, as demonstrated by data from LDH and MTS assays respectively. Based on a number of criteria, IEC-6 cells subjected to HS were arrested in the G1 phase Of the cell cycle. Magnolol pretreatment decreased HS-induced cell injury through relief of this cell-cycle arrest. Conclusions: Magnolol pretreatment attenuates HS-induced injury in IEC-6 cells. Magnolol is potentially promising as a protective strategy for HS in livestock.展开更多
The programmed cell death 10(PDCD10)gene was originally identified as an apoptosis-related gene,although it is now usually known as CCM3,as the third causative gene of cerebral cavernous malformation(CCM).CCM is a neu...The programmed cell death 10(PDCD10)gene was originally identified as an apoptosis-related gene,although it is now usually known as CCM3,as the third causative gene of cerebral cavernous malformation(CCM).CCM is a neurovascular disease that is characterized by vascular malformations and is associated with headaches,seizures,focal neurological deficits,and cerebral hemorrhage.The PDCD10/CCM3 protein has multiple subcellular localizations and interacts with several multi-protein complexes and signaling pathways.Thus PDCD10/CCM3 governs many cellular functions,which include cell-to-cell junctions and cytoskeleton organization,cell proliferation and apoptosis,and exocytosis and angiogenesis.Given its central role in the maintenance of homeostasis of the cell,dysregulation of PDCD10/CCM3 can result in a wide range of altered cell functions.This can lead to severe diseases,including CCM,cognitive disability,and several types of cancers.Here,we review the multifaceted roles of PDCD10/CCM3 in physiology and pathology,with a focus on its functions beyond CCM.展开更多
Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health.Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying80%of all lung cancer subtypes...Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health.Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying80%of all lung cancer subtypes.Except for other mutations (e.g.,KRAS^(G12V/D)) that are also vital for the occurrence,KRAS^(G12C) gene mutation is a significant driving force of NSCLC,with a prevalence of approximately 14% of all NSCLC patients.However,there are only a few therapeutic drugs targeting KRAS^(G12C) mutations currently.Here,we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRAS^(G12C) binding affinity and the same anti-tumor effect based on the a-helical peptide mimic SAH-SOS1_(A).The stapled peptide 3 effectively induced G2/M arrest and apoptosis,inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRASmediated RAF/MEK/ERK signaling,which was verified from the perspective of genomics and proteomics.Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities,as well as good plasma stability and human liver microsomal metabolic stability.Overall,peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1_(A) but with improved stability and affinity,superior to SAH-SOS1_(A).Our work offers a structural optimization approach of KRAS^(G12C) peptide inhibitors for cancer therapy.展开更多
Background Colorectal cancer(CRC)is one of the leading causes of cancer death worldwide.Novel drugs for CRC therapy are urgently needed.Digoxin has been in clinical use for treatment of heart failure and atrial arrhyt...Background Colorectal cancer(CRC)is one of the leading causes of cancer death worldwide.Novel drugs for CRC therapy are urgently needed.Digoxin has been in clinical use for treatment of heart failure and atrial arrhythmias for many years.Fragmentary reports suggested that digoxin might have antitumor efficacy on CRC.Here,we aimed to investigate the antitumor effect of digoxin on human CRC cells and the underlying mechanism.Methods Cell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT)assay and plate colony formation assay.The effects of digoxin on cell-cycle distribution and apoptosis were analysed by flow cytometry.The anti-metastatic effect on tumor cells was determined by wound-healing assay and transwell assay.Anti-angiogenic effect was examined by determining the inhibition against proliferation,migration,and tube formation of human umbilical vein endothelial cells(HUVECs).Mechanism study was performed by Western blot,enzyme-linked immunosorbent assay(ELISA),and gelatin-zymography assay.Results Digoxin potently inhibited cell proliferation,induced G1-phase and G2/M-phase arrest in colorectal-cancer HCT8 and SW620 cells,respectively.No obvious apoptosis was observed in the treated cells.Anti-metastatic activities were shown on HCT8 cells by inhibiting the migration and invasion.Meanwhile,the expression of MMP2,MMP9,and phosphorylated Integrinb1 were decreased.Digoxin inhibited the proliferation,migration,and tube formation of HUVECs and reduced HIF1a expression and vascular endothelial growth factor A(VEGF-A)secretion in HCT8 cells,suggesting anti-angiogenic activity.Furthermore,digoxin significantly reversed ABCB1-mediated multidrug resistance on SW620/Ad300 cells.Conclusion Our findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting proliferation and metastasis as well as reversing the ABCB1-mediated multidrug resistance of colorectal cancer.展开更多
基金the National Natural Science Foundation of China, No. 39970651
文摘BACKGROUND: Previous studies have suggested that the hippocampus is one of the neurotoxic target sites for lead. However, the molecular mechanisms of action, including the effect of lead on cell-cycle arrest, remain poorly understood. OBJECTIVE: To investigate the effects of different lead concentrations on cell-cycle arrest, DNA damage, and cyclin D1 expression in primary cultured rat hippocampal neurons. DESIGN, TIME AND SETTING: A randomized, controlled, in vitro experiment was performed at the China Medical University between July 2008 and May 2009. MATERIALS: Antibodies specific to cyclin D1 and actin were synthesized and purified by Santa Cruz Biotechnology, USA. FACStar flow cytometer was purchased from Becton Dickinson, San Jose, California, USA. METHODS: Wistar rat hippocampal neurons were primary cultured for 7 days. Neurons in the control group were treated with 0.01 mol/L phosphate buffered saline. Neurons in the 0.2, 1.0, and 10 umol/L lead acetate groups were subjected to 0.2, 1.0, and 10 umol/L lead acetate. Subsequently hippocampal neurons in each group were cultured for 24 hours. MAIN OUTCOME MEASURES: The effects of lead on cell cycle were measured by flow cytometry, DNA damage was measured using the comet assay, and cyclin D1 expression was measured using Western blot analysis. RESULTS: Treatment of hippocampal neurons with 0.2 umol/L lead acetate did not significantly alter cell cycle phase distribution, i.e., sub-G1, S, G0/G1, G2/M, whereas treatment with 1.0 and 10 umol/L lead acetate significantly increased the percentage of S and sub-G1 phase cells (P 〈 0.05). Olive tail moment in all lead-treated groups and the percentage of DNA in the tail in 1.0 umol/L and 10 umol/L lead acetate groups were significantly greater compared with the control group (P 〈 0.05). In addition, the percentage of tail DNA was greater in the 0.2 umol/L lead acetate group compared with the control group (P 〉 0.05). Following incubation with 0.2, 1.0, and 10 umol/L lead acetate for 24 hours, cyclin D1 expression gradually decreased with exposure to increasing lead acetate concentrations (1.0-10 umol/L). CONCLUSION: Lead exposure to primary cultured rat hippocampal neurons resulted in dose-dependently disturbed cellular homeostasis, including DNA damage, reduced cyclin D1 expression, and stagnation of cell-cycle progression.
文摘<strong>Introduction</strong>.<span><span><span style="font-family:;" "=""><span style="font-family:Verdana;"> The molecular biological mechanism of the increased incidence of the various types of cancer in obesity or type 2 diabetes in rodents or humans has largely been resolved in recent years. By contrast, the molecular biological mechanism of the decreased, not increased, incidence of the various types of cancer in the homozygous long-lived Ames dwarf mice still remains unresolved. </span><b><span style="font-family:Verdana;">Objective.</span></b><span style="font-family:Verdana;"> The first objective of the present study was to investigate whether the decrease in the incidence of cancer in the homozygous long-lived Ames dwarf mice is due to the increase, not decrease, in the expression of p27Kip1, a cell cycle repressor protein. The second objective was to investigate whether the decrease in the incidence of cancer in the homozygous long-lived Ames dwarf mice is due to the decrease, not increase, in the levels of glucose or insulin. </span><b><span style="font-family:Verdana;">Methods.</span></b><span style="font-family:Verdana;"> To achieve these objectives, we first performed western immunoblot analysis of the hepatic expression of p27Kip1 protein. We then performed, using a human breast cancer cell line </span><i><span style="font-family:Verdana;">in</span></i> <i><span style="font-family:Verdana;">vitro</span></i><span style="font-family:Verdana;">, the luciferase reporter plasmid assay to determine whether the translation initiation activity of the p27Kip1 mRNA is increased when the concentrations of either glucose or insulin are decreased. </span><b><span style="font-family:Verdana;">Results and Conclusion. </span></b><span style="font-family:Verdana;">The results of the first objective indicated that the hepatic expression of p27Kip1 protein was up-regulated in the homozygous long-lived Ames dwarf mice as expected. We also found that the lower concentrations of glucose or insulin increased the translation initiation activity of the p27Kip1 mRNA.</span></span></span></span>
文摘Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cellcycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors, p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase (CDK) 4 and CDK6 with cyclin DI, is frequently inactivated in HCC via CpG methylation of its promoter region, p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients, p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC.
文摘Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtained from the root of Sanguinaria canadensis, and from other poppy Fumaria species, with recognized anti-microbial, anti-oxidant and anti-inflammatory properties. Recently, increasing evidence that sanguinarine exibits anticancer potential through its capability of inducing apoptosis and/or antiproliferative effects on tumor cells, has been proved. Moreover, its antitumor seems to be due not only to its pro-apoptotic and inhibitory effects on tumor growth, but also to its antiangiogenic and anti-invasive properties. Although the precise mechanisms underlying the antitumor activity of this compound remain not fully understood, in this review we will focus on the most recent findings about the cellular and molecular pathways affected by sanguinarine, together with the rationale of its potential application in clinic. The complex of data currently available suggest the potential application of sanguinarine as an adjuvant in the therapy of cancer, but further pre-clinical studies are needed before such an antitumor strategy can be effectively translated in the clinical practice.
基金This experiment was supported by the National Natural Science Foundation of China(No.81872972).
文摘Objective:The morbidity of malignant melanoma keeps increasing annually.It has high risks of metastasis,drug resistance,and poor prognosis in clinics.Moreover,the available medicines used commonly,such as dacarbazine,temozolomide,the v-Raf murine sarcoma viral oncogene homolog B1(BRAF)inhibitor vemurafenib,and the programmed cell death protein 1 inhibitor pembrolizumab,have some limitations at some extent.Therefore,a more effective therapeutic strategy is still urgently necessary.Methods:In this study,Brucea javanica(L.)Merr.globulins were hydrolyzed with pepsin,then ultra-filtrated to collect small molecular peptides(≤3 kDa).The peptides were then analyzed by antiproliferative assay,cell-cycle distribution,apoptosis assay,and in vitro wound-scratch assay.Finally,western blotting was conducted to elucidate the underlying anti-melanoma mechanism.Results:The small molecular peptide from B.javanica significantly inhibited malignant melanoma cell proliferation with the IC_(50) of 2.72 mg/mL for 72 h.Further analysis indicated that B.javanica peptides arrested cell cycle at the S and G2/M phases and induced apoptosis by upregulating p21,p53,Bax,caspase-3,and cleaved PARP while downregulating Bcl-2 expression.The inhibitory migration effects were also confirmed by wound-healing assay.Conclusion:The small molecular biopeptides from B.javanica may be a promising bioactive agent candidate for melanoma treatment.
文摘Recent progresses in the protein regulatory network of budding yeast Saccharomyces cerevisiae have provided a global picture of its protein network for further dynamical research. We simplify and modularize the protein regulatory networks in yeast nucleus, and study the dynamical properties of the core 37-node network by a Boolean network model, especially the evolution steps and final fixed points. Our simulation results show that the number of fixed points N(k) for a given size of the attraction basin k obeys a power-law distribution N(k) χ k^-2.024. The yeast network is more similar to a scale-free network than a random network in the above dynamical properties.
文摘The effects of tumor necrosis factor-α(TNF) on protein metabolism and cell-cycle kinetics were investigated in malignant tumor. Sprague-Dawley rats, subcutaneously inoculated with Walker 256 carcinosarcoma,were injected intraperitoneally with recombinant human TNF at a dose of 4-75×106 U/kg for 3 consecutive days.Tumor protein metabolism and cell-cycle kinetics were analyzed. The results showed a significant decrease in tumor volume and weight in comparison with control.TNF resulted in significant decrease in tumor Protein fractional synthesis rate, Protein synthesis and fractional growth rate, but no change of tumor protein fractional degradation rate. TNF also resulted in remarkable decline in labelling index and GI phase increase of tumor cells, 6 hours after bromodeoxyuridine injection, by cytometry. The results indicated that TNF inhibits tumor growth as a result of decreases in tumor cell DNA and protein syntheses.
基金Eleventh Five-Year Plan for National Science and Technology Major Project(Grant No.2009ZX0930-010)National Science Foundation of China(Grant No.81172915)a grant from Major New Drugs Research and Development Platform of Peking University(Grant No.2009ZX09301-010)
文摘Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aimed to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human ovarian cancer SK-OV-3 cells. The results suggested that YSY-01A significantly (P〈0.05) inhibited cellular proliferation of SK-OV-3 cells in a concentration-dependent and time-dependent manner. Furthermore, YSY-01A induced a G2/M cell cycle arrest of SK-OV-3 cells. Further investigation revealed that YSY-01A significantly (P〈0.05) changed the expression levels of a series of cell cycle related protein, such as cyclin B1, cdc2, and p-cdc2 (T14). Meanwhile, YSY-01A could inhibit the TNF-a-induced NF-kB nuclear translocation and lead to the increase of 1kBa as well as the decrease of IKK and Gadd45a In conclusion, YSY-01A showed remarkable anti-cancer activity on SK-OV-3 cells, and its molecular mechanisms were related to G2/M cell cycle arrest.
基金Eleventh Five-Year Plan for National Science and Technology Major Project (Grant No.2009ZX0930-010)National Science Foundation of China (NSFC81172915)A grant from Major New Drugs Research and Development Platform of Peking University (Grant No.2009ZX09301-010)
文摘Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aims to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human colorectal adenocarcinoma cells HT-29. The results suggested that YSY-01A significantly (P0.05) inhibited cellular proliferation of HT-29 cells in a time and concentration-dependent manner. Furthermore, YSY-01A suppressed the G 2 /M transition of HT-29 cells, whereas the mitotic inhibitor paclitaxel induced M phase accumulation. Further investigation revealed that YSY-01A significantly (P0.05) up-regulated the expression levels of a series of cell cycle related protein, such as cyclin B1, Wee1, p-cdc2 (Tyr15), p53, p21, and p27. The HT-29 cells only exhibited typical cytotoxic symptom when YSY-01A concentration reached 0.5 μM (P0.05), which was above the dose we used in the mechanism research. In conclusion, YSY-01A showed remarkable anti-cancer activity on HT-29 cells, and its molecular mechanisms are related to G 2 /M cell cycle transition arrest.
基金Project supported by the National Natural Science Foundation of China(No.31272478)the National Twelve-Five Technological Supported Plan of China(No.2013BAD10B04)+1 种基金the Ministry of Agriculture,Public Service Sectors Agriculture Research Projects(No.201403051-07)the Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions(No.CIT&TCD20130324),China
文摘Objective: Heat stress (HS) is an important environmental stressor that adversely influences livestock during the summer. The aim of this study was to investigate whether magnolol protects against HS-induced intestinal epithelial cell injury. Materials and methods: An intestinal epithelial cell line (IEC-6) was subjected to HS at 42℃, with and without magnolol pretreatment. Cell injury was detected by monitoring lactate dehydrogenase (LDH) release. MTS (3-(4,5-dimethyithiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay was used to as- sess cell proliferation and viability, including identifying effective concentrations of magnolol. Flow cytometry confirmed Gl-phase cell-cycle arrest and its alleviation by magnolol. Active DNA synthesis was measured by incorporation of nucleic acid 5-ethynyl-2'-deoxyuridine (EdU). Gl-phase cell-cycle-related gene expression was assessed by real-time reverse transcription polymerase chain reaction (RT-PCR) and levels of Gl-phase-related proteins by Western blotting Results: HS induced IEC-6 cell injury and decreased cell viability, as demonstrated by data from LDH and MTS assays respectively. Based on a number of criteria, IEC-6 cells subjected to HS were arrested in the G1 phase Of the cell cycle. Magnolol pretreatment decreased HS-induced cell injury through relief of this cell-cycle arrest. Conclusions: Magnolol pretreatment attenuates HS-induced injury in IEC-6 cells. Magnolol is potentially promising as a protective strategy for HS in livestock.
基金The lab of ED is supported by:The Swedish Research Council(contract No.2013-9279),the Knut and Alice Wallenberg Foundation(contract No.2015-0030),the European Research Council(project EC-ERC-VEPC,contract 74292),Associazione Italiana per la Ricerca sul Cancro(AIRC IG 23223),AIRC 5x1000 call"Metastatic disease:the key unmet need in oncology"to the MYNERVA Project(MYeloid NEoplasms Research Venture AIRC 21267),Telethon(New insight on the pathogenesis of hereditary Cerebral Cavernous Malformation,contract GGP19202)AIFA(a multicellular randomized clinical trial on propranolol in familial Cerebral Cavernous Malformation,contract AIFA-2016-02364593).Be Brave for Life Foundation Micro Grant 2019.
文摘The programmed cell death 10(PDCD10)gene was originally identified as an apoptosis-related gene,although it is now usually known as CCM3,as the third causative gene of cerebral cavernous malformation(CCM).CCM is a neurovascular disease that is characterized by vascular malformations and is associated with headaches,seizures,focal neurological deficits,and cerebral hemorrhage.The PDCD10/CCM3 protein has multiple subcellular localizations and interacts with several multi-protein complexes and signaling pathways.Thus PDCD10/CCM3 governs many cellular functions,which include cell-to-cell junctions and cytoskeleton organization,cell proliferation and apoptosis,and exocytosis and angiogenesis.Given its central role in the maintenance of homeostasis of the cell,dysregulation of PDCD10/CCM3 can result in a wide range of altered cell functions.This can lead to severe diseases,including CCM,cognitive disability,and several types of cancers.Here,we review the multifaceted roles of PDCD10/CCM3 in physiology and pathology,with a focus on its functions beyond CCM.
基金supported by projects of the National Natural Science Foundation of China(81803354 and 81773693)the Natural Science Foundation of Jiangsu Province of China(BK20180564)+2 种基金the Fundamental Research Funds for the Central Universities(2632021ZD13,China)Double First-Class Innovation Team of China Pharmaceutical University(CPU2018GY02,China)the Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education(YY20180315004,China)
文摘Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health.Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying80%of all lung cancer subtypes.Except for other mutations (e.g.,KRAS^(G12V/D)) that are also vital for the occurrence,KRAS^(G12C) gene mutation is a significant driving force of NSCLC,with a prevalence of approximately 14% of all NSCLC patients.However,there are only a few therapeutic drugs targeting KRAS^(G12C) mutations currently.Here,we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRAS^(G12C) binding affinity and the same anti-tumor effect based on the a-helical peptide mimic SAH-SOS1_(A).The stapled peptide 3 effectively induced G2/M arrest and apoptosis,inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRASmediated RAF/MEK/ERK signaling,which was verified from the perspective of genomics and proteomics.Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities,as well as good plasma stability and human liver microsomal metabolic stability.Overall,peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1_(A) but with improved stability and affinity,superior to SAH-SOS1_(A).Our work offers a structural optimization approach of KRAS^(G12C) peptide inhibitors for cancer therapy.
基金supported by the Science&Technology Development Fund of Tianjin Education Commission for Higher Education[2017KJ230].
文摘Background Colorectal cancer(CRC)is one of the leading causes of cancer death worldwide.Novel drugs for CRC therapy are urgently needed.Digoxin has been in clinical use for treatment of heart failure and atrial arrhythmias for many years.Fragmentary reports suggested that digoxin might have antitumor efficacy on CRC.Here,we aimed to investigate the antitumor effect of digoxin on human CRC cells and the underlying mechanism.Methods Cell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT)assay and plate colony formation assay.The effects of digoxin on cell-cycle distribution and apoptosis were analysed by flow cytometry.The anti-metastatic effect on tumor cells was determined by wound-healing assay and transwell assay.Anti-angiogenic effect was examined by determining the inhibition against proliferation,migration,and tube formation of human umbilical vein endothelial cells(HUVECs).Mechanism study was performed by Western blot,enzyme-linked immunosorbent assay(ELISA),and gelatin-zymography assay.Results Digoxin potently inhibited cell proliferation,induced G1-phase and G2/M-phase arrest in colorectal-cancer HCT8 and SW620 cells,respectively.No obvious apoptosis was observed in the treated cells.Anti-metastatic activities were shown on HCT8 cells by inhibiting the migration and invasion.Meanwhile,the expression of MMP2,MMP9,and phosphorylated Integrinb1 were decreased.Digoxin inhibited the proliferation,migration,and tube formation of HUVECs and reduced HIF1a expression and vascular endothelial growth factor A(VEGF-A)secretion in HCT8 cells,suggesting anti-angiogenic activity.Furthermore,digoxin significantly reversed ABCB1-mediated multidrug resistance on SW620/Ad300 cells.Conclusion Our findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting proliferation and metastasis as well as reversing the ABCB1-mediated multidrug resistance of colorectal cancer.