Oral microbiota is an important part of the human microbiota.Oral microbes can be colonized into the intestine in various ways.Oral microbiota is associated with a variety of oral diseases.Recently,increasing evidence...Oral microbiota is an important part of the human microbiota.Oral microbes can be colonized into the intestine in various ways.Oral microbiota is associated with a variety of oral diseases.Recently,increasing evidence has shown that the oral microbiota is closely related to the physical state of humans,such as diabetes,obesity,and cancer.In the future,oral microbiota will become a new target for improving the physical state of humans.展开更多
Previous study have demonstrated that a compound composed of water-soluable Ganoderma lucidum polysaccharides(GLP)and Polyporus umbellatus polysaccharides(PUP)in a ratio of 3:1 named GPP enhances innate immune functio...Previous study have demonstrated that a compound composed of water-soluable Ganoderma lucidum polysaccharides(GLP)and Polyporus umbellatus polysaccharides(PUP)in a ratio of 3:1 named GPP enhances innate immune function in mice through enhancing the function of macrophage cells and activity of natural killer(NK)cells.Here in our research,we further investigated the effect of GPP on the diversity and composition of intestinal flora,and explored its effect on colitis model mice.The immunoregulatory verification experiments of GPP were conducted in both normal and DSS-induced mice model.Our research showed that GPP increased the diversity of intestinal microorganisms in mice with the extension of administration time.Daily GPP intake attenuated DSS-induced colon injury,protected the splenic lymphocyte proliferation ability,enhanced the serum hemolysin synthesis,and increased peripheral phagocytes and NK cell activity in model mice.Comparisons of the predominant gene pathways of the bacterial microbiota showed that DNA repair and recombination,base mismatch repair pathways was stronger in GPP-treatment group than in control group,indicating the possible molecular mechanisms of immune function regulation.Our study showed that GPP regulated immune function in both health and colitis model,and had a positive effect on maintaining intestinal flora homeostasis.展开更多
Dear Editor, Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups on histone and non-histone proteins, thereby playing a vital role in the modulation of gene expression and protein activity. ...Dear Editor, Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups on histone and non-histone proteins, thereby playing a vital role in the modulation of gene expression and protein activity. Eighteen HDACs have been identified in human and subdivided into four classes including I, II (Ila, lib), III and IV (Seto et al., 2014). Among them, HDAC6 is a unique lib HD AC with dominant cytoplasmic localization and two functional catalytic domains. Besides the functions for deacetylation of histone, and modulation of a-tubulin, HSP90 and cortactin, HDAC6 also participates in protein trafficking and degradation, cell shape and migration (Valenzuela-Fernandez et al., 2008). The deregulation of HDAC6 is related to various diseases, such as neurodegenerative diseases, cancer and pathological autoimmune response (Batchu et al., 2016). Hence, it is especially important for directly controlling cellular HDAC6 protein levels to achieve therapeutic purposes. The traditional approaches of red u ci ng cellular protein levels mainly rely on genetic modifications, such as RNA interference, transcription activator-like effector nucleases, recombination-based gene knockout and clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)(Boettcher et al., 2015). However, these approaches have failed to a certain degree to achieve acute and reversible changes of gene function. Furthermore, the complications of potential genetic compensation and/or spontaneous mutations arising in geneknockout models may lead to misinterpretations (Davisson etal., 2012;El-Brolosy etal., 2017). Therefore, it is urgent for developing a rapid, robust, and reversible approach to directly modulate HDAC6 protein levels.展开更多
In the original publication the title of X axis in Fig.1G is in correctly published as"Compound(pmol/L)".The correct title of X axis in Fig.1G should be read as"Compound(nmol/L)M.Figure 1.Development of...In the original publication the title of X axis in Fig.1G is in correctly published as"Compound(pmol/L)".The correct title of X axis in Fig.1G should be read as"Compound(nmol/L)M.Figure 1.Development of selective HDAC6-degrading PROTACs.(A)The principle of PROTAC.(B)The structure of PROTAC,as shown in the upper portion.A binding mode of PROTAC(ball stick),HDAC6(PDB 5G0J,purple)and CRL4-CRBN(PDB 2HYE and 4CI3,colored cyan and gray)was simulated by Pymol.展开更多
Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component ...Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.展开更多
The human gut microbiota is a huge ecosystem that provides lots of functions for host development,immune system,and metabolism.Gut microbiota is linked to lots of diseases,including human metabolic diseases such as ob...The human gut microbiota is a huge ecosystem that provides lots of functions for host development,immune system,and metabolism.Gut microbiota is linked to lots of diseases,including human metabolic diseases such as obesity,type 2 diabetes(T2D),irritable bowel syndrome,and cardiovascular disease(CVD).Few studies,however,have noted the relationship between aging and microbiota,the connection between aging and microbiota remain largely to be researched.In this review,recent research findings are summarized on the role of gut microbiota in aging processes with emphasis on therapeutic potential of microbiome-targeted interventions in anti-aging medicine.展开更多
OBJECTIVE To investigate the effect of Pinctadafucata mantle gene 1(pfmg1)on osteoporotic bone lossand the role in osteoblast differentiation and matrix mineralization,and to explore the molecular mechanismof how PFMG...OBJECTIVE To investigate the effect of Pinctadafucata mantle gene 1(pfmg1)on osteoporotic bone lossand the role in osteoblast differentiation and matrix mineralization,and to explore the molecular mechanismof how PFMG1 functions through both animal and cellular experiments.METHODS For animal experiments,female BALB/c mice were subjected to sham-operation(sham)or ovariectomy(ovx)at 5weeks of age,control and pfmg1 lentiviral particles were packaged and injected through tail vein to ovx mice(2×107TU/mouse),respectively.Bone mineral density(BMD)was detected 2 months after the surgery,and the proximal tibia was scanned in three dimensions byμCT.For cellular experiments,GST-PFMG1 protein was expressed and purified,then added to MC3T3E1 cell culture medium.MTT,ALP activity and the level of matrix mineralization were detected after the treatment.RESULTSEctopic expression of pfmg1 gene enhanced the BMD level of ovx mice.μCT images revealed that PFMG1 improvedthe osteoporotic characteristics caused by ovariectomy,including the decreases in trabecular number(Tb.N),trabecular thickness(Tb.Th),and in trabecular bone volume as a percentage of total bone volume(BV/TV);and the increases in trabecular spacing(Tb.Sp)and trabecular bone pattern factor(TBPf).The alkaline phosphatase(ALP)activity and the level of matrix mineralization increased,while the MTT activity decreased after treated with PFMG1 in the osteoblast cell line MC3T3E1.CONCLUSION PFMG1 from the mental of P.fucatacould promote osteoblast differentiation and matrix mineralization in vitro,and couldprevent bone loss caused by ovariectomy in vivo.These findings showed the potential of PFMG1 from nacre as a therapeutic drug for osteoporosis.展开更多
Background and Aims:Liver iron overload can induce hepatic expression of bone morphogenic protein(BMP)6 and activate the BMP/SMAD pathway.However,serum iron overload can also activate SMAD but does not induce BMP6 exp...Background and Aims:Liver iron overload can induce hepatic expression of bone morphogenic protein(BMP)6 and activate the BMP/SMAD pathway.However,serum iron overload can also activate SMAD but does not induce BMP6 expression.Therefore,the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear.This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.Methods:A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin(Holo-Tf).A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days.Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.Results:Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6.The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression;specifically,SMURF1 expression dramatically decreased when the serum iron concentration was increased.Additionally,the expression of SMURF1 substrates,which are important molecules involved in the transduction of BMP/SMAD signaling,was significantly upregulated.Furthermore,in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.Conclusions:SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.展开更多
This article has been retracted:please see Elsevier Policy on Article Withdrawal(https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the Editor.Th...This article has been retracted:please see Elsevier Policy on Article Withdrawal(https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the Editor.The authors have plagiarized part of a paper that had already appeared in Microbiome,2017,5(1):80,https://doi.org/10.1186/s40168-017-0296-0.One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere.Re-use of any data should be appropriately cited.As such this article represents a severe abuse of the scientific publishing system.The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.展开更多
DearEditor,The Arenaviridae family(recently assigned to the Bunyavirales order)is a group of emerging viruses that include causative agents of severe hemorrhagic fevers with high mortality in humans(de la Torre,2009)....DearEditor,The Arenaviridae family(recently assigned to the Bunyavirales order)is a group of emerging viruses that include causative agents of severe hemorrhagic fevers with high mortality in humans(de la Torre,2009).Lymphocytic choriomeningitis virus(LCMV)is the prototypic member of the Arenaviridae family and belongs to the Old World(OW)arenavirus together with Lassa virus(LASV),which are distinct from the New World(NW)arenavirus[e.g.Machupo virus(MACV)and Junin virus(JUNV)].LCMV infection in the fetus and newborm results in severe impairment of brain development associated with sensory loss and mental retardation and is also known to be associated with severe systemic infection with high mortality in transplantation patients(Palacios et al.,2008).展开更多
The Arabidopsis Jasmonate ZIM-domain proteins （JAZs） act as substrates of SCF complex to repress their downstream targets, which are essential for JA-regulated plant development and defense. The bHLH transcription f...The Arabidopsis Jasmonate ZIM-domain proteins （JAZs） act as substrates of SCF complex to repress their downstream targets, which are essential for JA-regulated plant development and defense. The bHLH transcription factor MYC2 was found to interact with JAZs and mediate JA responses including JA-inhibitory root growth. Here, we identified another bHLH transcription factor MYC3 which directly interacted with JAZs by virtue of its N-terminal region to regulate JA responses. The transgenic plants with overexpression of MYC3 exhibited hypersensitivity in JA-inhibitory root elon- gation and seedling development. The JAZ-interacting pattern and the JA-induced expression pattern of MYC3 were distinguishable from those of MYC2. We speculate that MYC3 and MYC2 may have redundant but also distinguishable functions in regulation of JA responses.展开更多
Angelica dahurica(A. dahurica) is a traditional Chinese medicinal plant being used in clinical practice. The present study demonstrated that A. dahurica could reduce white-fat weight in high-fat-diet hyperlipidemic mi...Angelica dahurica(A. dahurica) is a traditional Chinese medicinal plant being used in clinical practice. The present study demonstrated that A. dahurica could reduce white-fat weight in high-fat-diet hyperlipidemic mice, decrease total cholesterol and triglyceride concentrations in the livers of both high-fat-diet and Triton WR1339 induced hyperlipidemic mice, and enhance the total hepatic lipase activities of them. These findings were further supported by the results derived from the experiments with Hep G2 cells in vitro. In addition, the proteins related to lipids metabolism were investigated using LC-MS/MS, indicating that genes of lipid metabolism and lipid transport were regulated by A. dhurica. The results from LC-MS/MS were further conformed by Western blot and real time PCR assays. A. dahurica could down-regulate the expression of catalase(CAT) and sterol carrier protein2(SCP2) and up-regulate the expression of lipid metabolism related genes-lipase member C(LIPC) and peroxisome proliferator-activated receptor gamma(PPARγ). In the Triton WR1339 mouse liver and Hep G2 cells in vitro, A. dahurica was able to increase the expression of LIPC and PPARγ, confirming the results from in vivo experiments. Imperatorin showed the same activity as A. dahurica, suggesting it was one of the major active ingredients of the herb. In conclusion, our work represented a first investigation demonstrating that A. dahurica was able to regulate lipid metabolism and could be developed as a novel approach to fighting against fatty liver and obesity.展开更多
Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models....Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models.Ras-re-lated C3 botulinum toxin substrate 1(Rac1),a small GTPase,has been shown to regulate active forgetting in Drosophila and mice?Here,we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models.Moreover,amyloid-beta 42 could induce Rac1 activation in cultured cells.The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice,but also significantly contributed to severe memory loss in aged APP/PS1 mice.A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model.Moreover,inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models.Finally,two novel compounds,identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models,were found to be capable of inhibiting Rac1 activity.Thus,multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.展开更多
Objective: To explore the anti-nociceptive effect of patchouli alcohol(PA), the essential oil isolated from Pogostemon cablin(Blanco) Bent, and determine the mechanism in molecular levels. Methods: The acetic acid-ind...Objective: To explore the anti-nociceptive effect of patchouli alcohol(PA), the essential oil isolated from Pogostemon cablin(Blanco) Bent, and determine the mechanism in molecular levels. Methods: The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to con?rm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor(MOR). Cyclooxygenase 2(COX2)and MOR of mouse brain were expressed for determination of PA’s target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. Results: PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution(P<0.01) and allodynia after intra-plantar formalin(P<0.01) in mice. PA also up-regulated COX2 mRNA and protein(P<0.05) with a down-regulation of MOR(P<0.05) both in in vivo and in vitro experiments, which devote to the analgesic effect of PA. A decrease in the intracellular calcium level(P<0.05) induced by PA may play an important role in its anti-nociceptive effect.PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. Conclusions: Both COX2 and MOR are involved in the mechanism of PA’s anti-nociceptive effect,and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA’s effect on MOR.展开更多
Tripartite motif 33(TRIM33), a member of the transcription intermediate factor 1(TIF1) family of transcription cofactors,mediates transforming growth factor-beta(TGF-β) signaling through its PHD-Bromo cassette in mes...Tripartite motif 33(TRIM33), a member of the transcription intermediate factor 1(TIF1) family of transcription cofactors,mediates transforming growth factor-beta(TGF-β) signaling through its PHD-Bromo cassette in mesendoderm differentiation during early mouse embryonic development. However, the role of the TRIM33 RING domain in embryonic differentiation is less clear. Here, we report that TRIM33 mediates Wnt signaling by directly regulating the expression of a specific subset of Wnt target genes, and this action is independent of its RING domain. We show that TRIM33 interacts with β-catenin, a central player in Wnt signaling in mouse embryonic stem cells(mESCs). In contrast to previous reports in cancer cell lines, the RING domain does not appear to function as the E3 ligase for β-catenin, since neither knockout nor overexpression of TRIM33 had an effect on β-catenin protein levels in mESCs. Furthermore, we show that although TRIM33 seems to be dispensable for Wnt signaling through a reporter assay, loss of TRIM33 significantly impairs the expression of a subset of Wnt target genes, including Mixl1,in a Wnt signaling-dependent manner. Together, our results indicate that TRIM33 regulates Wnt signaling independent of the E3 ligase activity of its RING domain for β-catenin in mESCs.展开更多
Dear Editor,Animal models,most commonly mice,that lack a protein of interest play an important role in phenotypic and functional studies of a target gene,allowing researchers to answer various biological questions(Cha...Dear Editor,Animal models,most commonly mice,that lack a protein of interest play an important role in phenotypic and functional studies of a target gene,allowing researchers to answer various biological questions(Chaible et al,2010).At pre-sent,a variety of tools act at the DNA or RNA level to enable researchers to model gene function(and thus protein)deficiency,including nucleic acid based RNA interference(EI-bashir et al.,2001),antisense oligonucleotides(Schoch and Miller,2017),and genome editing-based CRISPR-Cas9(Doudna and Charpentier,2014)strategies.However,challenges remain.展开更多
4-Hydroxyphenylpyruvate dioxygenase(HPPD)is a promising target for drug and pesticide discovery.Te unknown binding mode of substrate is still a big challenge for the understanding of enzymatic reaction mechanism and n...4-Hydroxyphenylpyruvate dioxygenase(HPPD)is a promising target for drug and pesticide discovery.Te unknown binding mode of substrate is still a big challenge for the understanding of enzymatic reaction mechanism and novel HPPD inhibitor design.Herein,we determined the frst crystal structure of Arabidopsis thaliana HPPD(AtHPPD)in complex with its natural substrate(HPPA)at a resolution of 2.80˚A.Ten,combination of hybrid quantum mechanics/molecular mechanics(QM/MM)calculations confrmed that HPPA takes keto rather than enol form inside the HPPD active pocket.Subsequent site-directed mutagenesis and kinetic analysis further showed that residues(Phe424,Asn423,Glu394,Gln307,Asn282,and Ser267)played important roles in substrate binding and catalytic cycle.Structural comparison between HPPA-AtHPPD and holo-AtHPPD revealed that Gln293 underwent a remarkable rotation upon the HPPA binding and formed H-bond network of Ser267-Asn282-Gln307-Gln293,resulting in the transformation of HPPD from an inactive state to active state.Finally,taking the conformation change of Gln293 as a target,we proposed a new strategy of blocking the transformation of HPPD from inactive state to active state to design a novel inhibitor with K_(i) value of 24.10 nM towards AtHPPD.Te inhibitor has entered into industry development as the frst selective herbicide used for the weed control in sorghum feld.Te crystal structure of AtHPPD in complex with the inhibitor(2.40˚A)confrmed the rationality of the design strategy.We believe that the present work provides a new starting point for the understanding of enzymatic reaction mechanism and the design of next generation HPPD inhibitors.展开更多
The p21 activated kinase 4(PAK4) is serine/threonine protein kinase that is critical for cancer progression.Guided by X-ray crystallography and structure-based optimization,we report a novel subseries of C-3-substitut...The p21 activated kinase 4(PAK4) is serine/threonine protein kinase that is critical for cancer progression.Guided by X-ray crystallography and structure-based optimization,we report a novel subseries of C-3-substituted 6-ethynyl-1 H-indole derivatives that display high potential and specificity towards group Ⅱ PAKs.Among these inhibitors,compound 55 exhibited excellent inhibitory activity and kinase selectivity,displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16.Compound 55 exhibited potent in vivo antitumor metastatic efficacy,with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models,respectively.Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition(EMT).展开更多
Berberine （BBR） is a natural small molecule with various pharmacological activities and biological targets. BBR has been shown to inhibit mRNA decay in our previous studies, which is associated with its high binding...Berberine （BBR） is a natural small molecule with various pharmacological activities and biological targets. BBR has been shown to inhibit mRNA decay in our previous studies, which is associated with its high binding affinity to the poly-adenine （poly A） tail at the 3＇ end of mRNA. However, the exact mechanism remains unknown. In this research, we discovered that deficiency of cytoplasmic poly A binding protein （PABP）, which protects mRNA from nucleolytic attack as a poly A-PABP complex, led to the loss of BBR＇s effect on mRNA decay inhibition. We also demonstrated using fluorescence spectroscopy, RNA-EMSA （RNA-electrophoretic mobility shift assay） in vitro, and RIP （RNA immunoprecipitation） that BBR could significantly promote PABP binding to poly A. We might conclude that BBR could stabilize mRNA by enhancing the interaction between poly A and PABP. In addition, the HMBC （~H detected heteronuclear multiple bond correlation） studies demonstrated that BBR could bind to AMP, a monomer of poly A, directly and specifically. Further evidence of molecular docking suggested that BBR might act as a linker to stabilize the poly A-PABP, and elongate the half-life of mRNAs. This demonstrates that BBR might affect protein translation initiation and up-regulate protein expression.展开更多
The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-...The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-β activated kinase 1 (TAK1) is an upstream kinase in p38α signaling, and its full activation requires a specific activator, the TAK1-binding protein (TAB1). TAB1 was also shown to be an inducer of p38α's autophosphorylation and/or a substrate driving the feedback control of p38α signaling. Here we determined the complex structure of the unphosphorylated p38α and a docking peptide of TAB1, which shows that the TAB1 peptide binds to the classical MAPK docking groove and induces long-range conformational changes on p38α. Our structural and biochemical analyses suggest that TAB1 is a reasonable substrate of p38α, yet the interaction between the docking peptide and p38α may not be sufficient to trigger trans-autophosphorylation of p38α.展开更多
基金the National Key R&D Program of China(2018YFD0400204)the Key International S&T Cooperation Program of China(2016YFE113700)+3 种基金the European Union’s Horizon 2020 Research and Innovation Program(633589)the National Natural Science Foundation of China(81471396,81871095)SME Technology Innovation Fund Program funded by Hebei science and Technology Office(No.000218018/2015-00337)The Introduction of Foreign Intelligence Program funded by Hebei Provincial Department of Human Resource and Social security(000218296/2005-00593).
文摘Oral microbiota is an important part of the human microbiota.Oral microbes can be colonized into the intestine in various ways.Oral microbiota is associated with a variety of oral diseases.Recently,increasing evidence has shown that the oral microbiota is closely related to the physical state of humans,such as diabetes,obesity,and cancer.In the future,oral microbiota will become a new target for improving the physical state of humans.
基金financially supported by grants from the National Key R&D Program of China(2018YFD0400204)the National Natural Science Foundation of China(81974503,81871095)the Key International S&T Cooperation Program of China(2016YFE113700)。
文摘Previous study have demonstrated that a compound composed of water-soluable Ganoderma lucidum polysaccharides(GLP)and Polyporus umbellatus polysaccharides(PUP)in a ratio of 3:1 named GPP enhances innate immune function in mice through enhancing the function of macrophage cells and activity of natural killer(NK)cells.Here in our research,we further investigated the effect of GPP on the diversity and composition of intestinal flora,and explored its effect on colitis model mice.The immunoregulatory verification experiments of GPP were conducted in both normal and DSS-induced mice model.Our research showed that GPP increased the diversity of intestinal microorganisms in mice with the extension of administration time.Daily GPP intake attenuated DSS-induced colon injury,protected the splenic lymphocyte proliferation ability,enhanced the serum hemolysin synthesis,and increased peripheral phagocytes and NK cell activity in model mice.Comparisons of the predominant gene pathways of the bacterial microbiota showed that DNA repair and recombination,base mismatch repair pathways was stronger in GPP-treatment group than in control group,indicating the possible molecular mechanisms of immune function regulation.Our study showed that GPP regulated immune function in both health and colitis model,and had a positive effect on maintaining intestinal flora homeostasis.
基金National Natural Science Foundation of China (Grant Nos. 81573277, 81622042 and 81773567)National Major Scientific and Technological Special Project for "Significant New Drugs Development"(#SQ2017ZX095003)+2 种基金Drug Innovatio n Major Project (2018ZX09711 -001)Tsinghua University Initiative Scientific Research Program to YRthe National Natural Science Foundation of China (Grant No. 81672950) to WW.
文摘Dear Editor, Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups on histone and non-histone proteins, thereby playing a vital role in the modulation of gene expression and protein activity. Eighteen HDACs have been identified in human and subdivided into four classes including I, II (Ila, lib), III and IV (Seto et al., 2014). Among them, HDAC6 is a unique lib HD AC with dominant cytoplasmic localization and two functional catalytic domains. Besides the functions for deacetylation of histone, and modulation of a-tubulin, HSP90 and cortactin, HDAC6 also participates in protein trafficking and degradation, cell shape and migration (Valenzuela-Fernandez et al., 2008). The deregulation of HDAC6 is related to various diseases, such as neurodegenerative diseases, cancer and pathological autoimmune response (Batchu et al., 2016). Hence, it is especially important for directly controlling cellular HDAC6 protein levels to achieve therapeutic purposes. The traditional approaches of red u ci ng cellular protein levels mainly rely on genetic modifications, such as RNA interference, transcription activator-like effector nucleases, recombination-based gene knockout and clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)(Boettcher et al., 2015). However, these approaches have failed to a certain degree to achieve acute and reversible changes of gene function. Furthermore, the complications of potential genetic compensation and/or spontaneous mutations arising in geneknockout models may lead to misinterpretations (Davisson etal., 2012;El-Brolosy etal., 2017). Therefore, it is urgent for developing a rapid, robust, and reversible approach to directly modulate HDAC6 protein levels.
文摘In the original publication the title of X axis in Fig.1G is in correctly published as"Compound(pmol/L)".The correct title of X axis in Fig.1G should be read as"Compound(nmol/L)M.Figure 1.Development of selective HDAC6-degrading PROTACs.(A)The principle of PROTAC.(B)The structure of PROTAC,as shown in the upper portion.A binding mode of PROTAC(ball stick),HDAC6(PDB 5G0J,purple)and CRL4-CRBN(PDB 2HYE and 4CI3,colored cyan and gray)was simulated by Pymol.
基金financially supported by grants from the National Natural Science Foundation of China(8217087381871095)+1 种基金the National Key R&D Program of China(2018YFC2000304)the Tsinghua University Spring Breeze Fund(20211080005).
文摘Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.
基金This work was financially supported by grants from the National Key R&D Program of China(2018YFD0400204)the Key International S&T Cooperation Program of China(2016YFE113700)+1 种基金the European Union’s Horizon 2020 Research and Innovation Program(633589)the National Natural Science Foundation of China(81471396).
文摘The human gut microbiota is a huge ecosystem that provides lots of functions for host development,immune system,and metabolism.Gut microbiota is linked to lots of diseases,including human metabolic diseases such as obesity,type 2 diabetes(T2D),irritable bowel syndrome,and cardiovascular disease(CVD).Few studies,however,have noted the relationship between aging and microbiota,the connection between aging and microbiota remain largely to be researched.In this review,recent research findings are summarized on the role of gut microbiota in aging processes with emphasis on therapeutic potential of microbiome-targeted interventions in anti-aging medicine.
基金The project supported by Tsinghua University Initiative Scientific Research Program(2011THZ0)the National Natural Science Foundation of China(81270425)
文摘OBJECTIVE To investigate the effect of Pinctadafucata mantle gene 1(pfmg1)on osteoporotic bone lossand the role in osteoblast differentiation and matrix mineralization,and to explore the molecular mechanismof how PFMG1 functions through both animal and cellular experiments.METHODS For animal experiments,female BALB/c mice were subjected to sham-operation(sham)or ovariectomy(ovx)at 5weeks of age,control and pfmg1 lentiviral particles were packaged and injected through tail vein to ovx mice(2×107TU/mouse),respectively.Bone mineral density(BMD)was detected 2 months after the surgery,and the proximal tibia was scanned in three dimensions byμCT.For cellular experiments,GST-PFMG1 protein was expressed and purified,then added to MC3T3E1 cell culture medium.MTT,ALP activity and the level of matrix mineralization were detected after the treatment.RESULTSEctopic expression of pfmg1 gene enhanced the BMD level of ovx mice.μCT images revealed that PFMG1 improvedthe osteoporotic characteristics caused by ovariectomy,including the decreases in trabecular number(Tb.N),trabecular thickness(Tb.Th),and in trabecular bone volume as a percentage of total bone volume(BV/TV);and the increases in trabecular spacing(Tb.Sp)and trabecular bone pattern factor(TBPf).The alkaline phosphatase(ALP)activity and the level of matrix mineralization increased,while the MTT activity decreased after treated with PFMG1 in the osteoblast cell line MC3T3E1.CONCLUSION PFMG1 from the mental of P.fucatacould promote osteoblast differentiation and matrix mineralization in vitro,and couldprevent bone loss caused by ovariectomy in vivo.These findings showed the potential of PFMG1 from nacre as a therapeutic drug for osteoporosis.
基金supported by the National Natural Science Foundation of China(No.82370898)Beijing Natural Science Foundation(No.7202034).
文摘Background and Aims:Liver iron overload can induce hepatic expression of bone morphogenic protein(BMP)6 and activate the BMP/SMAD pathway.However,serum iron overload can also activate SMAD but does not induce BMP6 expression.Therefore,the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear.This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.Methods:A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin(Holo-Tf).A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days.Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.Results:Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6.The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression;specifically,SMURF1 expression dramatically decreased when the serum iron concentration was increased.Additionally,the expression of SMURF1 substrates,which are important molecules involved in the transduction of BMP/SMAD signaling,was significantly upregulated.Furthermore,in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.Conclusions:SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.
文摘This article has been retracted:please see Elsevier Policy on Article Withdrawal(https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the Editor.The authors have plagiarized part of a paper that had already appeared in Microbiome,2017,5(1):80,https://doi.org/10.1186/s40168-017-0296-0.One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere.Re-use of any data should be appropriately cited.As such this article represents a severe abuse of the scientific publishing system.The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.
基金facility support.This work was supported by the National Natural Science Foundation of China(32188101 and U20A20135)the National Program on Key Research Project of China(2020YFA0707500),and Tsinghua University Spring Breeze Fund.
文摘DearEditor,The Arenaviridae family(recently assigned to the Bunyavirales order)is a group of emerging viruses that include causative agents of severe hemorrhagic fevers with high mortality in humans(de la Torre,2009).Lymphocytic choriomeningitis virus(LCMV)is the prototypic member of the Arenaviridae family and belongs to the Old World(OW)arenavirus together with Lassa virus(LASV),which are distinct from the New World(NW)arenavirus[e.g.Machupo virus(MACV)and Junin virus(JUNV)].LCMV infection in the fetus and newborm results in severe impairment of brain development associated with sensory loss and mental retardation and is also known to be associated with severe systemic infection with high mortality in transplantation patients(Palacios et al.,2008).
文摘The Arabidopsis Jasmonate ZIM-domain proteins （JAZs） act as substrates of SCF complex to repress their downstream targets, which are essential for JA-regulated plant development and defense. The bHLH transcription factor MYC2 was found to interact with JAZs and mediate JA responses including JA-inhibitory root growth. Here, we identified another bHLH transcription factor MYC3 which directly interacted with JAZs by virtue of its N-terminal region to regulate JA responses. The transgenic plants with overexpression of MYC3 exhibited hypersensitivity in JA-inhibitory root elon- gation and seedling development. The JAZ-interacting pattern and the JA-induced expression pattern of MYC3 were distinguishable from those of MYC2. We speculate that MYC3 and MYC2 may have redundant but also distinguishable functions in regulation of JA responses.
基金supported in part by National Natural Science Foundation of China(Nos.81473321 and 81374006)the National Key Technology R&D Program of China(No.2012BAI29B02)the National S&T Major Special Project for New Drug R&D Program of China(Nos.2012ZX09102-201-008,2012ZX09103-201-041,and 2011ZX09101-002-11)
文摘Angelica dahurica(A. dahurica) is a traditional Chinese medicinal plant being used in clinical practice. The present study demonstrated that A. dahurica could reduce white-fat weight in high-fat-diet hyperlipidemic mice, decrease total cholesterol and triglyceride concentrations in the livers of both high-fat-diet and Triton WR1339 induced hyperlipidemic mice, and enhance the total hepatic lipase activities of them. These findings were further supported by the results derived from the experiments with Hep G2 cells in vitro. In addition, the proteins related to lipids metabolism were investigated using LC-MS/MS, indicating that genes of lipid metabolism and lipid transport were regulated by A. dhurica. The results from LC-MS/MS were further conformed by Western blot and real time PCR assays. A. dahurica could down-regulate the expression of catalase(CAT) and sterol carrier protein2(SCP2) and up-regulate the expression of lipid metabolism related genes-lipase member C(LIPC) and peroxisome proliferator-activated receptor gamma(PPARγ). In the Triton WR1339 mouse liver and Hep G2 cells in vitro, A. dahurica was able to increase the expression of LIPC and PPARγ, confirming the results from in vivo experiments. Imperatorin showed the same activity as A. dahurica, suggesting it was one of the major active ingredients of the herb. In conclusion, our work represented a first investigation demonstrating that A. dahurica was able to regulate lipid metabolism and could be developed as a novel approach to fighting against fatty liver and obesity.
文摘Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models.Ras-re-lated C3 botulinum toxin substrate 1(Rac1),a small GTPase,has been shown to regulate active forgetting in Drosophila and mice?Here,we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models.Moreover,amyloid-beta 42 could induce Rac1 activation in cultured cells.The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice,but also significantly contributed to severe memory loss in aged APP/PS1 mice.A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model.Moreover,inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models.Finally,two novel compounds,identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models,were found to be capable of inhibiting Rac1 activity.Thus,multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.
基金Supported by the National Natural Science Foundation of China(No.81374006 and No.81073092)the Special Foundation for New Drug Innovation of Tsinghua University(No.20142000077),China
文摘Objective: To explore the anti-nociceptive effect of patchouli alcohol(PA), the essential oil isolated from Pogostemon cablin(Blanco) Bent, and determine the mechanism in molecular levels. Methods: The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to con?rm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor(MOR). Cyclooxygenase 2(COX2)and MOR of mouse brain were expressed for determination of PA’s target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. Results: PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution(P<0.01) and allodynia after intra-plantar formalin(P<0.01) in mice. PA also up-regulated COX2 mRNA and protein(P<0.05) with a down-regulation of MOR(P<0.05) both in in vivo and in vitro experiments, which devote to the analgesic effect of PA. A decrease in the intracellular calcium level(P<0.05) induced by PA may play an important role in its anti-nociceptive effect.PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. Conclusions: Both COX2 and MOR are involved in the mechanism of PA’s anti-nociceptive effect,and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA’s effect on MOR.
基金supported by the National Natural Science Foundation of China (20141300584, 20151301548 to Qiaoran Xi)the THU-PKU Center for Life Sciences
文摘Tripartite motif 33(TRIM33), a member of the transcription intermediate factor 1(TIF1) family of transcription cofactors,mediates transforming growth factor-beta(TGF-β) signaling through its PHD-Bromo cassette in mesendoderm differentiation during early mouse embryonic development. However, the role of the TRIM33 RING domain in embryonic differentiation is less clear. Here, we report that TRIM33 mediates Wnt signaling by directly regulating the expression of a specific subset of Wnt target genes, and this action is independent of its RING domain. We show that TRIM33 interacts with β-catenin, a central player in Wnt signaling in mouse embryonic stem cells(mESCs). In contrast to previous reports in cancer cell lines, the RING domain does not appear to function as the E3 ligase for β-catenin, since neither knockout nor overexpression of TRIM33 had an effect on β-catenin protein levels in mESCs. Furthermore, we show that although TRIM33 seems to be dispensable for Wnt signaling through a reporter assay, loss of TRIM33 significantly impairs the expression of a subset of Wnt target genes, including Mixl1,in a Wnt signaling-dependent manner. Together, our results indicate that TRIM33 regulates Wnt signaling independent of the E3 ligase activity of its RING domain for β-catenin in mESCs.
文摘Dear Editor,Animal models,most commonly mice,that lack a protein of interest play an important role in phenotypic and functional studies of a target gene,allowing researchers to answer various biological questions(Chaible et al,2010).At pre-sent,a variety of tools act at the DNA or RNA level to enable researchers to model gene function(and thus protein)deficiency,including nucleic acid based RNA interference(EI-bashir et al.,2001),antisense oligonucleotides(Schoch and Miller,2017),and genome editing-based CRISPR-Cas9(Doudna and Charpentier,2014)strategies.However,challenges remain.
基金We thank Dr.Jiang-Qing Dong for the help in structural analysis and Dr.Jun-Jun Liu for the help in QM-MM calculation.This work was funded in part by the National Key Research and Development Program of China(no.2017YFD0200500)National Natural Science Foundation of China(nos.21837001 and 21672079)+1 种基金Hubei Province Natural Science Foundation(no.2018CFA072)the self-determined research funds of Central China Normal University(CCNU18ZDPY01 and CCNU18TS007)from the colleges’basic research and operation of MOE.We thank the Shanghai Synchrotron Radiation Facility for providing the facility support.
文摘4-Hydroxyphenylpyruvate dioxygenase(HPPD)is a promising target for drug and pesticide discovery.Te unknown binding mode of substrate is still a big challenge for the understanding of enzymatic reaction mechanism and novel HPPD inhibitor design.Herein,we determined the frst crystal structure of Arabidopsis thaliana HPPD(AtHPPD)in complex with its natural substrate(HPPA)at a resolution of 2.80˚A.Ten,combination of hybrid quantum mechanics/molecular mechanics(QM/MM)calculations confrmed that HPPA takes keto rather than enol form inside the HPPD active pocket.Subsequent site-directed mutagenesis and kinetic analysis further showed that residues(Phe424,Asn423,Glu394,Gln307,Asn282,and Ser267)played important roles in substrate binding and catalytic cycle.Structural comparison between HPPA-AtHPPD and holo-AtHPPD revealed that Gln293 underwent a remarkable rotation upon the HPPA binding and formed H-bond network of Ser267-Asn282-Gln307-Gln293,resulting in the transformation of HPPD from an inactive state to active state.Finally,taking the conformation change of Gln293 as a target,we proposed a new strategy of blocking the transformation of HPPD from inactive state to active state to design a novel inhibitor with K_(i) value of 24.10 nM towards AtHPPD.Te inhibitor has entered into industry development as the frst selective herbicide used for the weed control in sorghum feld.Te crystal structure of AtHPPD in complex with the inhibitor(2.40˚A)confrmed the rationality of the design strategy.We believe that the present work provides a new starting point for the understanding of enzymatic reaction mechanism and the design of next generation HPPD inhibitors.
基金supported by National Natural Science Foundation of China (Grant Nos.81230077,81872729 and 22077086)Overseas Expertise Introduction Project for Discipline Innovation (Grant No.D20029,China)Program for Innovative Talents of Higher Education of Liaoning (2012520005,China)。
文摘The p21 activated kinase 4(PAK4) is serine/threonine protein kinase that is critical for cancer progression.Guided by X-ray crystallography and structure-based optimization,we report a novel subseries of C-3-substituted 6-ethynyl-1 H-indole derivatives that display high potential and specificity towards group Ⅱ PAKs.Among these inhibitors,compound 55 exhibited excellent inhibitory activity and kinase selectivity,displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16.Compound 55 exhibited potent in vivo antitumor metastatic efficacy,with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models,respectively.Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition(EMT).
基金National Natural Science Foundation of China(Grant No.81374006,81073092 and 90713043)
文摘Berberine （BBR） is a natural small molecule with various pharmacological activities and biological targets. BBR has been shown to inhibit mRNA decay in our previous studies, which is associated with its high binding affinity to the poly-adenine （poly A） tail at the 3＇ end of mRNA. However, the exact mechanism remains unknown. In this research, we discovered that deficiency of cytoplasmic poly A binding protein （PABP）, which protects mRNA from nucleolytic attack as a poly A-PABP complex, led to the loss of BBR＇s effect on mRNA decay inhibition. We also demonstrated using fluorescence spectroscopy, RNA-EMSA （RNA-electrophoretic mobility shift assay） in vitro, and RIP （RNA immunoprecipitation） that BBR could significantly promote PABP binding to poly A. We might conclude that BBR could stabilize mRNA by enhancing the interaction between poly A and PABP. In addition, the HMBC （~H detected heteronuclear multiple bond correlation） studies demonstrated that BBR could bind to AMP, a monomer of poly A, directly and specifically. Further evidence of molecular docking suggested that BBR might act as a linker to stabilize the poly A-PABP, and elongate the half-life of mRNAs. This demonstrates that BBR might affect protein translation initiation and up-regulate protein expression.
基金supported in part by National Natural Science Foundation of China (31130062, 31070643)Tsinghua University (20121080028)
文摘The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-β activated kinase 1 (TAK1) is an upstream kinase in p38α signaling, and its full activation requires a specific activator, the TAK1-binding protein (TAB1). TAB1 was also shown to be an inducer of p38α's autophosphorylation and/or a substrate driving the feedback control of p38α signaling. Here we determined the complex structure of the unphosphorylated p38α and a docking peptide of TAB1, which shows that the TAB1 peptide binds to the classical MAPK docking groove and induces long-range conformational changes on p38α. Our structural and biochemical analyses suggest that TAB1 is a reasonable substrate of p38α, yet the interaction between the docking peptide and p38α may not be sufficient to trigger trans-autophosphorylation of p38α.
