Prostate cancer （PCa） is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically...Prostate cancer （PCa） is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.展开更多
Objective: Heat shock factor 1(HSF1), a transcriptional regulator of heat shock proteins(HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods: ...Objective: Heat shock factor 1(HSF1), a transcriptional regulator of heat shock proteins(HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods: The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies.Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.Results: Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.Conclusions: Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance.Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.展开更多
Objective: To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics,yeast b-glucans, minerals and silymarin(Silybum marianum), on lipid and glycidic metabolism, inflammatory and m...Objective: To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics,yeast b-glucans, minerals and silymarin(Silybum marianum), on lipid and glycidic metabolism, inflammatory and mitochondrial proteins of the liver, in control and high-fat diet-induced obese mice.Methods: After an acclimation period, 32 male C57 BL/6 mice were divided into the following groups:nonfat diet(NFD) vehicle, NFD supplemented, high-fat diet(HFD) vehicle and HFD supplemented. The vehicle and experimental formulation were administered orally by gavage once a day during the last four weeks of the diet(28 consecutive days). We then evaluated energy homeostasis, inflammation, and mitochondrial protein expression in these groups of mice.Results: After four weeks of supplementation, study groups experienced reduced glycemia, dyslipidemia,fat, and hepatic fibrosis levels. Additionally, proliferator-activated receptor-α, AMP-activated protein kinase-1α, peroxisome proliferator-activated receptor γ co-activator-1α, and mitochondrial transcription factor A expression levels were augmented;however, levels of inhibitor of nuclear factor-κB kinase subunit a and p65 nuclear factor-κB expression, and oxidative markers were reduced. Notably, the cortisol/C-reactive protein ratio, a well-characterized marker of the hypothalamic–pituitary–adrenal axis immune interface status, was found to be modulated by the supplement.Conclusion: We discovered that the novel supplement was able to modify different antioxidant, metabolic and inflammatory pathways, improving the energy homeostasis and inflammatory status, and consequently alleviated hepatic steatosis.展开更多
IFN-γ is an extraordinarily pleotropic cytokine. It can not only heighten both the innate and adaptive immune response against pathogens and tumors, but also has the ability to maintain immune homeostasis. Since the ...IFN-γ is an extraordinarily pleotropic cytokine. It can not only heighten both the innate and adaptive immune response against pathogens and tumors, but also has the ability to maintain immune homeostasis. Since the effects of IFN-γ are cell and tissue specific, it is important to consider the recent advances in IFN-γ signaling in the context of different diseases. To this end, we review the involvement of IFN-γ in the pathogenesis of several inflammatory diseases, its therapeutic potential as an anti-tumor agent and its effects upon stem cells.展开更多
For the past twenty years,chemokines have emerged as a family of critical mediators of cell migration during immune surveillance,development,inflammation and cancer progression.Chemokines bind to seven transmembrane G...For the past twenty years,chemokines have emerged as a family of critical mediators of cell migration during immune surveillance,development,inflammation and cancer progression.Chemokines bind to seven transmembrane G protein-coupled receptors(GPCRs)that are expressed by a wide variety of cell types and cause conformational changes in trimeric G proteins that trigger the intracellular signaling pathways necessary for cell movement and activation.Although chemokines have evolved to benefit the host,inappropriate regulation or utilization of these small proteins may contribute to or even cause diseases.Therefore,understanding the role of chemokines and their GPCRs in the complex physiological and diseased microenvironment is important for the identification of novel therapeutic targets.This review introduces the functional array and signals of multiple chemokine GPCRs in guiding leukocyte trafficking as well as their roles in homeostasis,inflammation,immune responses and cancer.展开更多
The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus （SARS-CoV）, Middle East respiratory syndrome coronavirus （MERS-CoV）, and Ebola virus, poses serious challenges to global public...The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus （SARS-CoV）, Middle East respiratory syndrome coronavirus （MERS-CoV）, and Ebola virus, poses serious challenges to global public health and highlights the urgent need for novel antiviral approaches. Monoclonal antibodies （mAbs） have been successfully used to treat various diseases, particularly cancer and immunological disorders. Antigen-specific mAbs have been isolated using several different approaches, including hybridoma, transgenic mice, phage display, yeast display, and single B-celi isolation. Consequently, an increasing number of mAbs, which exhibit high potency against emerging viruses in vitro and in animal models of infection, have been developed. In this paper, we summarize historical trends and recent developments in mAb discovery, compare the advantages and disadvantages of various approaches to mAb production, and discuss the potential use of such strategies for the development of antivirals against emerging diseases. We also review the application of recently developed human mAbs against SARS-CoV, MERS-CoV, and Ebola virus and discuss prospects for the development of mAbs as therapeutic agents against emerging viral diseases.展开更多
We are very excited to publish our article in the“Chemokine Special Issue”of Cellular and Molecular Immunology,which has received increasing attention in the field of immunology.A natural question emerging regarding...We are very excited to publish our article in the“Chemokine Special Issue”of Cellular and Molecular Immunology,which has received increasing attention in the field of immunology.A natural question emerging regarding this issue is,why chemokines?The answer may of course not be simple,but if we consider only the essential,a shortened answer should be because chemokines are among the first mobilizers of host responses in homeostasis and diseases associated with inflammation(Figure 1).展开更多
文摘Prostate cancer （PCa） is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.
基金supported by grants from the National Key Research and Development Program of China (Grant No.2017YFC1601702)China Postdoctoral Science Foundation (Grant No.2011M500825)
文摘Objective: Heat shock factor 1(HSF1), a transcriptional regulator of heat shock proteins(HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods: The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies.Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.Results: Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.Conclusions: Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance.Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.
基金financed in part by the Coordenacao de Aperfeicoamento de Pessoal de Nível Superior,Brasil (CAPES),Finance Code 001. With a PNPD fellow from Graduate Program in Anesthesiology,Surgical Sciences,and Perioperative Medicine,FMUSP,and Efeom Nutricao SA。
文摘Objective: To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics,yeast b-glucans, minerals and silymarin(Silybum marianum), on lipid and glycidic metabolism, inflammatory and mitochondrial proteins of the liver, in control and high-fat diet-induced obese mice.Methods: After an acclimation period, 32 male C57 BL/6 mice were divided into the following groups:nonfat diet(NFD) vehicle, NFD supplemented, high-fat diet(HFD) vehicle and HFD supplemented. The vehicle and experimental formulation were administered orally by gavage once a day during the last four weeks of the diet(28 consecutive days). We then evaluated energy homeostasis, inflammation, and mitochondrial protein expression in these groups of mice.Results: After four weeks of supplementation, study groups experienced reduced glycemia, dyslipidemia,fat, and hepatic fibrosis levels. Additionally, proliferator-activated receptor-α, AMP-activated protein kinase-1α, peroxisome proliferator-activated receptor γ co-activator-1α, and mitochondrial transcription factor A expression levels were augmented;however, levels of inhibitor of nuclear factor-κB kinase subunit a and p65 nuclear factor-κB expression, and oxidative markers were reduced. Notably, the cortisol/C-reactive protein ratio, a well-characterized marker of the hypothalamic–pituitary–adrenal axis immune interface status, was found to be modulated by the supplement.Conclusion: We discovered that the novel supplement was able to modify different antioxidant, metabolic and inflammatory pathways, improving the energy homeostasis and inflammatory status, and consequently alleviated hepatic steatosis.
文摘IFN-γ is an extraordinarily pleotropic cytokine. It can not only heighten both the innate and adaptive immune response against pathogens and tumors, but also has the ability to maintain immune homeostasis. Since the effects of IFN-γ are cell and tissue specific, it is important to consider the recent advances in IFN-γ signaling in the context of different diseases. To this end, we review the involvement of IFN-γ in the pathogenesis of several inflammatory diseases, its therapeutic potential as an anti-tumor agent and its effects upon stem cells.
基金This project was funded in part by federal funds from the National Cancer Institute,National Institutes of Health,under Contract No.HHSN261200800001Ewas supported in part by the Intramural Research Program of the NCI,NIH.
文摘For the past twenty years,chemokines have emerged as a family of critical mediators of cell migration during immune surveillance,development,inflammation and cancer progression.Chemokines bind to seven transmembrane G protein-coupled receptors(GPCRs)that are expressed by a wide variety of cell types and cause conformational changes in trimeric G proteins that trigger the intracellular signaling pathways necessary for cell movement and activation.Although chemokines have evolved to benefit the host,inappropriate regulation or utilization of these small proteins may contribute to or even cause diseases.Therefore,understanding the role of chemokines and their GPCRs in the complex physiological and diseased microenvironment is important for the identification of novel therapeutic targets.This review introduces the functional array and signals of multiple chemokine GPCRs in guiding leukocyte trafficking as well as their roles in homeostasis,inflammation,immune responses and cancer.
文摘The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus （SARS-CoV）, Middle East respiratory syndrome coronavirus （MERS-CoV）, and Ebola virus, poses serious challenges to global public health and highlights the urgent need for novel antiviral approaches. Monoclonal antibodies （mAbs） have been successfully used to treat various diseases, particularly cancer and immunological disorders. Antigen-specific mAbs have been isolated using several different approaches, including hybridoma, transgenic mice, phage display, yeast display, and single B-celi isolation. Consequently, an increasing number of mAbs, which exhibit high potency against emerging viruses in vitro and in animal models of infection, have been developed. In this paper, we summarize historical trends and recent developments in mAb discovery, compare the advantages and disadvantages of various approaches to mAb production, and discuss the potential use of such strategies for the development of antivirals against emerging diseases. We also review the application of recently developed human mAbs against SARS-CoV, MERS-CoV, and Ebola virus and discuss prospects for the development of mAbs as therapeutic agents against emerging viral diseases.
基金This project has been funded in part by federal funds from the National Cancer Institute,National Institutes of Health,under Contract No.HHSN261200800001EPT is also funded in part by the China State Scholarship Fund(No.201603170050)the National Natural Science Foundation of China(No.81302315).
文摘We are very excited to publish our article in the“Chemokine Special Issue”of Cellular and Molecular Immunology,which has received increasing attention in the field of immunology.A natural question emerging regarding this issue is,why chemokines?The answer may of course not be simple,but if we consider only the essential,a shortened answer should be because chemokines are among the first mobilizers of host responses in homeostasis and diseases associated with inflammation(Figure 1).
