Ras-associated protein-1 （Rapl）, a small GTPase in the Ras-related protein family, is an important regulator of basic cellular functions （e.g., formation and control of cell adhesions and junctions）, cellular migr...Ras-associated protein-1 （Rapl）, a small GTPase in the Ras-related protein family, is an important regulator of basic cellular functions （e.g., formation and control of cell adhesions and junctions）, cellular migration, and polarization. Through its interaction with other proteins, Rapl plays many roles during cell invasion and metastasis in different cancers. The basic function of Rapl is straightforward; it acts as a switch during cellular signaling transduction and regulated by its binding to either guanosine triphosphate （GTP） or guanosine diphosphate （GDP）. However, its remarkably diverse function is rendered by its interplay with a large number of distinct Rap guanine nucleotide exchange factors and Rap GTPase activating proteins. This review summarizes the mechanisms by which Rap 1 signaling can regulate cell invasion and metastasis, focusing on its roles in integrin and cadherin regulation, Rho GTPase control, and matrix metalloproteinase expression.展开更多
Soy consumption has been associated with potential health benefits in reducing chronic diseases.These physiological functions have been attributed to soy proteins or more commonly to bioactive peptides.Thus,more studi...Soy consumption has been associated with potential health benefits in reducing chronic diseases.These physiological functions have been attributed to soy proteins or more commonly to bioactive peptides.Thus,more studies are required to identify these bioactive peptides,and elucidate their biological mechanisms of action.In the present study,a novel peptide iglycin was purifi ed from soybean seeds with a molecular mass of 3.88 k Da.Thereafter,iglycin reduced fasting blood glucose and restored insulin sensitivity of C57 BL/6 J mice on a high-fat diet with increased phosphorylation of insulin receptor substrate 1(IRS1)and AKT in adipose tissue.Furthermore,it improved glucose uptake,induced translocation of intracellular GLUT4 to plasma membrane and activation of insulin signaling in adipocytes under insulin-resistant condition.In addition,it decreased reactive oxygen species production,lipid peroxidation and inhibited adipocyte apoptosis with improved mitochondrial function as evidenced by up-regulation of succinate dehydrogenase activity,mitochondrial membrane potential and intracellular ATP store.These data suggested that iglycin ameliorated insulin resistance via activation of insulin signaling,which was associated with inhibition of oxidative stress,adipocyte apoptosis,and improvement of mitochondrial function.展开更多
Atrial septal defect (ASD)is a common acyanotic congenital cardiac disorder associated with genetic mutations.The objective of this study was to identify the genetic factors in a Chinese family with ASD patients by a ...Atrial septal defect (ASD)is a common acyanotic congenital cardiac disorder associated with genetic mutations.The objective of this study was to identify the genetic factors in a Chinese family with ASD patients by a whole exome sequencing approach.Causative ASD gene mutations were examined in 16 members from a three-generation family,among which 6 individuals were diagnosed as having ASD.One hundred and eighty-three unrelated healthy Chinese were recruited as a normal control group.Peripheral venous blood was collected from every subject for genetic analysis.Exome sequencing was performed in the ASD patients.Potential causal mutations were detected in non-ASD family members and normal controls by polymerase chain reaction and sequencing analysis.The results showed that all affected family members carried two novel compound mutations,c.1187delT of PCDHGA4 and c.2557insC of SLFN14,and these two mutations were considered to have synergetic function on ASD.In conclusion,the mutations of c.1187delT of PCDHGA4 and c.2557insC of SLFN14 may be pathogenic factors contributing to the development of ASD.展开更多
Systemic lupus erythematosus（SLE） and clear cell renal cell carcinoma（CC-RCC） are serious disorders and usually fatal, and always accompanied with pathological changes in the kidney. Signal-induced proliferation-a...Systemic lupus erythematosus（SLE） and clear cell renal cell carcinoma（CC-RCC） are serious disorders and usually fatal, and always accompanied with pathological changes in the kidney. Signal-induced proliferation-associated protein 1（SIPA-1） is a Rap1 GTPase activating protein（Rap1GAP） expressed in the normal distal and collecting tubules of the murine kidney. Lupus-like autoimmune disease and leukemia have been observed in SIPA-1 deficient mice, suggesting a pathological relevance of SIPA-1 to SLE and carcinoma in human being. The expression pattern of SIPA-1 is as yet undefined and the pathogenesis of these diseases in humans remains elusive. In this study, we used both immunohistochemistry and quantum dot（QD）-based immunofluorescence staining to investigate the expression of SIPA-1 in renal specimens from SLE and CC-RCC patients. MTT assay and Western blotting were employed to evaluate the effects of SIPA-1 overexpression on the proliferation and apoptosis of renal cell lines. Semi-quantitative reverse transcriptase-PCR（RT-PCR） was applied to examine the changes of hypoxia-inducible factor-1α（HIF-1α） mR NA level. Results showed that SIPA-1 was highly expressed in the proximal and collecting tubules of nephrons in SLE patients compared to normal ones, and similar results were obtained in the specimens of CC-RCC patients. Although SIPA-1 overexpression did not affect cellular proliferation and apoptosis of both human 786-O renal cell carcinoma cells and rat NRK-52 E renal epithelial cell lines, RT-PCR results showed that HIF-1α mR NA level was down-regulated by SIPA-1 overexpression in 786-O cells. These findings suggest that SIPA-1 may play critical roles in the pathological changes in kidney, and might provide a new biomarker to aid in the diagnosis of SLE and CC-RCC.展开更多
Circadian clock drives the 24-h rhythm in our behavior and physiology.The molecular clock consists of a series of transcriptional/translational feedback loops operated by a number of clock genes.A very recent study re...Circadian clock drives the 24-h rhythm in our behavior and physiology.The molecular clock consists of a series of transcriptional/translational feedback loops operated by a number of clock genes.A very recent study reported that the clock protein PERIOD(PER)is organized into discrete foci at the nuclear envelope in fly circadian neurons,which is believed to be important for controlling the subcellular localization of clock genes.Loss of inner nuclear membrane protein lamin B receptor(LBR)leads to disruption of these foci,but how they are regulated is yet unknown.Here,we found that PER foci are likely phase-separated condensates,the formation of which is mediated by intrinsically disordered region in PER.Phosphorylation promotes the accumulation of these foci.Protein phosphatase 2A,which is known to dephosphorylate PER,hampers the accumulation of the foci.On the other hand,the circadian kinase DOUBLETIME(DBT)which phosphorylates PER enhances the accumulation of the foci.LBR likely facilitates PER foci accumulation by destabilizing the catalytic subunit of protein phosphatase 2A,MICROTUBULE STAR(MTS).In conclusion,here,we demonstrate a key role for phosphorylation in promoting the accumulation of PER foci,while LBR modulates this process by impinging on the circadian phosphatase MTS.展开更多
Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup ...Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup C and 6,706-bp genomic DNA(g DNA) deletion, were identified in three families with focal epilepsy by linkage analysis, whole exome sequencing(WES) and Sanger sequencing. NPRL3 protein is a component of the GATOR1 complex, a major inhibitor of m TOR signaling. These mutations led to truncation of the NPRL3 protein and hampered the binding between NPRL3 and DEPDC5, which is another component of the GATOR1 complex. Consequently, the mutant proteins enhanced m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 by GATOR1. Knockdown of nprl3 in Drosophila resulted in epilepsy-like behavior and abnormal synaptic development. Taken together, these findings expand the genotypic spectrum of NPRL3-associated focal epilepsy and provide further insight into how NPRL3 mutations lead to epilepsy.展开更多
Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physi...Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physical embolization to tumor-feeding arteries.In the present work,a temperature sensitive polymer poly(N-isopropylacrylamide-b-methacrylic acid)(PNA),which was modified with gold nanoparticles(AuNP@PNA),was successfully used to encapsulate doxorubicin(DOX)by electrostatic binding with their carboxyl groups.The resultant gold nanomedicines(AuNP@PNA/DOX)exhibited temperature responsive sol-gel phase transition,favorable shear thinning effect and X-ray angiography.By in vivo evaluation of vascular embolization on VX2-tumor-bearing rabbits,AuNP@PNA/DOX exhibited far better antitumor efficacy than Lipiodol/DOX,on either tumor growth inhibition,proliferation,apoptosis,necrosis or anti-metastasis.Owing to sufficient embolization to tumor vascular networks,AuNP@PNA/DOX down-regulated the expression levels of HIF-1α,VEGF and MMP-9,and prompted more efficient activation on CD3+/CD8+T cells and the related cytokines,suggesting the synergistic effect between AuNP@PNA and DOX on the improvement of post-operative tumor immunosuppressive microenvironment.With their favorable pharmcokinetics and biocompatibility,AuNP@PNA/DOX is promising to be developed as a multi-functional artery-imaging/embolic agent with immune-chemo-embolization for enhancing TACE efficacy on HCC.展开更多
Sleep constitutes a third of human life and it is increasingly recognized as important for health.Over the past several decades,numerous genes have been identified to be involved in sleep regulation in animal models,b...Sleep constitutes a third of human life and it is increasingly recognized as important for health.Over the past several decades,numerous genes have been identified to be involved in sleep regulation in animal models,but most of these genes when disturbed impair not only sleep but also health and physiological functions.Human natural short sleepers are individuals with lifelong short sleep and no obvious adverse outcomes associated with the lack of sleep.These traits appear to be heritable,and thus characterization of the genetic basis of natural short sleep provides an opportunity to study not only the genetic mechanism of human sleep but also the relationship between sleep and physiological function.This review focuses on the current understanding of mutations associated with the natural short sleep trait and the mechanisms by which they contribute to this trait.展开更多
In eukaryotes,protein phosphorylation is specifically catalyzed by numerous protein kinases(PKs),faithfully orchestrates various biological processes,and reversibly determines cellular dynamics and plasticity.Here we ...In eukaryotes,protein phosphorylation is specifically catalyzed by numerous protein kinases(PKs),faithfully orchestrates various biological processes,and reversibly determines cellular dynamics and plasticity.Here we report an updated algorithm of Group-based Prediction System(GPS)5.0 to improve the performance for predicting kinase-specific phosphorylation sites(p-sites).Two novel methods,position weight determination(PWD)and scoring matrix optimization(SMO),were developed.Compared with other existing tools,GPS 5.0 exhibits a highly competitive accuracy.Besides serine/threonine or tyrosine kinases,GPS 5.0 also supports the prediction of dual-specificity kinase-specific p-sites.In the classical module of GPS 5.0,617 individual predictors were constructed for predicting p-sites of 479 human PKs.To extend the application of GPS5.0,a species-specific module was implemented to predict kinase-specific p-sites for 44,795 PKs in161 eukaryotes.The online service and local packages of GPS 5.0 are freely available for academic research at http://gps.biocuckoo.cn.展开更多
Post-translational modifications（PTMs） occurring at protein lysine residues,or protein lysine modifications（PLMs）,play critical roles in regulating biological processes.Due to the explosive expansion of the amount...Post-translational modifications（PTMs） occurring at protein lysine residues,or protein lysine modifications（PLMs）,play critical roles in regulating biological processes.Due to the explosive expansion of the amount of PLM substrates and the discovery of novel PLM types,here we greatly updated our previous studies,and presented a much more integrative resource of protein lysine modification database（PLMD）.In PLMD,we totally collected and integrated 284,780 modification events in 53,501 proteins across 176 eukaryotes and prokaryotes for up to 20 types of PLMs,including ubiquitination, acetylation, sumoylation, methylation ,succinylation,malonylation,glutarylation,giycation,formylation,hydroxylation,butyrylation,propionylation,crotonylation,pupylation,neddylation,2-hydroxyisobutyrylation,phosphoglycerylation,carboxylation,lipoylation and biotinylation.Using the data set,a motif-based analysis was performed for each PLM type,and the results demonstrated that different PLM types preferentially recognize distinct sequence motifs for the modifications.Moreover,various PLMs synergistically orchestrate specific cellular biological processes by mutual crosstalks with each other,and we totally found 65,297 PLM events involved in 90 types of PLM co-occurrences on the same lysine residues.Finally,various options were provided for accessing the data,while original references and other annotations were also present for each PLM substrate.Taken together,we anticipated the PLMD database can serve as a useful resource for further researches of PLMs.PLMD 3.0 was implemented in PHP ＋ MySQL and freely available at http：//plmd.biocuckoo.org.展开更多
The integration, analysis and visualization of the big omics data are critical for addressing a broad spectrum of biological questions. One of the most frequently conducted procedures is enrichment analysis, which sta...The integration, analysis and visualization of the big omics data are critical for addressing a broad spectrum of biological questions. One of the most frequently conducted procedures is enrichment analysis, which statistically tests whether individual functional an- notations of Gent Ontology （GO） or Kyoto Encyclopedia of Genes and Genomes （KEGG） are significantly over-or under-represented in an ＂interesting＂ gene or protein list against the reference set （Tavazoie et al., 1999）.展开更多
Photodynamic therapy with reactive oxygen species production is a prospective treatment to combat cancer stem cells(CSCs).However,the innate drawbacks,including short lifetime and diffusion distance of reactive oxygen...Photodynamic therapy with reactive oxygen species production is a prospective treatment to combat cancer stem cells(CSCs).However,the innate drawbacks,including short lifetime and diffusion distance of reactive oxygen species and hypoxia within solid tumors,have become bottlenecks for clinical applications of photodynamic therapy.Here,we develop a mitochondria-targeting hemicyanine-oleic acid conjugate(CyOA),which can self-assemble into supramolecular nanoparticles(NPs)without any exogenous excipients.CyOA is also shown for targeting the mitochondrial complex II protein succinate dehydrogenase to inhibit oxidative phosphorylation and reverse tumor hypoxia,resulting in 50.4-fold higher phototoxicity against breast cancer stem cells(BCSCs)compared to SO_(3)-CyOA NPs that cannot target to mitochondria.In 4T1 and BCSC tumor models,CyOA NPs achieve higher tumor inhibition and less lung metastasis nodules compared to the clinically used photosensitizer Hiporfin.This study develops a self-assembled small molecule that can serve as both oxidative phosphorylation inhibitor and photosensitizer for eradication of CSCs and treatment of solid tumors.展开更多
Fucoidan is an active component of seaweed, which inhibits proliferation and induces apoptosis of several tumor cells while the detailed mechanisms underlying this process are still not clear. In this study, the effec...Fucoidan is an active component of seaweed, which inhibits proliferation and induces apoptosis of several tumor cells while the detailed mechanisms underlying this process are still not clear. In this study, the effect of Fucoidan on the proliferation and apoptosis of human breast cancer MCF-7 cells and the molecular mechanism of Fucoidan action were investigated. Viable cell number of MCF-7 cells was decreased by Fucoidan treatment in a dose-dependent manner as measured by MTT assay. Fucoidan treatment resulted in G1 phase arrest of MCF-7 cells as revealed by flow cytometry, which was associated with the decrease in the gene expression of cyclin D 1 and CDK-4. Annexin V/PI staining results showed that the number of apoptotic cells was associated with regulation of cytochrome C, cas- pase-8, Bax and Bcl-2 at transcriptional and translational levels. Both morphologic observation and Hoechst 33258 assay results confirmed the pro-apoptotic effect of Fucoidan. Meanwhile, the ROS pro- duction was also increased by Fucoidan treatment, which suggested that Fucoidan induced oxidative damage in MCF-7 cells. The results of present study demonstrated that Fucoidan could induce GI phase arrest and apoptosis in MCF-7 cells through regulating the cell cycle and apoptosis-related genes or proteins expression, and ROS generation is also involved in these processes.展开更多
γ -actin （ACTG1） gene is a cytoplasmic nonmuscle actin gene, which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea. Mutations in ACTG1 were found to cause autosomal dominant, progressi...γ -actin （ACTG1） gene is a cytoplasmic nonmuscle actin gene, which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea. Mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing loss linked to the DFNA 20/26 locus on chromosome 17q25.3 in European and American families, respectively. In this study, a novel missense mutation （c.364A〉G; p.I122V） co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 150 unrelated normal controls. The alteration of residue Ile122 was predicted to damage its interaction with actin-binding proteins, which may cause disruption of hair cell organization and function. These findings strongly suggested that the I122V mutation in ACTG1 caused autosomal dominant non-syndromic hearing impairment in a Chinese family and expanded the spectrum of ACTG1 mutations causing hearing loss.展开更多
Bone regeneration remains a great clinical challenge. Low intensity near-infrared(NIR) light showed strong potential to promote tissue regeneration, offering a promising strategy for bone defect regeneration. However,...Bone regeneration remains a great clinical challenge. Low intensity near-infrared(NIR) light showed strong potential to promote tissue regeneration, offering a promising strategy for bone defect regeneration. However, the effect and underlying mechanism of NIR on bone regeneration remain unclear. We demonstrated that bone regeneration in the rat skull defect model was significantly accelerated with low-intensity NIR stimulation. In vitro studies showed that NIR stimulation could promote the osteoblast differentiation in bone mesenchymal stem cells(BMSCs) and MC3T3-E1 cells, which was associated with increased ubiquitination of the core circadian clock protein Cryptochrome 1(CRY1) in the nucleus. We found that the reduction of CRY1 induced by NIR light activated the bone morphogenetic protein(BMP) signaling pathways, promoting SMAD1/5/9 phosphorylation and increasing the expression levels of Runx2 and Osterix. NIR light treatment may act through sodium voltage-gated channel Scn4a, which may be a potential responder of NIR light to accelerate bone regeneration. Together, these findings suggest that low-intensity NIR light may promote in situ bone regeneration in a CRY1-dependent manner, providing a novel, efficient and non-invasive strategy to promote bone regeneration for clinical bone defects.展开更多
Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated...Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.展开更多
Recently, fluorescence technique becomes very useful. It can allow for addressing a fundamental problem of cellular mechanism besides characterizing the species inside the cell to facilitate the diagnostic and prognos...Recently, fluorescence technique becomes very useful. It can allow for addressing a fundamental problem of cellular mechanism besides characterizing the species inside the cell to facilitate the diagnostic and prognostic value. Manipulation with fluorescent dyes provides many possibilities for their use as tags, probes, and sensors. These types can be intrinsic or extrinsic to the cell. They can become not only silent observers, but also participants, modulators or disruptors of specific activities outline the biological functions can be successfully studied quantitatively and qualitatively with fluorescence techniques.展开更多
Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-ta...Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-targeting nanomedicine by conjugating doxorubicin(DOX)-loaded hydroxyethyl starch-IR780 nanoparticles(NPs)with Cys-Arg-Glu-Lys-Ala(CREKA)peptide,which had a special affinity for fibronectin overexpressed on CAFs.After systemic administration,the NPs efficiently targeted CAFs and generated hyperthermia upon light irradiation,decreasing CAFs through the combination of chemo-and photothermal-therapies.Thus,a series of changes in TMME were achieved by reducing CAFs,which further disrupted the niche of cancer stem cells(CSCs)to affect their survival.As a result,the tumor growth was significantly inhibited in 4T1 tumors.The strategy of TMME modulation and CSCs elimination through targeting and depleting CAFs provides a novel therapeutic treatment for desmoplastic solid tumors.展开更多
The coronavirus disease 2019(COVID-19)pandemic had a devastating impact on human society.Beginning with genome surveillance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the development of omics techn...The coronavirus disease 2019(COVID-19)pandemic had a devastating impact on human society.Beginning with genome surveillance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the development of omics technologies brought a clearer understanding of the complex SARS-CoV-2 and COVID-19.Here,we reviewed how omics,including genomics,proteomics,single-cell multi-omics,and clinical phenomics,play roles in answering biological and clinical questions about COVID-19.Large-scale sequencing and advanced analysis methods facilitate COVID-19 discovery from virus evolution and severity risk prediction to potential treatment identification.Omics would indicate precise and globalized prevention and medicine for the COVID-19 pandemic under the utilization of big data capability and phenotypes refinement.Furthermore,decoding the evolution rule of SARS-CoV-2 by deep learning models is promising to forecast new variants and achieve more precise data to predict future pandemics and prevent them on time.展开更多
Chaperone-mediated autophagy(CMA)is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.However,the mechanisms that regulate CMA are not fully und...Chaperone-mediated autophagy(CMA)is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.However,the mechanisms that regulate CMA are not fully understood.Here,using unbiased drug screening approaches,we discover Metformin,a drug that is commonly the first medication prescribed for type 2 diabetes,can induce CMA.We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA,Hsc70,and its activation.Notably,we find that amyloid-beta precursor protein(APP)is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner.The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity.Importantly,we find that in the APP/PS1 mouse model of Alzheimer's disease(AD),activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβplaque levels and reverses the molecular and behavioral AD phenotypes.Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases,such as AD,where such therapeutic intervention could be beneficial.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.31271504 and 31471310)the Shenzhen Science and Technology Innovation Committee,China(Grant No.JCYJ2013040 1144744187)
文摘Ras-associated protein-1 （Rapl）, a small GTPase in the Ras-related protein family, is an important regulator of basic cellular functions （e.g., formation and control of cell adhesions and junctions）, cellular migration, and polarization. Through its interaction with other proteins, Rapl plays many roles during cell invasion and metastasis in different cancers. The basic function of Rapl is straightforward; it acts as a switch during cellular signaling transduction and regulated by its binding to either guanosine triphosphate （GTP） or guanosine diphosphate （GDP）. However, its remarkably diverse function is rendered by its interplay with a large number of distinct Rap guanine nucleotide exchange factors and Rap GTPase activating proteins. This review summarizes the mechanisms by which Rap 1 signaling can regulate cell invasion and metastasis, focusing on its roles in integrin and cadherin regulation, Rho GTPase control, and matrix metalloproteinase expression.
基金jointly supported by the National Natural Science Foundation of China(31400794)Sichuan Province Science Fund s for Distinguished Young Scholar(2019JDJQ0017)+1 种基金Young and middle-aged Talents Project of the National People’s Commission(2799300127)Fundamental Research Funds for the Central Universities,Southwest Minzu University(2019XMJXPY08)。
文摘Soy consumption has been associated with potential health benefits in reducing chronic diseases.These physiological functions have been attributed to soy proteins or more commonly to bioactive peptides.Thus,more studies are required to identify these bioactive peptides,and elucidate their biological mechanisms of action.In the present study,a novel peptide iglycin was purifi ed from soybean seeds with a molecular mass of 3.88 k Da.Thereafter,iglycin reduced fasting blood glucose and restored insulin sensitivity of C57 BL/6 J mice on a high-fat diet with increased phosphorylation of insulin receptor substrate 1(IRS1)and AKT in adipose tissue.Furthermore,it improved glucose uptake,induced translocation of intracellular GLUT4 to plasma membrane and activation of insulin signaling in adipocytes under insulin-resistant condition.In addition,it decreased reactive oxygen species production,lipid peroxidation and inhibited adipocyte apoptosis with improved mitochondrial function as evidenced by up-regulation of succinate dehydrogenase activity,mitochondrial membrane potential and intracellular ATP store.These data suggested that iglycin ameliorated insulin resistance via activation of insulin signaling,which was associated with inhibition of oxidative stress,adipocyte apoptosis,and improvement of mitochondrial function.
文摘Atrial septal defect (ASD)is a common acyanotic congenital cardiac disorder associated with genetic mutations.The objective of this study was to identify the genetic factors in a Chinese family with ASD patients by a whole exome sequencing approach.Causative ASD gene mutations were examined in 16 members from a three-generation family,among which 6 individuals were diagnosed as having ASD.One hundred and eighty-three unrelated healthy Chinese were recruited as a normal control group.Peripheral venous blood was collected from every subject for genetic analysis.Exome sequencing was performed in the ASD patients.Potential causal mutations were detected in non-ASD family members and normal controls by polymerase chain reaction and sequencing analysis.The results showed that all affected family members carried two novel compound mutations,c.1187delT of PCDHGA4 and c.2557insC of SLFN14,and these two mutations were considered to have synergetic function on ASD.In conclusion,the mutations of c.1187delT of PCDHGA4 and c.2557insC of SLFN14 may be pathogenic factors contributing to the development of ASD.
基金supported by grants from National Natural Science Foundation of China(No.31271504)Shenzhen Science and Technology Innovations Committee,China(No.JCYJ20130401144744187)Health Department of Hubei Province,China(No.JX6A06)
文摘Systemic lupus erythematosus（SLE） and clear cell renal cell carcinoma（CC-RCC） are serious disorders and usually fatal, and always accompanied with pathological changes in the kidney. Signal-induced proliferation-associated protein 1（SIPA-1） is a Rap1 GTPase activating protein（Rap1GAP） expressed in the normal distal and collecting tubules of the murine kidney. Lupus-like autoimmune disease and leukemia have been observed in SIPA-1 deficient mice, suggesting a pathological relevance of SIPA-1 to SLE and carcinoma in human being. The expression pattern of SIPA-1 is as yet undefined and the pathogenesis of these diseases in humans remains elusive. In this study, we used both immunohistochemistry and quantum dot（QD）-based immunofluorescence staining to investigate the expression of SIPA-1 in renal specimens from SLE and CC-RCC patients. MTT assay and Western blotting were employed to evaluate the effects of SIPA-1 overexpression on the proliferation and apoptosis of renal cell lines. Semi-quantitative reverse transcriptase-PCR（RT-PCR） was applied to examine the changes of hypoxia-inducible factor-1α（HIF-1α） mR NA level. Results showed that SIPA-1 was highly expressed in the proximal and collecting tubules of nephrons in SLE patients compared to normal ones, and similar results were obtained in the specimens of CC-RCC patients. Although SIPA-1 overexpression did not affect cellular proliferation and apoptosis of both human 786-O renal cell carcinoma cells and rat NRK-52 E renal epithelial cell lines, RT-PCR results showed that HIF-1α mR NA level was down-regulated by SIPA-1 overexpression in 786-O cells. These findings suggest that SIPA-1 may play critical roles in the pathological changes in kidney, and might provide a new biomarker to aid in the diagnosis of SLE and CC-RCC.
基金grants from the Natural Science Foundation of China(3193002i and 32022035)the Ministry of Science and Technology of China STI 2030-Major Projects(2021ZD0203200-02)to L.Z.
文摘Circadian clock drives the 24-h rhythm in our behavior and physiology.The molecular clock consists of a series of transcriptional/translational feedback loops operated by a number of clock genes.A very recent study reported that the clock protein PERIOD(PER)is organized into discrete foci at the nuclear envelope in fly circadian neurons,which is believed to be important for controlling the subcellular localization of clock genes.Loss of inner nuclear membrane protein lamin B receptor(LBR)leads to disruption of these foci,but how they are regulated is yet unknown.Here,we found that PER foci are likely phase-separated condensates,the formation of which is mediated by intrinsically disordered region in PER.Phosphorylation promotes the accumulation of these foci.Protein phosphatase 2A,which is known to dephosphorylate PER,hampers the accumulation of the foci.On the other hand,the circadian kinase DOUBLETIME(DBT)which phosphorylates PER enhances the accumulation of the foci.LBR likely facilitates PER foci accumulation by destabilizing the catalytic subunit of protein phosphatase 2A,MICROTUBULE STAR(MTS).In conclusion,here,we demonstrate a key role for phosphorylation in promoting the accumulation of PER foci,while LBR modulates this process by impinging on the circadian phosphatase MTS.
基金supported by the National Natural Science Foundation of China (32270663, 31871262, U20A20355,32022035)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Ministry of Science and Technology of China STI2030-Major Projects (2021ZD0203202)。
文摘Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup C and 6,706-bp genomic DNA(g DNA) deletion, were identified in three families with focal epilepsy by linkage analysis, whole exome sequencing(WES) and Sanger sequencing. NPRL3 protein is a component of the GATOR1 complex, a major inhibitor of m TOR signaling. These mutations led to truncation of the NPRL3 protein and hampered the binding between NPRL3 and DEPDC5, which is another component of the GATOR1 complex. Consequently, the mutant proteins enhanced m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 by GATOR1. Knockdown of nprl3 in Drosophila resulted in epilepsy-like behavior and abnormal synaptic development. Taken together, these findings expand the genotypic spectrum of NPRL3-associated focal epilepsy and provide further insight into how NPRL3 mutations lead to epilepsy.
基金supported by the National Basic Research Program of China(Nos.2020YFA0710700 and 2018YFA0208900)the National Natural Science Foundation of China(Nos.82172758,81873919,and 81801810).
文摘Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physical embolization to tumor-feeding arteries.In the present work,a temperature sensitive polymer poly(N-isopropylacrylamide-b-methacrylic acid)(PNA),which was modified with gold nanoparticles(AuNP@PNA),was successfully used to encapsulate doxorubicin(DOX)by electrostatic binding with their carboxyl groups.The resultant gold nanomedicines(AuNP@PNA/DOX)exhibited temperature responsive sol-gel phase transition,favorable shear thinning effect and X-ray angiography.By in vivo evaluation of vascular embolization on VX2-tumor-bearing rabbits,AuNP@PNA/DOX exhibited far better antitumor efficacy than Lipiodol/DOX,on either tumor growth inhibition,proliferation,apoptosis,necrosis or anti-metastasis.Owing to sufficient embolization to tumor vascular networks,AuNP@PNA/DOX down-regulated the expression levels of HIF-1α,VEGF and MMP-9,and prompted more efficient activation on CD3+/CD8+T cells and the related cytokines,suggesting the synergistic effect between AuNP@PNA and DOX on the improvement of post-operative tumor immunosuppressive microenvironment.With their favorable pharmcokinetics and biocompatibility,AuNP@PNA/DOX is promising to be developed as a multi-functional artery-imaging/embolic agent with immune-chemo-embolization for enhancing TACE efficacy on HCC.
基金supported by grants from the Ministry of Science and Technology of China(Grant No.2021ZD0203202)the Natural Science Foundation of China(Grant Nos.31930021 and 32022035)。
文摘Sleep constitutes a third of human life and it is increasingly recognized as important for health.Over the past several decades,numerous genes have been identified to be involved in sleep regulation in animal models,but most of these genes when disturbed impair not only sleep but also health and physiological functions.Human natural short sleepers are individuals with lifelong short sleep and no obvious adverse outcomes associated with the lack of sleep.These traits appear to be heritable,and thus characterization of the genetic basis of natural short sleep provides an opportunity to study not only the genetic mechanism of human sleep but also the relationship between sleep and physiological function.This review focuses on the current understanding of mutations associated with the natural short sleep trait and the mechanisms by which they contribute to this trait.
基金Special Project on Precision Medicine under the National Key R&D Program of China(Grant Nos.2017YFC0906600 and 2018YFC0910500)National Natural Science Foundation of China(Grant Nos.31671360,81701567,and 31801095)+2 种基金National Program for Support of Top-Notch Young Professionals,Changjiang Scholars Program of Chinasupported by the program for HUST Academic Frontier Youth Team,Fundamental Research Funds for the Central Universities,China(Grant Nos.2017KFXKJC001 and 2019kfy RCPY043)China Postdoctoral Science Foundation(Grant Nos.2018M642816 and 2018M632870)
文摘In eukaryotes,protein phosphorylation is specifically catalyzed by numerous protein kinases(PKs),faithfully orchestrates various biological processes,and reversibly determines cellular dynamics and plasticity.Here we report an updated algorithm of Group-based Prediction System(GPS)5.0 to improve the performance for predicting kinase-specific phosphorylation sites(p-sites).Two novel methods,position weight determination(PWD)and scoring matrix optimization(SMO),were developed.Compared with other existing tools,GPS 5.0 exhibits a highly competitive accuracy.Besides serine/threonine or tyrosine kinases,GPS 5.0 also supports the prediction of dual-specificity kinase-specific p-sites.In the classical module of GPS 5.0,617 individual predictors were constructed for predicting p-sites of 479 human PKs.To extend the application of GPS5.0,a species-specific module was implemented to predict kinase-specific p-sites for 44,795 PKs in161 eukaryotes.The online service and local packages of GPS 5.0 are freely available for academic research at http://gps.biocuckoo.cn.
基金supported by grants from the National Basic Research Program(973 projectNo.2013CB933900)+1 种基金the Natural Science Foundation of China(Nos.31671360 andJ1103514)the International Science & Technology Cooperation Program of China (No.2014DFB30020)
文摘Post-translational modifications（PTMs） occurring at protein lysine residues,or protein lysine modifications（PLMs）,play critical roles in regulating biological processes.Due to the explosive expansion of the amount of PLM substrates and the discovery of novel PLM types,here we greatly updated our previous studies,and presented a much more integrative resource of protein lysine modification database（PLMD）.In PLMD,we totally collected and integrated 284,780 modification events in 53,501 proteins across 176 eukaryotes and prokaryotes for up to 20 types of PLMs,including ubiquitination, acetylation, sumoylation, methylation ,succinylation,malonylation,glutarylation,giycation,formylation,hydroxylation,butyrylation,propionylation,crotonylation,pupylation,neddylation,2-hydroxyisobutyrylation,phosphoglycerylation,carboxylation,lipoylation and biotinylation.Using the data set,a motif-based analysis was performed for each PLM type,and the results demonstrated that different PLM types preferentially recognize distinct sequence motifs for the modifications.Moreover,various PLMs synergistically orchestrate specific cellular biological processes by mutual crosstalks with each other,and we totally found 65,297 PLM events involved in 90 types of PLM co-occurrences on the same lysine residues.Finally,various options were provided for accessing the data,while original references and other annotations were also present for each PLM substrate.Taken together,we anticipated the PLMD database can serve as a useful resource for further researches of PLMs.PLMD 3.0 was implemented in PHP ＋ MySQL and freely available at http：//plmd.biocuckoo.org.
基金supported by the Special Project on Precision Medicine under the National Key R&D Program (2017YFC0906600)the Natural Science Foundation of China (No. 31671360)
文摘The integration, analysis and visualization of the big omics data are critical for addressing a broad spectrum of biological questions. One of the most frequently conducted procedures is enrichment analysis, which statistically tests whether individual functional an- notations of Gent Ontology （GO） or Kyoto Encyclopedia of Genes and Genomes （KEGG） are significantly over-or under-represented in an ＂interesting＂ gene or protein list against the reference set （Tavazoie et al., 1999）.
基金supported by the National Research and Development Program of China(2018YFA0208900,2020YFA0710700,and 2020YFA0211200)the National Science Foundation of China(82172757 and 31972927)+2 种基金the Program for HUST Academic Frontier Youth Team(2018QYTD01)the Scientific Research Foundation of HUST(3004170130)the HCP Program for HUST.
文摘Photodynamic therapy with reactive oxygen species production is a prospective treatment to combat cancer stem cells(CSCs).However,the innate drawbacks,including short lifetime and diffusion distance of reactive oxygen species and hypoxia within solid tumors,have become bottlenecks for clinical applications of photodynamic therapy.Here,we develop a mitochondria-targeting hemicyanine-oleic acid conjugate(CyOA),which can self-assemble into supramolecular nanoparticles(NPs)without any exogenous excipients.CyOA is also shown for targeting the mitochondrial complex II protein succinate dehydrogenase to inhibit oxidative phosphorylation and reverse tumor hypoxia,resulting in 50.4-fold higher phototoxicity against breast cancer stem cells(BCSCs)compared to SO_(3)-CyOA NPs that cannot target to mitochondria.In 4T1 and BCSC tumor models,CyOA NPs achieve higher tumor inhibition and less lung metastasis nodules compared to the clinically used photosensitizer Hiporfin.This study develops a self-assembled small molecule that can serve as both oxidative phosphorylation inhibitor and photosensitizer for eradication of CSCs and treatment of solid tumors.
基金supported by grants from The National Maritime Bureau Public Science and Technology Research Funds Projects of Ocean(No.201005013)the Wuhan Municipal Science and Technology Research Project of China(No.201260523185)
文摘Fucoidan is an active component of seaweed, which inhibits proliferation and induces apoptosis of several tumor cells while the detailed mechanisms underlying this process are still not clear. In this study, the effect of Fucoidan on the proliferation and apoptosis of human breast cancer MCF-7 cells and the molecular mechanism of Fucoidan action were investigated. Viable cell number of MCF-7 cells was decreased by Fucoidan treatment in a dose-dependent manner as measured by MTT assay. Fucoidan treatment resulted in G1 phase arrest of MCF-7 cells as revealed by flow cytometry, which was associated with the decrease in the gene expression of cyclin D 1 and CDK-4. Annexin V/PI staining results showed that the number of apoptotic cells was associated with regulation of cytochrome C, cas- pase-8, Bax and Bcl-2 at transcriptional and translational levels. Both morphologic observation and Hoechst 33258 assay results confirmed the pro-apoptotic effect of Fucoidan. Meanwhile, the ROS pro- duction was also increased by Fucoidan treatment, which suggested that Fucoidan induced oxidative damage in MCF-7 cells. The results of present study demonstrated that Fucoidan could induce GI phase arrest and apoptosis in MCF-7 cells through regulating the cell cycle and apoptosis-related genes or proteins expression, and ROS generation is also involved in these processes.
基金the National Natural Science Foundation of China (No. 30670736 and 30500168)the Department of Science and Technology of Jiangsu Province (No. BS2006533).
文摘γ -actin （ACTG1） gene is a cytoplasmic nonmuscle actin gene, which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea. Mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing loss linked to the DFNA 20/26 locus on chromosome 17q25.3 in European and American families, respectively. In this study, a novel missense mutation （c.364A〉G; p.I122V） co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 150 unrelated normal controls. The alteration of residue Ile122 was predicted to damage its interaction with actin-binding proteins, which may cause disruption of hair cell organization and function. These findings strongly suggested that the I122V mutation in ACTG1 caused autosomal dominant non-syndromic hearing impairment in a Chinese family and expanded the spectrum of ACTG1 mutations causing hearing loss.
基金funded by the National Key Research and Development Program of China(2021YFC2400404,to L.C.)the Key Program of National Natural Science of China(82030070,to L.C.)+1 种基金the National Science Foundation for Excellent Young Scholars of China(31725011,to L.C.)the Youth Clinical Research Fund of Chinese Stomatological Association(CSA-O2020-10,to Q.T.)。
文摘Bone regeneration remains a great clinical challenge. Low intensity near-infrared(NIR) light showed strong potential to promote tissue regeneration, offering a promising strategy for bone defect regeneration. However, the effect and underlying mechanism of NIR on bone regeneration remain unclear. We demonstrated that bone regeneration in the rat skull defect model was significantly accelerated with low-intensity NIR stimulation. In vitro studies showed that NIR stimulation could promote the osteoblast differentiation in bone mesenchymal stem cells(BMSCs) and MC3T3-E1 cells, which was associated with increased ubiquitination of the core circadian clock protein Cryptochrome 1(CRY1) in the nucleus. We found that the reduction of CRY1 induced by NIR light activated the bone morphogenetic protein(BMP) signaling pathways, promoting SMAD1/5/9 phosphorylation and increasing the expression levels of Runx2 and Osterix. NIR light treatment may act through sodium voltage-gated channel Scn4a, which may be a potential responder of NIR light to accelerate bone regeneration. Together, these findings suggest that low-intensity NIR light may promote in situ bone regeneration in a CRY1-dependent manner, providing a novel, efficient and non-invasive strategy to promote bone regeneration for clinical bone defects.
文摘Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.
文摘Recently, fluorescence technique becomes very useful. It can allow for addressing a fundamental problem of cellular mechanism besides characterizing the species inside the cell to facilitate the diagnostic and prognostic value. Manipulation with fluorescent dyes provides many possibilities for their use as tags, probes, and sensors. These types can be intrinsic or extrinsic to the cell. They can become not only silent observers, but also participants, modulators or disruptors of specific activities outline the biological functions can be successfully studied quantitatively and qualitatively with fluorescence techniques.
基金the National Research and Development Program of China(Nos.2018YFA0208900,2020YFA0211200,and 2020YFA0710700)the National Natural Science Foundation of China(Nos.82172757 and 31972927)+2 种基金the Scientific Research Foundation of Huazhong University of Science and Technology(No.3004170130)the Program for HUST Academic Frontier Youth Team(No.2018QYTD01)the HCP Program for HUST.
文摘Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-targeting nanomedicine by conjugating doxorubicin(DOX)-loaded hydroxyethyl starch-IR780 nanoparticles(NPs)with Cys-Arg-Glu-Lys-Ala(CREKA)peptide,which had a special affinity for fibronectin overexpressed on CAFs.After systemic administration,the NPs efficiently targeted CAFs and generated hyperthermia upon light irradiation,decreasing CAFs through the combination of chemo-and photothermal-therapies.Thus,a series of changes in TMME were achieved by reducing CAFs,which further disrupted the niche of cancer stem cells(CSCs)to affect their survival.As a result,the tumor growth was significantly inhibited in 4T1 tumors.The strategy of TMME modulation and CSCs elimination through targeting and depleting CAFs provides a novel therapeutic treatment for desmoplastic solid tumors.
基金We thank Professor S.Y.Liu for her revision suggestions for the article’s first draft.We acknowledge support from the CAS Research Fund,Grant No.XDB38050200the Self-supporting Program of Guangzhou Laboratory,Grant No.SRPG22-001 and SRPG22-007.
文摘The coronavirus disease 2019(COVID-19)pandemic had a devastating impact on human society.Beginning with genome surveillance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the development of omics technologies brought a clearer understanding of the complex SARS-CoV-2 and COVID-19.Here,we reviewed how omics,including genomics,proteomics,single-cell multi-omics,and clinical phenomics,play roles in answering biological and clinical questions about COVID-19.Large-scale sequencing and advanced analysis methods facilitate COVID-19 discovery from virus evolution and severity risk prediction to potential treatment identification.Omics would indicate precise and globalized prevention and medicine for the COVID-19 pandemic under the utilization of big data capability and phenotypes refinement.Furthermore,decoding the evolution rule of SARS-CoV-2 by deep learning models is promising to forecast new variants and achieve more precise data to predict future pandemics and prevent them on time.
基金Financial support was received from the National Key R&D Program of China(2017YFA0104200)the National Natural Science Foundation of China(No.91854108,81773182 and 31601121).
文摘Chaperone-mediated autophagy(CMA)is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.However,the mechanisms that regulate CMA are not fully understood.Here,using unbiased drug screening approaches,we discover Metformin,a drug that is commonly the first medication prescribed for type 2 diabetes,can induce CMA.We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA,Hsc70,and its activation.Notably,we find that amyloid-beta precursor protein(APP)is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner.The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity.Importantly,we find that in the APP/PS1 mouse model of Alzheimer's disease(AD),activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβplaque levels and reverses the molecular and behavioral AD phenotypes.Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases,such as AD,where such therapeutic intervention could be beneficial.
