Objective: To investigate the anti-depression mechanism of JiaWeiWenDan Decoction in regulating p38MAPK-ERK5 signal transduction pathway. Methods: Depression model rats were randomly divided into Blank Control Group, ...Objective: To investigate the anti-depression mechanism of JiaWeiWenDan Decoction in regulating p38MAPK-ERK5 signal transduction pathway. Methods: Depression model rats were randomly divided into Blank Control Group, Model Control Group, Chinese Medicine Treatment Group, and Western Medicine Treatment Group (hereinafter referred to as Blank Group, Model Group, Chinese Medicine Group, and Western Medicine Group), with 48 rats in each group. The mice were treated with p38MAPK-ERK5 on the 7th day, 14th day and 21st day, respectively, and the mice were treated for 28 days. The key targets and cytokines in p38MAPK-ERK5 signal transduction pathway were detected. Results: Compared with the Blank Group, the expression of p38MAPKmRNA in the hippocampus of the Model Group was increased. The Chinese Medicine Group and Western Medicine Group could reduce the expression of p38MAPK mRNA (P P P P Conclusion: The anti-inflammatory effect of JiaWeiWenDan Decoction may be related to the regulation of p38MAPK-ERK5 signaling pathway. With the advance of the treatment week, the best effect was obtained when the treatment was started on the 7th day of modeling.展开更多
Cold stress responses help insects to survive under low temperatures that would be lethal otherwise.This phenomenon might contribute to the invasion of some Bemisia tabaci cryptic species from subtropical areas to tem...Cold stress responses help insects to survive under low temperatures that would be lethal otherwise.This phenomenon might contribute to the invasion of some Bemisia tabaci cryptic species from subtropical areas to temperate regions.However,the molecular mechanisms regulating cold stress responses in whitefly are yet unclear.Mitogen-activated protein kinases(MAPKs)which including p38,ERK,and JNK,are well known for their roles in regulating metabolic responses to cold stress in many insects.In this study,we explored the possible roles of the MAPKs in response to low temperature stresses in the Mediterranean cryptic species(the Q-biotype)of the B.tabaci species complex.First,we cloned the p38 and ERK genes from the whitefly cDNA library.Next,we analyzed the activation of MAPKs during cold stress in the Mediterranean cryptic species by immuno-blotting.After cold stress,the level of phospho-p38 increased but no significant change was observed in the phosphorylation of ERK and JNK,thus suggesting that the p38 might be responsible for the defense response to low temperature stress.Furthermore,we demonstrated that:i)3 min chilling at 0°C was sufficient for the activation of p38 MAPK pathway in this whitefly;and ii)the amount of phosphorylated p38 increased significantly in the first 20 min of chilling,reversed by 60 min,and then returned to the original level by 120 min.Taken together,our results suggest that the p38 pathway is important during response to low temperature stress in the Mediterranean cryptic species of the B.tabaci species complex.展开更多
Signal transduction is an important and basic mechanism to cell life activities.The stochastic state transition of receptor induces the release of signaling molecular,which triggers the state transition of other recep...Signal transduction is an important and basic mechanism to cell life activities.The stochastic state transition of receptor induces the release of signaling molecular,which triggers the state transition of other receptors.It constructs a nonlinear sigaling network,and leads to robust switchlike properties which are critical to biological function.Network architectures and state transitions of receptor affect the performance of this biological network.In this work,we perform a study of nonlinear signaling on biological polymorphic network by analyzing network dynamics of the Ca^(2+)-induced Ca^(2+)release(CICR)mechanism,where fast and slow processes are involved and the receptor has four conformational states.Three types of networks,Erdos–R´enyi(ER)network,Watts–Strogatz(WS)network,and BaraB´asi–Albert(BA)network,are considered with different parameters.The dynamics of the biological networks exhibit different patterns at different time scales.At short time scale,the second open state is essential to reproduce the quasi-bistable regime,which emerges at a critical strength of connection for all three states involved in the fast processes and disappears at another critical point.The pattern at short time scale is not sensitive to the network architecture.At long time scale,only monostable regime is observed,and difference of network architectures affects the results more seriously.Our finding identifies features of nonlinear signaling networks with multistate that may underlie their biological function.展开更多
Metamorphosis is a complex developmental process involving multiple pathways and a large number of genes that are regulated by juvenile hormone(JH)and 20-hydroxyecdysone(20E).Despite important progress in understandin...Metamorphosis is a complex developmental process involving multiple pathways and a large number of genes that are regulated by juvenile hormone(JH)and 20-hydroxyecdysone(20E).Despite important progress in understanding various aspects of silkworm biology,the hormone signaling pathway in the silkworm remains poorly understood.Genome-wide screening using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)-based libraries has recently emerged as a novel method for analyzing genome function,enabling further research into essential genes,drug targets,and virus-host interaction.Previously,we constructed a genome-wide CRISPR/Cas9-based library of the silkworm(Bombyx mori)and successfully revealed the genes involved in biotic or abiotic stress factor responses.In this study,we used our silkworm CRISPR library and large-scale genome-wide screening to analyze the key genes in the silkworm 20E signaling pathway and their mechanisms of action.Functional annotation showed that 20E regulates key proteins in processes that mainly occur in the cytoplasm and nucleus.Pathway enrichment analysis showed that 20E can activate phosphorylation and may affect innate immunity,interfere with intracellular nutrition and energy metabolism,and eventually cause cell apoptosis.The screening results were experimentally validated by generating cells with knockout alleles of the relevant genes,which had increased tolerance to 20E.Our findings provide a panoramic overview of signaling in response to 20E in the silkworm,underscoring the utility of genome-wide CRISPR mutant libraries in deciphering hormone signaling pathways and the mechanisms that regulate metamorphosis in insects.展开更多
Signal transduction across lipid bilayers is of profound importance in biological processes.In biological systems,natural enzymes mediate biochemical effects by binding to substrates and facilitating the conversion of...Signal transduction across lipid bilayers is of profound importance in biological processes.In biological systems,natural enzymes mediate biochemical effects by binding to substrates and facilitating the conversion of external signals into physiological responses.Sequential transmission of biological signals from one enzyme to the next promotes signal transduction with feedforward and feedback mechanisms.Reconstructing these processes in an artificial system provides potential applications and offers a new way to understand fundamental biological processes in depth.However,the design of artificial signal transduction systems regulated by artificial enzyme receptors in a predictable and intelligent manner remains a challenge.Herein,benefiting from the polarity-regulated characteristics of Se-containing compounds with artificial glutathione peroxidase(GPx)activity,we constructed an artificial transmembrane signaling receptor with a Se-containing GPx-like recognition head group,a membrane-anchoring group,and a pre-enzyme end group.The artificial supramolecular signal transduction system containing such signal transduction receptors extends the range of signaling systems based on enzyme regulation,which provides a new way to study natural signal processes in cells and artificially regulated biological processes.展开更多
Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^...Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.展开更多
Following injury,tissue autonomously initiates a complex repair process,resulting in either partial recovery or regeneration of tissue architecture and function in most organisms.Both the repair and regeneration proce...Following injury,tissue autonomously initiates a complex repair process,resulting in either partial recovery or regeneration of tissue architecture and function in most organisms.Both the repair and regeneration processes are highly coordinated by a hierarchy of interplay among signal transduction pathways initiated by different growth factors,cytokines and other signaling molecules under normal conditions.However,under chronic traumatic or pathological conditions,the reparative or regenerative process of most tissues in different organs can lose control to different extents,leading to random,incomplete or even flawed cell and tissue reconstitution and thus often partial restoration of the original structure and function,accompanied by the development of fibrosis,scarring or even pathogenesis that could cause organ failure and death of the organism.Ample evidence suggests that the various combinatorial fibroblast growth factor(FGF)and receptor signal transduction systems play prominent roles in injury repair and the remodeling of adult tissues in addition to embryonic development and regulation of metabolic homeostasis.In this review,we attempt to provide a brief update on our current understanding of the roles,the underlying mechanisms and clinical application of FGFs in tissue injury repair.展开更多
Protein kinase C epsilon(PKCε)is one of major isoforms in novel PKC family.Although it has been extensively characterized in the past decade,the role of PKCεin neuron is still not well understood.Advances in molecul...Protein kinase C epsilon(PKCε)is one of major isoforms in novel PKC family.Although it has been extensively characterized in the past decade,the role of PKCεin neuron is still not well understood.Advances in molecular biology have now removed significant barriers to the direct investigation of PKCεfunctions in vivo,and PKCεhas been increasingly implicated in the neural biological functions and associated neurogenic diseases.Recent studies have provided important insights into the influence of PKCεon cortical processing at both the single cell level and network level.These studies provide compelling evidence that PKCεcould regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKCεsignal pathway in the developing brain.展开更多
Like olfaction,the sense of taste allows the detection and discrimination of chemicals in the environment.However,while olfaction is specialized in the detection of volatile chemicals,taste is restricted to the detect...Like olfaction,the sense of taste allows the detection and discrimination of chemicals in the environment.However,while olfaction is specialized in the detection of volatile chemicals,taste is restricted to the detection of contact-chemicals.Two families of mammalian taste receptors,T1R and T2R,involved in recognition of sweet,umami(the taste of monosodium glutamate)and bitter stimuli have been identified and characterized.Although much progress has been made in studies on the basic mechanisms of taste recognition and signal transduction in mammals,we are still far from a full understanding of different taste qualities.This review presents a current perspective on sweet,bitter and umami taste receptors and their signal transduction mechanism.We also discuss the evolution of taste and taste-related molecules.展开更多
This paper aims to investigate the effects of Zhihuang(枳黄)decoction on CD14 expression in the lipopolysaccharide signal transduction pathway of alcohol-induced liver disease in rats.Seventy-five Wistar rats were rand...This paper aims to investigate the effects of Zhihuang(枳黄)decoction on CD14 expression in the lipopolysaccharide signal transduction pathway of alcohol-induced liver disease in rats.Seventy-five Wistar rats were randomly divided into three groups.Ethanol(56%,weight/volumn)was intragastrically administrated to 50 rats(14 mL/kg body weight per day)for 10 days to establish a model of alcohol-induced liver disease,and 25 of these 50 rats were treated with Zhihuang decoction simulta-neously.Liver injury was evaluated by biochemical examination.The plasma content of endotoxin was assayed by biochemistry.The expression of CD14 mRNA and protein in rat liver was measured by reverse transcription polymerase chain reaction and immunohis-tochemistry,respectively.Zhihuang decoction pretreat-ment significantly protected against acute alcohol-induced liver injury,which was evidenced by the decrease of elevated serum alanine aminotransferase and aspartate aminotransferase.In addition,the level of plasma endo-toxin and up-regulation of CD14 was also suppressed by Zhihuang decoction in alcohol-intoxicated rats.Zhihuang decoction can significantly reduce CD14 expression in the lipopolysaccharide signal transduction pathway,which is one of the most important mechanisms of Zhihuang decoction to treat hepatic injury induced by alcohol in rats.展开更多
Fos-related antigen 1(Fra-1)is a nuclear transcription factor that regulates cell growth,differentiation,and apoptosis.It is involved in the proliferation,invasion,apoptosis and epithelial mesenchymal transformation o...Fos-related antigen 1(Fra-1)is a nuclear transcription factor that regulates cell growth,differentiation,and apoptosis.It is involved in the proliferation,invasion,apoptosis and epithelial mesenchymal transformation of malignant tumor cells.Fra-1 is highly expressed in gastric cancer(GC),affects the cycle distribution and apoptosis of GC cells,and participates in GC occurrence and development.However,the detailed mechanism of Fra-1 in GC is unclear,such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis.In this study,we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta(YWHAH)as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry.Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression,and affected GC cell proliferation.Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1(HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway in GC cells.Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation.These results will help to discover new molecular targets for the early diagnosis,treatment,and prognosis prediction of GC.展开更多
Scaffold proteins are crucial regulators of signaling networks,and their abnormal expression may favor the development of tumors.Among the scaffold proteins,immunophilin covers a unique role as‘protein-philin’(Greek...Scaffold proteins are crucial regulators of signaling networks,and their abnormal expression may favor the development of tumors.Among the scaffold proteins,immunophilin covers a unique role as‘protein-philin’(Greek‘philin’=friend)that interacts with proteins to guide their proper assembly.The growing list of human syndromes associated with the immunophilin defect underscores the biological relevance of these proteins that are largely opportunistically exploited by cancer cells to support and enable the tumor’s intrinsic properties.Among the members of the immunophilin family,the FKBP5 gene was the only one identified to have a splicing variant.Cancer cells impose unique demands on the splicing machinery,thus acquiring a particular susceptibility to splicing inhibitors.This review article aims to overview the current knowledge of the FKBP5 gene functions in human cancer,illustrating how cancer cells exploit the scaffolding function of canonical FKBP51 to foster signaling networks that support their intrinsic tumor properties and the spliced FKBP51s to gain the capacity to evade the immune system.展开更多
BACKGROUND The development of cancer is thought to involve the dynamic crosstalk between the tumor cells and the microenvironment they inhabit.Such crosstalk is thought to involve mechanotransduction,a process whereby...BACKGROUND The development of cancer is thought to involve the dynamic crosstalk between the tumor cells and the microenvironment they inhabit.Such crosstalk is thought to involve mechanotransduction,a process whereby the cells sense mechanical cues such as stiffness,and translate these into biochemical signals,which have an impact on the subsequent cellular activities.Bibliometric analysis is a statistical method that involves investigating different aspects(including authors’names and affiliations,article keywords,journals and citations)of large volumes of literature.Despite an increase in mechanotransduction-related research in recent years,there are currently no bibliometric studies that describe the global status and trends of mechanotransduction-related research in the cancer field.AIM To investigate the global research status and trends of mechanotransduction in cancer from a bibliometric viewpoint.METHODS Literature on mechanotransduction in cancer published from January 1,1900 to December 31,2022 was retrieved from the Web of Science Core Collection.Excel and GraphPad software carried out the statistical analysis of the relevant author,journal,organization,and country information.The co-authorship,keyword cooccurrence,and keyword burst analysis were visualized with VOSviewer and CiteSpace.RESULTS Of 597 publications from 745 institutions in 45 countries were published in 268 journals with 35510 citation times.With 270 articles,the United States is a well-established global leader in this field,and the University of California system,the most productive(n=36)and influential institution(n=4705 citations),is the most highly active in collaborating with other organizations.Cancers was the most frequent publisher with the highest H-index.The most productive researcher was Valerie M.Weaver,with 10 publications.The combined analysis of concurrent and burst keywords revealed that the future research hotspots of mechanotransduction in cancer were related to the plasma membrane,autophagy,piezo1/2,heterogeneity,cancer diagnosis,and post-transcriptional modifications.CONCLUSION Mechanotransduction-related cancer research remains a hot topic.The United States is in the leading position of global research on mechano-oncology after almost 30 years of investigations.Research group cooperations exist but remain largely domestic,lacking cross-national communications.The next big topic in this field is to explore how the plasma membrane and its localized mechanosensor can transduce mechanical force through post-transcriptional modifications and thereby participate in cellular activity regulations and cancer development.展开更多
As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and dis...As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and disorders have been linked to imbalances in mTOR's regulatory systems.Multiple mTOR inhibitor therapy has recently acquired popularity as a method of treating cancers brought on by abnormal signal transduction pathways.We also explore potential processes behind tumor cell resistance to mTOR inhibitors and suggest workarounds to overcome this challenge.We hold the potential to pioneer cutting-edge methods for tumor therapy by methodically examining the complex mTOR signaling system and its regulatory complexity.Increasing our knowledge of mTOR-related mechanisms not only creates opportunities for cutting-edge methods to target and treat cancers but also has the potential to improve patient outcomes and general quality of life significantly.This review paper explores the most recent developments in understanding mTOR signaling pathways and the use of mTOR inhibitors in treating tumors.展开更多
Cellular biological activities are tightly controlled by intracellular signaling processes initiated by extracellular signals. Protein tyrosine phosphatases, which remove phosphate groups from phosphorylated signaling...Cellular biological activities are tightly controlled by intracellular signaling processes initiated by extracellular signals. Protein tyrosine phosphatases, which remove phosphate groups from phosphorylated signaling molecules, play equally important tyrosine roles as protein tyrosine kinases in signal transduction. SHP-2, a cytoplajsmic SH2 domain containing protein tyrosine phosphatase, is involved in the signaling pathways of a variety of growth factors and cytokines. Recent studies have clearly demonstrated that this phosphatase plays an important role in transducing signal relay from the cell surface to the nucleus, and is a critical intracellular regulator in mediating cell proliferation and differentiation.展开更多
Detailed mechanisms behind regeneration after nerve injury, in particular signal transduction and the fate of Schwann cells(SCs), are poorly understood. Here, we investigated axotomy-induced activation of extracellula...Detailed mechanisms behind regeneration after nerve injury, in particular signal transduction and the fate of Schwann cells(SCs), are poorly understood. Here, we investigated axotomy-induced activation of extracellular-signal-regulated kinase-1/2(ERK1/2; important for proliferation) and m-calpain in vitro, and the relation to Ca2+ deletion and Schwann cell proliferation and death after rat sciatic nerve axotomy. Nerve segments were cultured for up to 72 hours with and without ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid(EGTA). In some experiments, 5-bromo-2′-deoxyuridine(Brd U) was added during the last 24 hours to detect proliferating cells and propidium iodide(PI) was added at the last hour to detect dead and/or dying cells. Immunohistochemistry of sections of the cultured nerve segments was performed to label m-calpain and the phosphorylated and activated form of ERK1/2. The experiments revealed that immunoreactivity for p-ERK1/2 increased with time in organotypically cultured SCs. p-ERK1/2 and m-calpain were also observed in axons. A significant increase in the number of dead or dying SCs was observed in nerve segments cultured for 24 hours. When deprived of Ca2+, activation of axonal m-calpain was reduced, whereas p-ERK1/2 was increased in SCs. Ca2+ deprivation also significantly reduced the number of proliferating SCs, and instead increased the number of dead or dying SCs. Ca2+ seems to play an important role in activation of ERK1/2 in SCs and in SC survival and proliferation. In addition, extracellular Ca2+ levels are also required for m-calpain activation and up-regulation in axons. Thus, regulation of Ca2+ levels is likely to be a useful method to promote SC proliferation.展开更多
Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,ti...Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.展开更多
Objective To determine whether transforming growth factor betal (TGF-β1)/Smad signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines.Methods Three human hepatic carcinoma cell lines, HepG2, Huh-7, ...Objective To determine whether transforming growth factor betal (TGF-β1)/Smad signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines.Methods Three human hepatic carcinoma cell lines, HepG2, Huh-7, and Hep3B, were used in this study.TGF-β1-induced apoptosis in hepatic carcinoma cell lines was analyzed using TUNEL assay.For identifying the mechanism of apoptosis induced by TGF-β1, cell lines were transfected with a TGF-β1-inducible luciferase reportor plasmid containing Smad4 binding elements.After transfection, cells were treated with TGF-β1, then assayed for luciferase activity.Results The apoptosis rate of HepG2 cell lines (48.51%± 8.21%) was significantly higher than control ( 12.72%±2.18%, P<0.05).But TGF-β1 was not able to induce apoptosis of Huh-7 and Hep3B cell lines.The relative luciferase activity of TGF-β1-treated HepG2 cell lines (4.38) was significantly higher than control (1.00, P< 0.05).But the relative luciferase activity of TGF-β1-treated Huh-7 and Hep3B cell lines less increased compared with control.Conclusions HepG2 cells seem to be highly susceptible to TGF-β1-induced apoptosis compared with Hep3B and Huh-7 cell lines.Smad4 is a central mediator of TGF-β1 signaling transdution pathway.TGF-β1/Smad signaling pathway might mediate p53-dependent apoptosis in hepatoma cell lines.展开更多
Dynamic protein-protein interactions are essential for proper cell functioning.Homointeraction events—physical interactions between the same type of proteins—represent a pivotal subset of protein-protein interaction...Dynamic protein-protein interactions are essential for proper cell functioning.Homointeraction events—physical interactions between the same type of proteins—represent a pivotal subset of protein-protein interactions that are widely exploited in activating intracellular signaling pathways.Capacities of modulating protein-protein interactions with spatial and temporal resolution are greatly desired to decipher the dynamic nature of signal transduction mechanisms.The emerging optogenetic technology,based on genetically encoded light-sensitive proteins,provides promising opportunities to dissect the highly complex signaling networks with unmatched specificity and spatiotemporal precision.Here we review recent achievements in the development of optogenetic tools enabling light-inducible protein-protein homo-interactions and their applications in optical activation of signaling pathways.展开更多
文摘Objective: To investigate the anti-depression mechanism of JiaWeiWenDan Decoction in regulating p38MAPK-ERK5 signal transduction pathway. Methods: Depression model rats were randomly divided into Blank Control Group, Model Control Group, Chinese Medicine Treatment Group, and Western Medicine Treatment Group (hereinafter referred to as Blank Group, Model Group, Chinese Medicine Group, and Western Medicine Group), with 48 rats in each group. The mice were treated with p38MAPK-ERK5 on the 7th day, 14th day and 21st day, respectively, and the mice were treated for 28 days. The key targets and cytokines in p38MAPK-ERK5 signal transduction pathway were detected. Results: Compared with the Blank Group, the expression of p38MAPKmRNA in the hippocampus of the Model Group was increased. The Chinese Medicine Group and Western Medicine Group could reduce the expression of p38MAPK mRNA (P P P P Conclusion: The anti-inflammatory effect of JiaWeiWenDan Decoction may be related to the regulation of p38MAPK-ERK5 signaling pathway. With the advance of the treatment week, the best effect was obtained when the treatment was started on the 7th day of modeling.
基金supported by the National Natural Science Foundation of China(30730061)the National Basic Research Program of China(2009CB119203)
文摘Cold stress responses help insects to survive under low temperatures that would be lethal otherwise.This phenomenon might contribute to the invasion of some Bemisia tabaci cryptic species from subtropical areas to temperate regions.However,the molecular mechanisms regulating cold stress responses in whitefly are yet unclear.Mitogen-activated protein kinases(MAPKs)which including p38,ERK,and JNK,are well known for their roles in regulating metabolic responses to cold stress in many insects.In this study,we explored the possible roles of the MAPKs in response to low temperature stresses in the Mediterranean cryptic species(the Q-biotype)of the B.tabaci species complex.First,we cloned the p38 and ERK genes from the whitefly cDNA library.Next,we analyzed the activation of MAPKs during cold stress in the Mediterranean cryptic species by immuno-blotting.After cold stress,the level of phospho-p38 increased but no significant change was observed in the phosphorylation of ERK and JNK,thus suggesting that the p38 might be responsible for the defense response to low temperature stress.Furthermore,we demonstrated that:i)3 min chilling at 0°C was sufficient for the activation of p38 MAPK pathway in this whitefly;and ii)the amount of phosphorylated p38 increased significantly in the first 20 min of chilling,reversed by 60 min,and then returned to the original level by 120 min.Taken together,our results suggest that the p38 pathway is important during response to low temperature stress in the Mediterranean cryptic species of the B.tabaci species complex.
基金Project supported by the National Natural Science Foundation of China(Grant No.11675228)China Postdoctoral Science Foundation(Grant No.2015M572662XB).
文摘Signal transduction is an important and basic mechanism to cell life activities.The stochastic state transition of receptor induces the release of signaling molecular,which triggers the state transition of other receptors.It constructs a nonlinear sigaling network,and leads to robust switchlike properties which are critical to biological function.Network architectures and state transitions of receptor affect the performance of this biological network.In this work,we perform a study of nonlinear signaling on biological polymorphic network by analyzing network dynamics of the Ca^(2+)-induced Ca^(2+)release(CICR)mechanism,where fast and slow processes are involved and the receptor has four conformational states.Three types of networks,Erdos–R´enyi(ER)network,Watts–Strogatz(WS)network,and BaraB´asi–Albert(BA)network,are considered with different parameters.The dynamics of the biological networks exhibit different patterns at different time scales.At short time scale,the second open state is essential to reproduce the quasi-bistable regime,which emerges at a critical strength of connection for all three states involved in the fast processes and disappears at another critical point.The pattern at short time scale is not sensitive to the network architecture.At long time scale,only monostable regime is observed,and difference of network architectures affects the results more seriously.Our finding identifies features of nonlinear signaling networks with multistate that may underlie their biological function.
基金This work was supported by grants from the National Natural Science Foundation of China(No.32122084)Chongqing Natural Science Foundation(No.cstc2021ycjh-bgzxm0005)+1 种基金PhD Start-Up Foundation of Southwest University(No.SWU120012)Fundamental Research Funds for the Central Universities(No.SWU-KT22042).None of these fundings played any role in the design of the study,collection,analysis,or interpretation of data or in the writing of the manuscript.
文摘Metamorphosis is a complex developmental process involving multiple pathways and a large number of genes that are regulated by juvenile hormone(JH)and 20-hydroxyecdysone(20E).Despite important progress in understanding various aspects of silkworm biology,the hormone signaling pathway in the silkworm remains poorly understood.Genome-wide screening using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)-based libraries has recently emerged as a novel method for analyzing genome function,enabling further research into essential genes,drug targets,and virus-host interaction.Previously,we constructed a genome-wide CRISPR/Cas9-based library of the silkworm(Bombyx mori)and successfully revealed the genes involved in biotic or abiotic stress factor responses.In this study,we used our silkworm CRISPR library and large-scale genome-wide screening to analyze the key genes in the silkworm 20E signaling pathway and their mechanisms of action.Functional annotation showed that 20E regulates key proteins in processes that mainly occur in the cytoplasm and nucleus.Pathway enrichment analysis showed that 20E can activate phosphorylation and may affect innate immunity,interfere with intracellular nutrition and energy metabolism,and eventually cause cell apoptosis.The screening results were experimentally validated by generating cells with knockout alleles of the relevant genes,which had increased tolerance to 20E.Our findings provide a panoramic overview of signaling in response to 20E in the silkworm,underscoring the utility of genome-wide CRISPR mutant libraries in deciphering hormone signaling pathways and the mechanisms that regulate metamorphosis in insects.
基金This work was supported by the National Key Research and Development Program of China(Nos.2020YFA0908500 and 2018YFA0901600)the National Natural Science Foundation of China(No.22161142015).
文摘Signal transduction across lipid bilayers is of profound importance in biological processes.In biological systems,natural enzymes mediate biochemical effects by binding to substrates and facilitating the conversion of external signals into physiological responses.Sequential transmission of biological signals from one enzyme to the next promotes signal transduction with feedforward and feedback mechanisms.Reconstructing these processes in an artificial system provides potential applications and offers a new way to understand fundamental biological processes in depth.However,the design of artificial signal transduction systems regulated by artificial enzyme receptors in a predictable and intelligent manner remains a challenge.Herein,benefiting from the polarity-regulated characteristics of Se-containing compounds with artificial glutathione peroxidase(GPx)activity,we constructed an artificial transmembrane signaling receptor with a Se-containing GPx-like recognition head group,a membrane-anchoring group,and a pre-enzyme end group.The artificial supramolecular signal transduction system containing such signal transduction receptors extends the range of signaling systems based on enzyme regulation,which provides a new way to study natural signal processes in cells and artificially regulated biological processes.
基金supported by the National Natural Science Foundation of China,No.82173800 (to JB)Shenzhen Science and Technology Program,No.KQTD20200820113040070 (to JB)。
文摘Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.
基金supported by start-up funds from Wenzhou Medical University and The First Affiliated Hospital to YL,and Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-I2M-5-028)to XL.
文摘Following injury,tissue autonomously initiates a complex repair process,resulting in either partial recovery or regeneration of tissue architecture and function in most organisms.Both the repair and regeneration processes are highly coordinated by a hierarchy of interplay among signal transduction pathways initiated by different growth factors,cytokines and other signaling molecules under normal conditions.However,under chronic traumatic or pathological conditions,the reparative or regenerative process of most tissues in different organs can lose control to different extents,leading to random,incomplete or even flawed cell and tissue reconstitution and thus often partial restoration of the original structure and function,accompanied by the development of fibrosis,scarring or even pathogenesis that could cause organ failure and death of the organism.Ample evidence suggests that the various combinatorial fibroblast growth factor(FGF)and receptor signal transduction systems play prominent roles in injury repair and the remodeling of adult tissues in addition to embryonic development and regulation of metabolic homeostasis.In this review,we attempt to provide a brief update on our current understanding of the roles,the underlying mechanisms and clinical application of FGFs in tissue injury repair.
基金This work was supported by the National Natural Science Foundation of China(Grant No 30870785).
文摘Protein kinase C epsilon(PKCε)is one of major isoforms in novel PKC family.Although it has been extensively characterized in the past decade,the role of PKCεin neuron is still not well understood.Advances in molecular biology have now removed significant barriers to the direct investigation of PKCεfunctions in vivo,and PKCεhas been increasingly implicated in the neural biological functions and associated neurogenic diseases.Recent studies have provided important insights into the influence of PKCεon cortical processing at both the single cell level and network level.These studies provide compelling evidence that PKCεcould regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKCεsignal pathway in the developing brain.
基金the grants of National Natural Science Foundation of China(31572259)the Fundamental Research Funds for the Central Universities of China(201822020,201841013).
文摘Like olfaction,the sense of taste allows the detection and discrimination of chemicals in the environment.However,while olfaction is specialized in the detection of volatile chemicals,taste is restricted to the detection of contact-chemicals.Two families of mammalian taste receptors,T1R and T2R,involved in recognition of sweet,umami(the taste of monosodium glutamate)and bitter stimuli have been identified and characterized.Although much progress has been made in studies on the basic mechanisms of taste recognition and signal transduction in mammals,we are still far from a full understanding of different taste qualities.This review presents a current perspective on sweet,bitter and umami taste receptors and their signal transduction mechanism.We also discuss the evolution of taste and taste-related molecules.
基金supported by a grant from the Post-Doctoral Research Foundation of China(No.2004035198).
文摘This paper aims to investigate the effects of Zhihuang(枳黄)decoction on CD14 expression in the lipopolysaccharide signal transduction pathway of alcohol-induced liver disease in rats.Seventy-five Wistar rats were randomly divided into three groups.Ethanol(56%,weight/volumn)was intragastrically administrated to 50 rats(14 mL/kg body weight per day)for 10 days to establish a model of alcohol-induced liver disease,and 25 of these 50 rats were treated with Zhihuang decoction simulta-neously.Liver injury was evaluated by biochemical examination.The plasma content of endotoxin was assayed by biochemistry.The expression of CD14 mRNA and protein in rat liver was measured by reverse transcription polymerase chain reaction and immunohis-tochemistry,respectively.Zhihuang decoction pretreat-ment significantly protected against acute alcohol-induced liver injury,which was evidenced by the decrease of elevated serum alanine aminotransferase and aspartate aminotransferase.In addition,the level of plasma endo-toxin and up-regulation of CD14 was also suppressed by Zhihuang decoction in alcohol-intoxicated rats.Zhihuang decoction can significantly reduce CD14 expression in the lipopolysaccharide signal transduction pathway,which is one of the most important mechanisms of Zhihuang decoction to treat hepatic injury induced by alcohol in rats.
基金This work was supported by the Hunan Provincial Natural Science Foundation(2021JJ30915).
文摘Fos-related antigen 1(Fra-1)is a nuclear transcription factor that regulates cell growth,differentiation,and apoptosis.It is involved in the proliferation,invasion,apoptosis and epithelial mesenchymal transformation of malignant tumor cells.Fra-1 is highly expressed in gastric cancer(GC),affects the cycle distribution and apoptosis of GC cells,and participates in GC occurrence and development.However,the detailed mechanism of Fra-1 in GC is unclear,such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis.In this study,we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta(YWHAH)as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry.Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression,and affected GC cell proliferation.Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1(HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway in GC cells.Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation.These results will help to discover new molecular targets for the early diagnosis,treatment,and prognosis prediction of GC.
基金Funded by National Center for Gene Therapy and Drugs Based on RNA Technology MUR-CN3 CUP E63C22000940007.
文摘Scaffold proteins are crucial regulators of signaling networks,and their abnormal expression may favor the development of tumors.Among the scaffold proteins,immunophilin covers a unique role as‘protein-philin’(Greek‘philin’=friend)that interacts with proteins to guide their proper assembly.The growing list of human syndromes associated with the immunophilin defect underscores the biological relevance of these proteins that are largely opportunistically exploited by cancer cells to support and enable the tumor’s intrinsic properties.Among the members of the immunophilin family,the FKBP5 gene was the only one identified to have a splicing variant.Cancer cells impose unique demands on the splicing machinery,thus acquiring a particular susceptibility to splicing inhibitors.This review article aims to overview the current knowledge of the FKBP5 gene functions in human cancer,illustrating how cancer cells exploit the scaffolding function of canonical FKBP51 to foster signaling networks that support their intrinsic tumor properties and the spliced FKBP51s to gain the capacity to evade the immune system.
基金Supported by the National Natural Science Foundation of China,No.32200557Natural Science Foundation of Shandong Province,No.ZR2022QH271the Postdoctoral Innovative Projects of Shandong Province,No.SDCX-ZG-202203047.
文摘BACKGROUND The development of cancer is thought to involve the dynamic crosstalk between the tumor cells and the microenvironment they inhabit.Such crosstalk is thought to involve mechanotransduction,a process whereby the cells sense mechanical cues such as stiffness,and translate these into biochemical signals,which have an impact on the subsequent cellular activities.Bibliometric analysis is a statistical method that involves investigating different aspects(including authors’names and affiliations,article keywords,journals and citations)of large volumes of literature.Despite an increase in mechanotransduction-related research in recent years,there are currently no bibliometric studies that describe the global status and trends of mechanotransduction-related research in the cancer field.AIM To investigate the global research status and trends of mechanotransduction in cancer from a bibliometric viewpoint.METHODS Literature on mechanotransduction in cancer published from January 1,1900 to December 31,2022 was retrieved from the Web of Science Core Collection.Excel and GraphPad software carried out the statistical analysis of the relevant author,journal,organization,and country information.The co-authorship,keyword cooccurrence,and keyword burst analysis were visualized with VOSviewer and CiteSpace.RESULTS Of 597 publications from 745 institutions in 45 countries were published in 268 journals with 35510 citation times.With 270 articles,the United States is a well-established global leader in this field,and the University of California system,the most productive(n=36)and influential institution(n=4705 citations),is the most highly active in collaborating with other organizations.Cancers was the most frequent publisher with the highest H-index.The most productive researcher was Valerie M.Weaver,with 10 publications.The combined analysis of concurrent and burst keywords revealed that the future research hotspots of mechanotransduction in cancer were related to the plasma membrane,autophagy,piezo1/2,heterogeneity,cancer diagnosis,and post-transcriptional modifications.CONCLUSION Mechanotransduction-related cancer research remains a hot topic.The United States is in the leading position of global research on mechano-oncology after almost 30 years of investigations.Research group cooperations exist but remain largely domestic,lacking cross-national communications.The next big topic in this field is to explore how the plasma membrane and its localized mechanosensor can transduce mechanical force through post-transcriptional modifications and thereby participate in cellular activity regulations and cancer development.
文摘As a crucial protein kinase,the mammalian target of rapamycin(mTOR)intimately controls essential cellular processes like cell development,proliferation,metabolism,and other crucial activities.Different cancers and disorders have been linked to imbalances in mTOR's regulatory systems.Multiple mTOR inhibitor therapy has recently acquired popularity as a method of treating cancers brought on by abnormal signal transduction pathways.We also explore potential processes behind tumor cell resistance to mTOR inhibitors and suggest workarounds to overcome this challenge.We hold the potential to pioneer cutting-edge methods for tumor therapy by methodically examining the complex mTOR signaling system and its regulatory complexity.Increasing our knowledge of mTOR-related mechanisms not only creates opportunities for cutting-edge methods to target and treat cancers but also has the potential to improve patient outcomes and general quality of life significantly.This review paper explores the most recent developments in understanding mTOR signaling pathways and the use of mTOR inhibitors in treating tumors.
文摘Cellular biological activities are tightly controlled by intracellular signaling processes initiated by extracellular signals. Protein tyrosine phosphatases, which remove phosphate groups from phosphorylated signaling molecules, play equally important tyrosine roles as protein tyrosine kinases in signal transduction. SHP-2, a cytoplajsmic SH2 domain containing protein tyrosine phosphatase, is involved in the signaling pathways of a variety of growth factors and cytokines. Recent studies have clearly demonstrated that this phosphatase plays an important role in transducing signal relay from the cell surface to the nucleus, and is a critical intracellular regulator in mediating cell proliferation and differentiation.
基金supported by the Research School in Pharmaceutical Science in Lund,The Royal Physiographic Society in LundThe Swedish Research Council(Medicine)+1 种基金the Craaford’s and Thure Nilsson’s Funds for Medical ResearchFunds for diabetic research,Lund University and Region Skane
文摘Detailed mechanisms behind regeneration after nerve injury, in particular signal transduction and the fate of Schwann cells(SCs), are poorly understood. Here, we investigated axotomy-induced activation of extracellular-signal-regulated kinase-1/2(ERK1/2; important for proliferation) and m-calpain in vitro, and the relation to Ca2+ deletion and Schwann cell proliferation and death after rat sciatic nerve axotomy. Nerve segments were cultured for up to 72 hours with and without ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid(EGTA). In some experiments, 5-bromo-2′-deoxyuridine(Brd U) was added during the last 24 hours to detect proliferating cells and propidium iodide(PI) was added at the last hour to detect dead and/or dying cells. Immunohistochemistry of sections of the cultured nerve segments was performed to label m-calpain and the phosphorylated and activated form of ERK1/2. The experiments revealed that immunoreactivity for p-ERK1/2 increased with time in organotypically cultured SCs. p-ERK1/2 and m-calpain were also observed in axons. A significant increase in the number of dead or dying SCs was observed in nerve segments cultured for 24 hours. When deprived of Ca2+, activation of axonal m-calpain was reduced, whereas p-ERK1/2 was increased in SCs. Ca2+ deprivation also significantly reduced the number of proliferating SCs, and instead increased the number of dead or dying SCs. Ca2+ seems to play an important role in activation of ERK1/2 in SCs and in SC survival and proliferation. In addition, extracellular Ca2+ levels are also required for m-calpain activation and up-regulation in axons. Thus, regulation of Ca2+ levels is likely to be a useful method to promote SC proliferation.
文摘Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.
文摘Objective To determine whether transforming growth factor betal (TGF-β1)/Smad signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines.Methods Three human hepatic carcinoma cell lines, HepG2, Huh-7, and Hep3B, were used in this study.TGF-β1-induced apoptosis in hepatic carcinoma cell lines was analyzed using TUNEL assay.For identifying the mechanism of apoptosis induced by TGF-β1, cell lines were transfected with a TGF-β1-inducible luciferase reportor plasmid containing Smad4 binding elements.After transfection, cells were treated with TGF-β1, then assayed for luciferase activity.Results The apoptosis rate of HepG2 cell lines (48.51%± 8.21%) was significantly higher than control ( 12.72%±2.18%, P<0.05).But TGF-β1 was not able to induce apoptosis of Huh-7 and Hep3B cell lines.The relative luciferase activity of TGF-β1-treated HepG2 cell lines (4.38) was significantly higher than control (1.00, P< 0.05).But the relative luciferase activity of TGF-β1-treated Huh-7 and Hep3B cell lines less increased compared with control.Conclusions HepG2 cells seem to be highly susceptible to TGF-β1-induced apoptosis compared with Hep3B and Huh-7 cell lines.Smad4 is a central mediator of TGF-β1 signaling transdution pathway.TGF-β1/Smad signaling pathway might mediate p53-dependent apoptosis in hepatoma cell lines.
基金supported by a Shun Hing Institute of Advanced Engineering Grant(No.4720247)a General Research Fund/Early Career Scheme(No.24201919)from the Research Grants Council of Hong Kong Special Administrative Region(to LD)。
文摘Dynamic protein-protein interactions are essential for proper cell functioning.Homointeraction events—physical interactions between the same type of proteins—represent a pivotal subset of protein-protein interactions that are widely exploited in activating intracellular signaling pathways.Capacities of modulating protein-protein interactions with spatial and temporal resolution are greatly desired to decipher the dynamic nature of signal transduction mechanisms.The emerging optogenetic technology,based on genetically encoded light-sensitive proteins,provides promising opportunities to dissect the highly complex signaling networks with unmatched specificity and spatiotemporal precision.Here we review recent achievements in the development of optogenetic tools enabling light-inducible protein-protein homo-interactions and their applications in optical activation of signaling pathways.
