Extensive in vitro and in vivo research reveals multiple intracellular molecular targets of Antrodia camphorata,and these targets affect growth,apoptosis,angiogenesis,invasion and metastasis of cells.These targets inc...Extensive in vitro and in vivo research reveals multiple intracellular molecular targets of Antrodia camphorata,and these targets affect growth,apoptosis,angiogenesis,invasion and metastasis of cells.These targets include tumor suppressor,cell cycle regulator,transcription factor,angiogenesis and metastasis factor,apoptosis and survival regulator,etc.Additionally,more and more attention has been paid to the molecular mechanism of A.camphorata on the regulation of tumor stem cells.Meanwhile,there is evidence that the immunoregulation of A.camphorata is enhanced,which may lead cell cycle arrest or apoptosis.In this paper,molecular mechanism of tumor cells and tumor stem cells regulated at multiple targets by A.camphorata in vitro and in vivo in the past decade is summarized.展开更多
Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a maj...Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a major challenge in medicine largely because of the limited regenerative capacity of the adult brain.展开更多
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The patholog...Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.展开更多
An Ha-ras oncogene was isolated from a cell line of gastric carcinoma called BGE-823 in order to elucidate genetic control and the influence of DNA sequences. The oncogene was cloned and identified as a single nucleot...An Ha-ras oncogene was isolated from a cell line of gastric carcinoma called BGE-823 in order to elucidate genetic control and the influence of DNA sequences. The oncogene was cloned and identified as a single nucleotide substitution of thymine for guanine in the 12th codon through the sequencing of its first axon. We compared the differences of expression and regulation between the transformed Ha-ras cells and untransformed parent cells. Data indicated that the expression of Ha-ras in the transformed cells was five-fold higher than in the untransformed cells and that the Ha-ras gene in the former was hypersensitive toward DNase I. In addition, a nuclear protein of 35 kilodaltons bound strongly to the 2.5 Kb fragment located upstream of the 6.6 Kb Ha-ras gene and contained a CC rich region. These results suggest that there might be another mechanism of activation for the ras gene besides point mutation.展开更多
Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evoluti...Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.展开更多
Background:Despite the availability of chemotherapy drugs such as 5-fluorouracil(5-FU),the treatment of some cancers such as gastric cancer remains challenging due to drug resistance and side effects.This study aimed t...Background:Despite the availability of chemotherapy drugs such as 5-fluorouracil(5-FU),the treatment of some cancers such as gastric cancer remains challenging due to drug resistance and side effects.This study aimed to investigate the effect of celastrol in combination with the chemotherapy drug 5-FU on proliferation and induction of apoptosis in human gastric cancer cell lines(AGS and EPG85-257).Materials and Methods:In this in vitro study,AGS and EPG85-257 cells were treated with different concentrations of celastrol,5-FU,and their combination.Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide(MTT)assay.The synergistic effect of 5-FU and celastrol was studied using Compusyn software.The DNA content at different phases of the cell cycle and apoptosis rate was measured usingflow cytometry.Results:Co-treatment with low concentrations(10%inhibitory concentration(IC10))of celastrol and 5-FU significantly reduced IC50(p<0.05)so that 48 h after treatment,IC50 was calculated at 3.77 and 6.9μM for celastrol,20.7 and 11.6μM for 5-FU,and 5.03 and 4.57μM for their combination for AGS and EPG85-257 cells,respectively.The mean percentage of apoptosis for AGS cells treated with celastrol,5-FU,and their combination was obtained 23.9,41.2,and 61.9,and for EPG85-257 cells 5.65,46.9,and 55.7,respectively.In addition,the 5-FU and celastrol-5-FU combination induced cell cycle arrest in the synthesis phase.Conclusions:Although celastrol could decrease the concentration of 5-fluorouracil that sufficed to suppress gastric cancer cells,additional studies are required to arrive at conclusive evidence on the anticancer effects of celastrol.展开更多
RANKL signaling is essential for osteoclastogenesis. Its role in osteoblastic differentiation and bone formation is unknown. Here we demonstrate that RANK is expressed at an early stage of bone marrow mesenchymal stem...RANKL signaling is essential for osteoclastogenesis. Its role in osteoblastic differentiation and bone formation is unknown. Here we demonstrate that RANK is expressed at an early stage of bone marrow mesenchymal stem cells(BMSCs) during osteogenic differentiation in both mice and human and decreased rapidly. RANKL signaling inhibits osteogenesis by promoting β-catenin degradation and inhibiting its synthesis. In contrast, RANKL signaling has no significant effects on adipogenesis of BMSCs.Interestingly, conditional knockout of rank in BMSCs with Prx1-Cre mice leads to a higher bone mass and increased trabecular bone formation independent of osteoclasts. In addition, rank: Prx1-Cre mice show resistance to ovariectomy-(OVX) induced bone loss. Thus, our results reveal that RANKL signaling regulates both osteoclasts and osteoblasts by inhibition of osteogenic differentiation of BMSCs and promotion of osteoclastogenesis.展开更多
Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint k...Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint kinases,and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells.Given its importance in tumorigenesis,several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents.In this review,we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development,including both pan-CDK inhibitors and CDK4/6-selective inhibitors.In addition,we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.展开更多
Turbot harbor a relatively remarkable ability to adapt to opposing osmotic challenges and are an excellent model species to study the physiological adaptations of flounder associated with osmoregulatory plasticity.The...Turbot harbor a relatively remarkable ability to adapt to opposing osmotic challenges and are an excellent model species to study the physiological adaptations of flounder associated with osmoregulatory plasticity.The kidney transcriptome of turbot treated 24 h in water of hypo-salinity(salinity 5)and seawater(salinity 30)was sequenced and characterized.In silico analysis indicated that all unigenes had significant hits in seven databases.The functional annotation analysis of the transcriptome showed that the immune system and biological processes associated with digestion,absorption,and metabolism played an important role in the osmoregulation of turbot in response to hypo-salinity.Analysis of biological processes associated with inorganic channels and transporters indicated that mineral absorption and bile secretion contributed to iono-osmoregulation resulting in cell volume regulation and cell phenotypic plasticity.Moreover,we analyzed and predicted the mechanisms of canonical signaling transduction.Biological processes involved in renin secretion,ECM-receptor interaction,adherens junction,and focal adhesion played an important role in the plasticity phenotype in hypo-stress,while the signal transduction network composed of the MAPK signaling pathway and PI3K-Akt signaling pathway with GABAergic synapse,worked in hypoosmoregulation signal transduction in the turbot.In addition,analysis of the tissue specificity of targeted gene expression using qPCR during salinity stress was carried out.The results showed that the kidney,gill,and spleen were vital regulating organs of osmotic pressure,and the osmoregulation pattern of euryhaline fish dif fered among species.展开更多
Mutations in the liver/bone/kidney alkaline phosphatase(Alpl) gene cause hypophosphatasia(HPP) and early-onset bone dysplasia,suggesting that this gene is a key factor in human bone development. However, how and where...Mutations in the liver/bone/kidney alkaline phosphatase(Alpl) gene cause hypophosphatasia(HPP) and early-onset bone dysplasia,suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A(p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells(MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in Alpl+/-mice by improving the function of endogenous MSCs.These results identify a previously unknown role of Alpl in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.展开更多
A fundamental problem for cells with their fragile membranes is the control of their volume.The primordial solution to this problem is the active transport of ions across the cell membrane to modulate the intracellula...A fundamental problem for cells with their fragile membranes is the control of their volume.The primordial solution to this problem is the active transport of ions across the cell membrane to modulate the intracellular osmotic pressure.In this work,a theoretical model of the cellular pump-leak mechanism is proposed within the general framework of linear nonequilibrium thermodynamics.The model is expressed with phenomenological equations that describe passive and active ionic transport across cell membranes,supplemented by an equation for the membrane potential that accounts for the electrogenicity of the ionic pumps.For active ionic transport,the model predicts that the intracellular fluid pressure will be balanced by the osmotic pressure and a new pressure component that arises from the active ionic fluxes.A model for the pump-leak mechanism in an idealized human cell is introduced to demonstrate the applicability of the proposed theory.展开更多
Human adipose-derived stem cells(hASCs)are a promising cell type for bone tissue regeneration.Circular RNAs(circRNAs)have been shown to play a critical role in regulating various cell differentiation and involve in me...Human adipose-derived stem cells(hASCs)are a promising cell type for bone tissue regeneration.Circular RNAs(circRNAs)have been shown to play a critical role in regulating various cell differentiation and involve in mesenchymal stem cell osteogenesis.However,how circRNAs regulate hASCs in osteogenesis is still unclear.Herein,we found circ_0003204 was significantly downregulated during osteogenic differentiation of hASCs.Knockdown of circ_0003204 by si RNA or overexpression by lentivirus confirmed circ_0003204 could negatively regulate the osteogenic differentiation of hASCs.We performed dual-luciferase reporting assay and rescue experiments to verify circ_0003204 regulated osteogenic differentiation via sponging miR-370-3p.We predicted and confirmed that miR-370-3p had targets in the 3′-UTR of HDAC4 m RNA.The following rescue experiments indicated that circ_0003204 regulated the osteogenic differentiation of hASCs via miR-370-3p/HDAC4 axis.Subsequent in vivo experiments showed the silencing of circ_0003204 increased the bone formation and promoted the expression of osteogenic-related proteins in a mouse bone defect model,while overexpression of circ_0003204 inhibited bone defect repair.Our findings indicated that circ_0003204 might be a promising target to promote the efficacy of hASCs in repairing bone defects.展开更多
Overexpression of receptor-interacting protein 140(RIP140) promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2(ERK1/2) signaling.However,involvement of RIP140 in human neural dif...Overexpression of receptor-interacting protein 140(RIP140) promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2(ERK1/2) signaling.However,involvement of RIP140 in human neural differentiation remains unclear.We found both RIP140 and ERK1/2 expression increased during neural differentiation of H1 human embryonic stem cells.Moreover,RIP140 negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation,and positively correlated with the neural stem cell marker Nestin during later stages.Thus,ERK1/2 signaling may provide the molecular mechanism by which RIP140 takes part in neural differentiation to eventually affect the number of neurons produced.展开更多
Stem cells possess the ability to divide symmetrically or asymmet- rically to allow for maintenance of the stem cell pool or become committed progenitors and differentiate into various cell lineages. The unique self-r...Stem cells possess the ability to divide symmetrically or asymmet- rically to allow for maintenance of the stem cell pool or become committed progenitors and differentiate into various cell lineages. The unique self-renewal capabilities and pluripotency of stem cells are integral to tissue regeneration and repair (Oh et al., 2014). Mul- tiple mechanisms including intracellular programs and extrinsic cues are reported to regulate neural stem cell (NSC) fate (Bond et al., 2015). A recent study, published in Cell Stern Cell, identified a novel mechanism whereby mitochondrial dynamics drive NSC fate (Khacho et al., 2016).展开更多
Neural stem/progenitor cells:Radial glial cells constitute multipotent cells in the ventricular zone,lining the wall of the lateral ventricle of the embryonic brain.They have the capacity to give rise to cells belong...Neural stem/progenitor cells:Radial glial cells constitute multipotent cells in the ventricular zone,lining the wall of the lateral ventricle of the embryonic brain.They have the capacity to give rise to cells belonging to all three major linages(neurons,astrocytes and oligodendrocytes)of the nervous system(Tang and Illes,2017).展开更多
China’s first general standard for stem cells officially released on November 22,2017 is expected to lay a foundation for regulating the application of stem cells technology.Stem cells are a group of self-renewal cel...China’s first general standard for stem cells officially released on November 22,2017 is expected to lay a foundation for regulating the application of stem cells technology.Stem cells are a group of self-renewal cells that can differentiate into specialized cells.They are now used for the treatment of many diseases.Despite a series of documents for regulating basic research and achievement transformation of stem cells,the clinical application and industrialization still face great challenges due to展开更多
Objective:The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment.This study determined the effects of genetic variations in genes involved in apoptos...Objective:The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment.This study determined the effects of genetic variations in genes involved in apoptosis,pyroptosis,and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy(CRT).Methods:The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT.The associations between genetic variations and overall survival(OS)were evaluated using hazard ratios(HRs)and 95%confidence intervals(CIs)computed using a Cox proportional regression model.Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase(ALOX5)gene and the ALOX5 rs702365 variant.Results:We detected 16 genetic polymorphisms in CASP3,CASP7,TRAILR2,GSDME,CASP4,HO-1,ALOX5,GPX4,and NRF2 that were significantly associated with OS in the additive model(P<0.05).There was a substantial cumulative effect of three genetic polymorphisms(CASP4 rs571407,ALOX5 rs2242332,and HO-1 rs17883419)on OS.Genetic variations in the CASP4 and ALOX5 gene haplotypes were associated with a higher OS.We demonstrated,for the first time,that rs702365[G]>[C]represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response.Conclusions:Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.展开更多
Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancersubtype characterized by the absence of expression of estrogen receptor (ER), progesteronereceptor (PR), and human epidermal grow...Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancersubtype characterized by the absence of expression of estrogen receptor (ER), progesteronereceptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC exhibitsresistance to hormone and HER2-targeted therapy, along with a higher incidence ofrecurrence and poorer prognosis. Therefore, exploring the molecular features of TNBC andconstructing prognostic models are of significant importance for personalized treatmentstrategies. Methods: In this research, bioinformatics approaches were utilized to screendifferentially expressed genes in 405 TNBC cases and 128 normal tissue samples from 8 GEOdatasets. Key core genes and signaling pathways were further identified. Additionally, aprognostic model incorporating seven genes was established using clinical and pathologicalinformation from 169 TNBC cases in the TCGA dataset, and its predictive performance wasevaluated. Results: Functional analysis revealed dysregulated biological processes such asDNA replication, cell cycle, and mitotic chromosome separation in TNBC. Protein-proteininteraction network analysis identified ten core genes, including BUB1, BUB1B, CDK1,CDC20, CDCA8, CCNB1, CCNB2, KIF2C, NDC80, and CENPF. A prognostic model consistingof seven genes (EXO1, SHCBP1, ABRACL, DMD, THRB, DCDC2, and APOD) was establishedusing a step-wise Cox regression analysis. The model demonstrated good predictiveperformance in distinguishing patients' risk. Conclusion: This research provides importantinsights into the molecular characteristics of TNBC and establishes a reliable prognosticmodel for understanding its pathogenesis and predicting prognosis. These findingscontribute to the advancement of personalized treatment for TNBC.展开更多
Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all...Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.展开更多
The authors have investigated the biochemical events by which marine algal virus infection induces cell cycle arrest. The key G 2 /M-phase regulatory proteins are analyzed by immunobloting in unicel-lular Emiliania hu...The authors have investigated the biochemical events by which marine algal virus infection induces cell cycle arrest. The key G 2 /M-phase regulatory proteins are analyzed by immunobloting in unicel-lular Emiliania huxleyi,suggesting that virus induced cell cycle arrest is related with virus's effect on cyclins and cyclin dependent kinases. E. huxleyi virus(EhV) represses Cdc2/cyclinB complex activity by inhibiting the activity of Cdc2 kinase in a phosphorylation-related manner,blocking host cells G 2 /M checkpoint. Dephosphorylated /inactive Cdc25C combined with up-regulation of Wee1 expression at early infect period appears to be important mechanisms by which EhV represses Cdc2/cyclinB complex activity that is required for entry into M phase. This study has allowed us to confirm that algal virus infection leads to selective activation or inhibition of certain cell-cycle factors,which may play a significant role in establishing a more efficient environment for viral gene expression and DNA replication.展开更多
基金Shandong Medical and Health Development Plan(2018WS423).
文摘Extensive in vitro and in vivo research reveals multiple intracellular molecular targets of Antrodia camphorata,and these targets affect growth,apoptosis,angiogenesis,invasion and metastasis of cells.These targets include tumor suppressor,cell cycle regulator,transcription factor,angiogenesis and metastasis factor,apoptosis and survival regulator,etc.Additionally,more and more attention has been paid to the molecular mechanism of A.camphorata on the regulation of tumor stem cells.Meanwhile,there is evidence that the immunoregulation of A.camphorata is enhanced,which may lead cell cycle arrest or apoptosis.In this paper,molecular mechanism of tumor cells and tumor stem cells regulated at multiple targets by A.camphorata in vitro and in vivo in the past decade is summarized.
文摘Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a major challenge in medicine largely because of the limited regenerative capacity of the adult brain.
基金supported by the Helmholtz-Gemeinschaft,“Zukunft-sthema”Immunology and inflammation”(ZT-0027)supported by the Pertermax-Müller-Stiftung and the Niedersachsen Research Network on Neuroinfectiology(N-RENNT)of the Ministry of Science and Culture of Lower Saxony
文摘Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.
文摘An Ha-ras oncogene was isolated from a cell line of gastric carcinoma called BGE-823 in order to elucidate genetic control and the influence of DNA sequences. The oncogene was cloned and identified as a single nucleotide substitution of thymine for guanine in the 12th codon through the sequencing of its first axon. We compared the differences of expression and regulation between the transformed Ha-ras cells and untransformed parent cells. Data indicated that the expression of Ha-ras in the transformed cells was five-fold higher than in the untransformed cells and that the Ha-ras gene in the former was hypersensitive toward DNase I. In addition, a nuclear protein of 35 kilodaltons bound strongly to the 2.5 Kb fragment located upstream of the 6.6 Kb Ha-ras gene and contained a CC rich region. These results suggest that there might be another mechanism of activation for the ras gene besides point mutation.
基金supported by the National Natural Science Foundation of China,No.81501106(to CF)Fund of Taishan Scholar Project(to CF)+1 种基金the Natural Science Foundation of Shandong Province,No.ZR2020QH106(to YH)the Medical and Health Science and Technology Development Plan of Shandong Province,No.202203010799(to QS)。
文摘Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.
基金supported by Shahrekord University of Medical Sciences,Shahrekord,Iran(Ethics Code:IR.SKUMS.REC.1397.119,Grant No.3696 and Ethics Code:IR.SKUMS.REC.1401.197,Grant No.6651).
文摘Background:Despite the availability of chemotherapy drugs such as 5-fluorouracil(5-FU),the treatment of some cancers such as gastric cancer remains challenging due to drug resistance and side effects.This study aimed to investigate the effect of celastrol in combination with the chemotherapy drug 5-FU on proliferation and induction of apoptosis in human gastric cancer cell lines(AGS and EPG85-257).Materials and Methods:In this in vitro study,AGS and EPG85-257 cells were treated with different concentrations of celastrol,5-FU,and their combination.Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide(MTT)assay.The synergistic effect of 5-FU and celastrol was studied using Compusyn software.The DNA content at different phases of the cell cycle and apoptosis rate was measured usingflow cytometry.Results:Co-treatment with low concentrations(10%inhibitory concentration(IC10))of celastrol and 5-FU significantly reduced IC50(p<0.05)so that 48 h after treatment,IC50 was calculated at 3.77 and 6.9μM for celastrol,20.7 and 11.6μM for 5-FU,and 5.03 and 4.57μM for their combination for AGS and EPG85-257 cells,respectively.The mean percentage of apoptosis for AGS cells treated with celastrol,5-FU,and their combination was obtained 23.9,41.2,and 61.9,and for EPG85-257 cells 5.65,46.9,and 55.7,respectively.In addition,the 5-FU and celastrol-5-FU combination induced cell cycle arrest in the synthesis phase.Conclusions:Although celastrol could decrease the concentration of 5-fluorouracil that sufficed to suppress gastric cancer cells,additional studies are required to arrive at conclusive evidence on the anticancer effects of celastrol.
基金supported by the National Natural Science Foundation (NNSF) Key Research Program in Aging (91749204)National Natural Science Foundation of China (81871099, 31370958, 81701364, 81771491, 81501052)+1 种基金Shanghai Municipal Science and Technology Commission Key Program (15411950600, 18431902300)Municipal Human Resources Development Program for Outstanding Leaders in Medical Disciplines in Shanghai (2017BR011)
文摘RANKL signaling is essential for osteoclastogenesis. Its role in osteoblastic differentiation and bone formation is unknown. Here we demonstrate that RANK is expressed at an early stage of bone marrow mesenchymal stem cells(BMSCs) during osteogenic differentiation in both mice and human and decreased rapidly. RANKL signaling inhibits osteogenesis by promoting β-catenin degradation and inhibiting its synthesis. In contrast, RANKL signaling has no significant effects on adipogenesis of BMSCs.Interestingly, conditional knockout of rank in BMSCs with Prx1-Cre mice leads to a higher bone mass and increased trabecular bone formation independent of osteoclasts. In addition, rank: Prx1-Cre mice show resistance to ovariectomy-(OVX) induced bone loss. Thus, our results reveal that RANKL signaling regulates both osteoclasts and osteoblasts by inhibition of osteogenic differentiation of BMSCs and promotion of osteoclastogenesis.
文摘Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint kinases,and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells.Given its importance in tumorigenesis,several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents.In this review,we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development,including both pan-CDK inhibitors and CDK4/6-selective inhibitors.In addition,we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.
基金Supported by the Earmarked Fund for Modern Agro-Industry Technology Research System(No.CARS-47-G01)the Ao Shan Talents Cultivation Program supported by Qingdao National Laboratory for Marine Science and Technology(No.2017ASTCP-OS04)+3 种基金the National Natural Science Foundation of China(No.41706168)the Agricultural Fine Breed Project of Shandong(No.2019LZGC013)the Basal Research Fund,Chinese Academy of Fishery Sciences(No.2016HY-JC0301)the Yantai Science and Technology Project(No.2018ZDCX021)
文摘Turbot harbor a relatively remarkable ability to adapt to opposing osmotic challenges and are an excellent model species to study the physiological adaptations of flounder associated with osmoregulatory plasticity.The kidney transcriptome of turbot treated 24 h in water of hypo-salinity(salinity 5)and seawater(salinity 30)was sequenced and characterized.In silico analysis indicated that all unigenes had significant hits in seven databases.The functional annotation analysis of the transcriptome showed that the immune system and biological processes associated with digestion,absorption,and metabolism played an important role in the osmoregulation of turbot in response to hypo-salinity.Analysis of biological processes associated with inorganic channels and transporters indicated that mineral absorption and bile secretion contributed to iono-osmoregulation resulting in cell volume regulation and cell phenotypic plasticity.Moreover,we analyzed and predicted the mechanisms of canonical signaling transduction.Biological processes involved in renin secretion,ECM-receptor interaction,adherens junction,and focal adhesion played an important role in the plasticity phenotype in hypo-stress,while the signal transduction network composed of the MAPK signaling pathway and PI3K-Akt signaling pathway with GABAergic synapse,worked in hypoosmoregulation signal transduction in the turbot.In addition,analysis of the tissue specificity of targeted gene expression using qPCR during salinity stress was carried out.The results showed that the kidney,gill,and spleen were vital regulating organs of osmotic pressure,and the osmoregulation pattern of euryhaline fish dif fered among species.
基金financially supported by grants from the Nature Science Foundation of China (81620108007)National Key Research and Development Program of China (2016YFC1101400)+1 种基金Nature Science Foundation of China (31571532, 31601099)National Institutes of Health, Department of Health and Human Services (R01DE017449 to S.S.)
文摘Mutations in the liver/bone/kidney alkaline phosphatase(Alpl) gene cause hypophosphatasia(HPP) and early-onset bone dysplasia,suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A(p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells(MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in Alpl+/-mice by improving the function of endogenous MSCs.These results identify a previously unknown role of Alpl in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.
文摘A fundamental problem for cells with their fragile membranes is the control of their volume.The primordial solution to this problem is the active transport of ions across the cell membrane to modulate the intracellular osmotic pressure.In this work,a theoretical model of the cellular pump-leak mechanism is proposed within the general framework of linear nonequilibrium thermodynamics.The model is expressed with phenomenological equations that describe passive and active ionic transport across cell membranes,supplemented by an equation for the membrane potential that accounts for the electrogenicity of the ionic pumps.For active ionic transport,the model predicts that the intracellular fluid pressure will be balanced by the osmotic pressure and a new pressure component that arises from the active ionic fluxes.A model for the pump-leak mechanism in an idealized human cell is introduced to demonstrate the applicability of the proposed theory.
基金supported by grants from the National Natural Science Foundation of China(82071150,82170934,81870743,8190104 and 82171001)。
文摘Human adipose-derived stem cells(hASCs)are a promising cell type for bone tissue regeneration.Circular RNAs(circRNAs)have been shown to play a critical role in regulating various cell differentiation and involve in mesenchymal stem cell osteogenesis.However,how circRNAs regulate hASCs in osteogenesis is still unclear.Herein,we found circ_0003204 was significantly downregulated during osteogenic differentiation of hASCs.Knockdown of circ_0003204 by si RNA or overexpression by lentivirus confirmed circ_0003204 could negatively regulate the osteogenic differentiation of hASCs.We performed dual-luciferase reporting assay and rescue experiments to verify circ_0003204 regulated osteogenic differentiation via sponging miR-370-3p.We predicted and confirmed that miR-370-3p had targets in the 3′-UTR of HDAC4 m RNA.The following rescue experiments indicated that circ_0003204 regulated the osteogenic differentiation of hASCs via miR-370-3p/HDAC4 axis.Subsequent in vivo experiments showed the silencing of circ_0003204 increased the bone formation and promoted the expression of osteogenic-related proteins in a mouse bone defect model,while overexpression of circ_0003204 inhibited bone defect repair.Our findings indicated that circ_0003204 might be a promising target to promote the efficacy of hASCs in repairing bone defects.
基金supported by the National Natural Science Foundation of China,No.31340024
文摘Overexpression of receptor-interacting protein 140(RIP140) promotes neuronal differentiation of N2 a cells via extracellular regulated kinase 1/2(ERK1/2) signaling.However,involvement of RIP140 in human neural differentiation remains unclear.We found both RIP140 and ERK1/2 expression increased during neural differentiation of H1 human embryonic stem cells.Moreover,RIP140 negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation,and positively correlated with the neural stem cell marker Nestin during later stages.Thus,ERK1/2 signaling may provide the molecular mechanism by which RIP140 takes part in neural differentiation to eventually affect the number of neurons produced.
基金AJ-A is a Fonds de recherche du Québec-Santé(FRQS)scholarsupported by a grant from Natural Sciences and Engineering Research Council of Canada(NSERC RGPIN-2016-06605)
文摘Stem cells possess the ability to divide symmetrically or asymmet- rically to allow for maintenance of the stem cell pool or become committed progenitors and differentiate into various cell lineages. The unique self-renewal capabilities and pluripotency of stem cells are integral to tissue regeneration and repair (Oh et al., 2014). Mul- tiple mechanisms including intracellular programs and extrinsic cues are reported to regulate neural stem cell (NSC) fate (Bond et al., 2015). A recent study, published in Cell Stern Cell, identified a novel mechanism whereby mitochondrial dynamics drive NSC fate (Khacho et al., 2016).
基金supported by Deutsche Forschungsgemeinschaft(DFGIL 20/21-1)Sino-German Centre(GZ919)
文摘Neural stem/progenitor cells:Radial glial cells constitute multipotent cells in the ventricular zone,lining the wall of the lateral ventricle of the embryonic brain.They have the capacity to give rise to cells belonging to all three major linages(neurons,astrocytes and oligodendrocytes)of the nervous system(Tang and Illes,2017).
文摘China’s first general standard for stem cells officially released on November 22,2017 is expected to lay a foundation for regulating the application of stem cells technology.Stem cells are a group of self-renewal cells that can differentiate into specialized cells.They are now used for the treatment of many diseases.Despite a series of documents for regulating basic research and achievement transformation of stem cells,the clinical application and industrialization still face great challenges due to
基金supported by grants from the National Natural Science Foundation(Grant No.81972859 to WT)CAMS Innovation Fund for Medical Sciences(CIFMS)(Grant No.2019-I2M-1-003 to WT)the State Key Laboratory of Molecular Oncology Grant(Grant No.SKLMO-2021-03 to WT).
文摘Objective:The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment.This study determined the effects of genetic variations in genes involved in apoptosis,pyroptosis,and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy(CRT).Methods:The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT.The associations between genetic variations and overall survival(OS)were evaluated using hazard ratios(HRs)and 95%confidence intervals(CIs)computed using a Cox proportional regression model.Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase(ALOX5)gene and the ALOX5 rs702365 variant.Results:We detected 16 genetic polymorphisms in CASP3,CASP7,TRAILR2,GSDME,CASP4,HO-1,ALOX5,GPX4,and NRF2 that were significantly associated with OS in the additive model(P<0.05).There was a substantial cumulative effect of three genetic polymorphisms(CASP4 rs571407,ALOX5 rs2242332,and HO-1 rs17883419)on OS.Genetic variations in the CASP4 and ALOX5 gene haplotypes were associated with a higher OS.We demonstrated,for the first time,that rs702365[G]>[C]represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response.Conclusions:Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.
文摘Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancersubtype characterized by the absence of expression of estrogen receptor (ER), progesteronereceptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC exhibitsresistance to hormone and HER2-targeted therapy, along with a higher incidence ofrecurrence and poorer prognosis. Therefore, exploring the molecular features of TNBC andconstructing prognostic models are of significant importance for personalized treatmentstrategies. Methods: In this research, bioinformatics approaches were utilized to screendifferentially expressed genes in 405 TNBC cases and 128 normal tissue samples from 8 GEOdatasets. Key core genes and signaling pathways were further identified. Additionally, aprognostic model incorporating seven genes was established using clinical and pathologicalinformation from 169 TNBC cases in the TCGA dataset, and its predictive performance wasevaluated. Results: Functional analysis revealed dysregulated biological processes such asDNA replication, cell cycle, and mitotic chromosome separation in TNBC. Protein-proteininteraction network analysis identified ten core genes, including BUB1, BUB1B, CDK1,CDC20, CDCA8, CCNB1, CCNB2, KIF2C, NDC80, and CENPF. A prognostic model consistingof seven genes (EXO1, SHCBP1, ABRACL, DMD, THRB, DCDC2, and APOD) was establishedusing a step-wise Cox regression analysis. The model demonstrated good predictiveperformance in distinguishing patients' risk. Conclusion: This research provides importantinsights into the molecular characteristics of TNBC and establishes a reliable prognosticmodel for understanding its pathogenesis and predicting prognosis. These findingscontribute to the advancement of personalized treatment for TNBC.
基金supported by the National Natural Science Foundation of China,Nos.81772134(to KX),81971891(to KX),82172196(to KX),81571939(to KX)the Fundamental Research Funds for the Central Universities of Central South University of China,No.2020zzts218,(to WTY)Hunan Provincial Innovation Foundation For Postgraduate of China,Nos.CX20200116(to WTY),CX20190139(to LSL).
文摘Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.
基金The National High Technology Research and Development Program of China under contract No. 2008AA09Z408the National Natural Science Foundation of China under contract Nos 40930847, 30940002 and 40876061+1 种基金Fujian Province Natural Science Foundation, China under contract No. 2010J01261the Foundation for Innovative Research Team of Jimei University, China under contract No. 2010A007
文摘The authors have investigated the biochemical events by which marine algal virus infection induces cell cycle arrest. The key G 2 /M-phase regulatory proteins are analyzed by immunobloting in unicel-lular Emiliania huxleyi,suggesting that virus induced cell cycle arrest is related with virus's effect on cyclins and cyclin dependent kinases. E. huxleyi virus(EhV) represses Cdc2/cyclinB complex activity by inhibiting the activity of Cdc2 kinase in a phosphorylation-related manner,blocking host cells G 2 /M checkpoint. Dephosphorylated /inactive Cdc25C combined with up-regulation of Wee1 expression at early infect period appears to be important mechanisms by which EhV represses Cdc2/cyclinB complex activity that is required for entry into M phase. This study has allowed us to confirm that algal virus infection leads to selective activation or inhibition of certain cell-cycle factors,which may play a significant role in establishing a more efficient environment for viral gene expression and DNA replication.