Uveal and conjunctival melanomas are relatively rare tumors;nonetheless,they pose a significant risk of mortality for a large number of affected individuals.The pathogenesis of melanoma at different sites is very simil...Uveal and conjunctival melanomas are relatively rare tumors;nonetheless,they pose a significant risk of mortality for a large number of affected individuals.The pathogenesis of melanoma at different sites is very similar,however,the prognosis for patients with ocular melanoma remains unfavourable,primarily due to its distinctive genetic profile and tumor microenvironment.Regardless of considerable advances in understanding the genetic characteristics and biological behaviour,the treatment of uveal and conjunctival melanoma remains a formidable challenge.To enhance the prospect of success,collaborative efforts involving medical professionals and researchers in thefields of ocular biology and oncology are essential.Current data show a lack of well-designed randomized clinical trials and limited benefits in current forms of treatment for these tumors.Despite advancements in the development of effective melanoma therapeutic strategies,all current treatments for uveal melanoma(UM)and conjunctival melanoma(CoM)remain unsatisfactory,resulting in a poor long-term prognosis.Ongoing trials offer hope for positive outcomes in advanced and metastatic tumors.A more comprehensive understanding of the genetic and molecular abnormalities involved in the development and progression of ocular melanomas opens the way for the development of personalized therapy,with various potential therapeutic targets currently under consideration.Increased comprehension of the molecular pathogenesis of UM and CoM and their specificities may aid in the development of new and more effective systemic therapeutic agents,with the hope of improving the prognosis for patients with metastatic disease.展开更多
Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular function...Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.展开更多
In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells.Tumor cells mainly adopt the glycolysis as energy source to maintai...In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells.Tumor cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic conditions.Investigation on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the world.In recent years,plentiful studics suggest that targeting the peculiar cancer energy metabolic pathways,including glycolysis,mitochondrial respiration,amino acid metabolism,and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential nutrients.Natural products (NPs)are considered as the “treasure trove of small molecules drugs” and have played an extremely remarkable role in the discovery and development of anticancer drugs.And numerous NPs have been reported to act on cancer energy metabolism targets.Herein,a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.展开更多
Inflammatory bowel diseases(IBDs),with blurred etiology,show a rising trend and are of global concern.Of various factors involved in IBD pathogenesis and development,inflammation has been shown to play a major role.Re...Inflammatory bowel diseases(IBDs),with blurred etiology,show a rising trend and are of global concern.Of various factors involved in IBD pathogenesis and development,inflammation has been shown to play a major role.Recognition of the molecular and cellular pathways that induce IBD is an emerging subject to develop targeted therapies.Mammalian target of rapamycin(mTOR)is one the most common receptors of many inflammatory pathways,including that of IBD.To this end,we intend to overview the mTOR inhibitors for their possible efficacy in present and future approaches to treatment of IBD.展开更多
A resurging interest in targeted covalent inhibitors(TCIs)focus on compounds capable of irreversibly reacting with nucleophilic amino acids in a druggable target.p97 is an emerging protein target for cancer therapy,vi...A resurging interest in targeted covalent inhibitors(TCIs)focus on compounds capable of irreversibly reacting with nucleophilic amino acids in a druggable target.p97 is an emerging protein target for cancer therapy,viral infections and neurodegenerative diseases.Extensive efforts were devoted to the development of p97 inhibitors.The most promising inhibitor of p97 was in phase 1 clinical trials,but failed due to the off-target-induced toxicity,suggesting the selective inhibitors of p97 are highly needed.We report herein a new type of TCIs(i.e.,FL-18)that showed proteome-wide selectivity towards p97.Equipped with a Michael acceptor and a basic imidazole,FL-18 showed potent inhibition towards U87 MG tumor cells,and in proteome-wide profiling,selectively modified endogenous p97 as confirmed by in situ fluorescence scanning,label-free quantitative proteomics and functional validations.FL-18 selectively modified cysteine residues located within the D2 ATP site of p97.This covalent labeling of cysteine residue in p97 was verified by LC-MS/MS-based site-mapping and site-directed mutagenesis.Further structure-activity relationship(SAR)studies with FL-18 analogs were established.Collectively,FL-18 is the first known small-molecule TCI capable of covalent engagement of p97 with proteome-wide selectivity,thus providing a promising scaffold for cancer therapy.展开更多
Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae(MP)pneumonia(MPP).MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MP...Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae(MP)pneumonia(MPP).MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP(SMPP).SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans.Therefore,identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency.In this study,serum samples were collected from patients with general MPP(GMPP)and SMPP to conduct proteomics profiling.The Fc fragment of the IgG-binding protein(FCGBP)was identified as the most promising indicator of SMPP.Biological enrichment analysis indicated uncontrolled inflammation in SMPP.ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP.Furthermore,the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression.Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment.Among them,a mechanistic target of rapamycin kinase(mTOR)inhibitor,which is a macrolide compound and a cell proliferation inhibitor,was the most promising candidate for targeting SMPP.To our knowledge,this study was the first proteomics-based characterization of patients with SMPP and GMPP.展开更多
Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nuclea...Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine,etc.) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5'-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential "druggable" targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.展开更多
文摘Uveal and conjunctival melanomas are relatively rare tumors;nonetheless,they pose a significant risk of mortality for a large number of affected individuals.The pathogenesis of melanoma at different sites is very similar,however,the prognosis for patients with ocular melanoma remains unfavourable,primarily due to its distinctive genetic profile and tumor microenvironment.Regardless of considerable advances in understanding the genetic characteristics and biological behaviour,the treatment of uveal and conjunctival melanoma remains a formidable challenge.To enhance the prospect of success,collaborative efforts involving medical professionals and researchers in thefields of ocular biology and oncology are essential.Current data show a lack of well-designed randomized clinical trials and limited benefits in current forms of treatment for these tumors.Despite advancements in the development of effective melanoma therapeutic strategies,all current treatments for uveal melanoma(UM)and conjunctival melanoma(CoM)remain unsatisfactory,resulting in a poor long-term prognosis.Ongoing trials offer hope for positive outcomes in advanced and metastatic tumors.A more comprehensive understanding of the genetic and molecular abnormalities involved in the development and progression of ocular melanomas opens the way for the development of personalized therapy,with various potential therapeutic targets currently under consideration.Increased comprehension of the molecular pathogenesis of UM and CoM and their specificities may aid in the development of new and more effective systemic therapeutic agents,with the hope of improving the prognosis for patients with metastatic disease.
基金Supported by Novartis Espana and by grant to Pons JA as Principal Investigator from Instituto Salud Carlos III,No.PI12/02042
文摘Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.
基金This work was financially supported by grants from the National Natural Science Foundation of China(No.81773594,U1703111,81473254 and 81773637,31270399)Liaoning Revitalization Talents Program(No.XLYC1807182)+2 种基金Program for Liaoning Innovation Talents in University(No.LR2016002)Liaoning Province Natural Science Foundation(No.2019-MS-299)Shenyang Planning Project of Science and Technology(No.18-013-0-46).
文摘In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells.Tumor cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic conditions.Investigation on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the world.In recent years,plentiful studics suggest that targeting the peculiar cancer energy metabolic pathways,including glycolysis,mitochondrial respiration,amino acid metabolism,and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential nutrients.Natural products (NPs)are considered as the “treasure trove of small molecules drugs” and have played an extremely remarkable role in the discovery and development of anticancer drugs.And numerous NPs have been reported to act on cancer energy metabolism targets.Herein,a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.
文摘Inflammatory bowel diseases(IBDs),with blurred etiology,show a rising trend and are of global concern.Of various factors involved in IBD pathogenesis and development,inflammation has been shown to play a major role.Recognition of the molecular and cellular pathways that induce IBD is an emerging subject to develop targeted therapies.Mammalian target of rapamycin(mTOR)is one the most common receptors of many inflammatory pathways,including that of IBD.To this end,we intend to overview the mTOR inhibitors for their possible efficacy in present and future approaches to treatment of IBD.
基金the funding support from Institute of Materia Medica,Peking Union Medical College,CAMS Innovation Fund for Medical Sciences(CIFMS)(2017-I2M-4-005,China)The Natural Science Foundation of China(No.22177136)+1 种基金the Synthetic Biology Research&Development Programme(SBP)of National Research Foundation(SBP-P4 and SBP-P8)of Singapore。
文摘A resurging interest in targeted covalent inhibitors(TCIs)focus on compounds capable of irreversibly reacting with nucleophilic amino acids in a druggable target.p97 is an emerging protein target for cancer therapy,viral infections and neurodegenerative diseases.Extensive efforts were devoted to the development of p97 inhibitors.The most promising inhibitor of p97 was in phase 1 clinical trials,but failed due to the off-target-induced toxicity,suggesting the selective inhibitors of p97 are highly needed.We report herein a new type of TCIs(i.e.,FL-18)that showed proteome-wide selectivity towards p97.Equipped with a Michael acceptor and a basic imidazole,FL-18 showed potent inhibition towards U87 MG tumor cells,and in proteome-wide profiling,selectively modified endogenous p97 as confirmed by in situ fluorescence scanning,label-free quantitative proteomics and functional validations.FL-18 selectively modified cysteine residues located within the D2 ATP site of p97.This covalent labeling of cysteine residue in p97 was verified by LC-MS/MS-based site-mapping and site-directed mutagenesis.Further structure-activity relationship(SAR)studies with FL-18 analogs were established.Collectively,FL-18 is the first known small-molecule TCI capable of covalent engagement of p97 with proteome-wide selectivity,thus providing a promising scaffold for cancer therapy.
基金supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2019-12M-003)the National Natural Science Foundation of China(No.81741060)the Beijing Municipal Natural Science Foundation(No,7182051).
文摘Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae(MP)pneumonia(MPP).MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP(SMPP).SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans.Therefore,identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency.In this study,serum samples were collected from patients with general MPP(GMPP)and SMPP to conduct proteomics profiling.The Fc fragment of the IgG-binding protein(FCGBP)was identified as the most promising indicator of SMPP.Biological enrichment analysis indicated uncontrolled inflammation in SMPP.ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP.Furthermore,the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression.Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment.Among them,a mechanistic target of rapamycin kinase(mTOR)inhibitor,which is a macrolide compound and a cell proliferation inhibitor,was the most promising candidate for targeting SMPP.To our knowledge,this study was the first proteomics-based characterization of patients with SMPP and GMPP.
文摘Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine,etc.) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5'-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential "druggable" targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.