Regulation of the number of aetivin receptors that are present in the cell membrane plays a key role in the modulation of cellular responses to activin. In order to find the regulators, a novel protein ARIPzip, intera...Regulation of the number of aetivin receptors that are present in the cell membrane plays a key role in the modulation of cellular responses to activin. In order to find the regulators, a novel protein ARIPzip, interacting with activin type II receptors, was searched and identified by using yeast two-hybrid screening. ARIPzip is a splicing variant of ARIP2. This has been discussed previously. ARIPzip can specifically interact with ActR Ⅱ A, and is widely distributed in mouse tissues. Overexpression of ARIPzip can cause the activin-induced transcriptional activities to increase in a dose-dependent manner while the overexpression of ARIV2 can decrease these activities. These data suggest that the C-terminal rezions of ARIP2 and ARIPzip are involved in the regulation of activin signaling.展开更多
Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine（DA）system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4（TLR4）, an important pattern...Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine（DA）system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4（TLR4）, an important pattern-recognition receptor in the innate immune system,can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient（TLR4^（-/-））and wild-type（WT） mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed,large spaces. We found that TLR4^（-/-）mice exhibitedreduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4^（-/-）mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4^（-/-）mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly,the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell（NAc Sh） in TLR4^（-/-）mice than in WT mice. Partially inactivating the NAc Sh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4^（-/-）mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAc Sh may contribute to this phenomenon.展开更多
Tumor necrosis factor-α(TNF-α)is a key player in the pathogenesis of rheumatoid arthritis(RA)and considered a promising target for therapeutic drug development.Activation of the nuclear factor-kappa B(NF-κB)pathway...Tumor necrosis factor-α(TNF-α)is a key player in the pathogenesis of rheumatoid arthritis(RA)and considered a promising target for therapeutic drug development.Activation of the nuclear factor-kappa B(NF-κB)pathway upon TNF-αbinding to its receptor is crucial for progression of RA.Stephanine(SA),an isoquinoline aporphine-type alkaloid recently identified in Stephania plants,exhibits anti-inflammatory properties,but its underlying mechanisms of action are unknown at present.In this study,we explored whether SA could ameliorate RA through inhibition of the NF-κB signaling pathway in association with TNF-αactivity.Our experiments revealed a binding affinity(K_(D))of SA for TNF-αof 2.934×10^(-6)mol/L.Additionally,SA at a concentration of 10μmol/L effectively hindered the binding of TNF-αto its receptors tumor necrosis factor receptor 1(TNFR1)and TNFR2.In vitro,SA prevented TNF-α-induced death of L929 cells and blocked NF-κB activation triggered by TNF-αin 293-TNF-αresponsive,as well as human fibroblast-like synoviocytes(HFLS)and human RA fibroblast-like synoviocytes(MH7A)cell lines.Furthermore,in a collagen-induced arthritis(CIA)mouse model,SA alleviated the symptoms of RA through suppression of NF-κB signaling.Our collective findings support the therapeutic efficacy of SA,a natural compound targeting TNF-α,in the management of RA.展开更多
OBJECTIVE:To evaluate the effects of Sanren Tang(SRT,三仁汤)on a high-fat diet(HFD)-induced non-alcoholic fatty liver disease(NAFLD)in mice and to investigate the hepatic transcriptome regulated by SRT.METHODS:The pri...OBJECTIVE:To evaluate the effects of Sanren Tang(SRT,三仁汤)on a high-fat diet(HFD)-induced non-alcoholic fatty liver disease(NAFLD)in mice and to investigate the hepatic transcriptome regulated by SRT.METHODS:The primary SRT components were identified using ultra-high-performance liquid chromatography-high-resolution accurate mass spectrometry.The SRT-induced pharmacological effects on HFD-induced NAFLD were evaluated in mice for 16 weeks.Obeticholic acid was used as a control drug.Body weight,food intake,and homeostatic model assessment for insulin resistance(HOMA-IR)index were analysed.Hepatic histological changes were observed in haematoxylin and eosin-stained sections and quantified using the NAFLD activity score(NAS).Serum alanine aminotransferase(ALT)and hepatic triglyceride(TG)levels were measured.Lipids in hepatocytes were visualised by Oil red staining.RNA-sequencing was performed to determine the transcriptome profile of the liver tissue.The differentially expressed genes were validated using real-time polymerase chain reaction and Western blotting.RESULTS:Four principal compounds were identified in the SRT:adenosine,amygdalin,luteoloside,and magnolol.SRT ameliorated hepatic histology and lipid deposition in the NAFLD mice,and decreased HOMA-IR,NAS and ALT,and hepatic TG levels.Hepatic transcriptome analysis revealed 232 HFD-regulated genes that were reversed by SRT simultaneously.Retinol metabolism,cytokine-cytokine receptor interaction,and peroxisome proliferator-activated receptor(PPAR)γsignalling were the top three SRT-regulated pathways in NAFLD.CONCLUSIONS:SRT significantly ameliorated HFD-induced NAFLD,which was correlated with the regulation of genes enriched in the retinol metabolism,cytokine-cytokine receptor interaction,and PPARγsignalling pathways.展开更多
The mirid bug Apolygus lucorum(Hemiptera:Miridae)is a polyphagous pest that affects a wide range of host plants.Its control remains challenging mainly due to its rapid reproduction,necessitating an understanding of se...The mirid bug Apolygus lucorum(Hemiptera:Miridae)is a polyphagous pest that affects a wide range of host plants.Its control remains challenging mainly due to its rapid reproduction,necessitating an understanding of sex pheromone communication.The recognition of sex pheromones is vital for courtship and mating behaviors,and is mediated by various chemosensory-associated proteins.Among these,sensory neuron membrane protein(SNMP),a CD36-related protein,is suggested to play crucial roles in detecting sex pheromones.In this study,we employed transcriptomic and genomic data from A.lucorum and phylogenetic approaches,and identified four putative SNMP genes(AlucSNMP1a,AlucSNMP1b,AlucSNMP2a,and AlucSNMP2b)with full open reading frames.Expression analysis revealed the ubiquitous presence of AlucSNMP transcripts in multiple tissues,with only AlucSNMP1a exhibiting male-biased expression in the antennae,suggesting its potential role in male chemosensation.Functional analysis using the Xenopus oocyte expression system,coupled with two-electrode voltage clamp recording,demonstrated that the co-expression of AlucSNMP1a with specific pheromone receptors(PRs)and the Odorant receptor co-receptor(Orco)significantly enhanced electrophysiological responses to sex pheromones compared to the co-expression of PRs and Orco alone.Moreover,the results indicated that the presence of AlucSNMP1a not only affected the responsiveness to sex pheromones but also influenced the kinetics(activation and inactivation)of the induced signals.In contrast,the co-expression of AlucSNMP1b with AlucPR/Orco complexes had no impact on the inward currents induced by two pheromone compounds.An examination of the selective pressures on SNMP1 genes across 20 species indicated strong purifying selection,implying potential functional conservation in various insects.These findings highlight the crucial role of AlucSNMP1a in the response to sex pheromones.展开更多
BACKGROUND Receptor interacting protein kinase 1(RIPK1)-mediated cell death,including apoptosis and necroptosis,belongs to programmed cell death.It has been reported that RIPK1-mediated necroptosis exists in lesions o...BACKGROUND Receptor interacting protein kinase 1(RIPK1)-mediated cell death,including apoptosis and necroptosis,belongs to programmed cell death.It has been reported that RIPK1-mediated necroptosis exists in lesions of cerebral hemorrhage(CH).Electroacupuncture,a treatment derived from traditional Chinese medicine,could improve neurological impairment in patients with brain injury.AIM To investigate the protective role of cross electro-nape acupuncture(CENA)in CH,and clarify the potential mechanism.METHODS CH rat models were established,and CENA was applied to the experimental rats.Neurological functions and encephaledema were then measured.Necrotic cells in the brain of rats with CH were evaluated by propidium iodide staining.Necroptosis was assessed by immunofluorescence.Activation of the necroptosisrelated pathway was detected by western blot.Extraction of brain tissue,cerebrospinal fluid and serum samples was conducted to measure the expression and secretion of inflammatory cytokines by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay.RESULTS The necroptotic marker p-MLKL was detectable in the brains of rats with CH.Next,we found that CENA could ameliorate neurological functions in rat models of CH.Moreover,the upregulation of RIPK1-mediated necroptosis-related molecules in the brains of rats with CH were inhibited by CENA.Further investigation revealed that CENA partially blocked the interaction between RIPK1 and RIPK3.Finally,in vivo assays showed that CENA decreased the expression of the inflammatory cytokines tumor necrosis factor-α,interleukin-6 and interleukin-8 in CH rat models.CONCLUSION These findings revealed that CENA exerts a protective role in CH models by inhibiting RIPK1-mediated necroptosis.展开更多
Guo-Qiang XuFor a long time, it was believed that apoptosis and necrosis were the main pathways for cell death, but a growing body of research has shown that there are other pathways. Among these, necroptosis, a regul...Guo-Qiang XuFor a long time, it was believed that apoptosis and necrosis were the main pathways for cell death, but a growing body of research has shown that there are other pathways. Among these, necroptosis, a regulatory caspase-independent, programmed cell death pathway, is supposed to be of importance in the pathogenesis of many diseases. The mechanism of regulating, in-ducing and blocking necroptosis is a complex process that involves expression and regulation of a series of molecules including receptor interacting protein kinase 1 （RIPK1）, RIPK3, and mixed lineage kinase like protein. By blocking or downregulating expression of key molecules in the necroptotic pathway, intestinal inflammation can be affected to some extent. In this paper, we introduce the concept of necroptosis, its main pathway, and its impact on the pathogenesis ofinfammatory bowel disease （IBD） and other intestinal diseases, to explore new drug targets for intestinal diseases, including IBD.展开更多
Receptors interaction protein 2(RIP2)is a specific adaptor molecule in the downstream of NOD2.The role of RIP2 during foot-and-mouth disease virus(FMDV)infection remains unknown.Here,our results showed that RIP2 inhib...Receptors interaction protein 2(RIP2)is a specific adaptor molecule in the downstream of NOD2.The role of RIP2 during foot-and-mouth disease virus(FMDV)infection remains unknown.Here,our results showed that RIP2 inhibited FMDV replication and played an important role in the activation of IFN-βand NF-κB signal pathways during FMDV infection.FMDV infection triggered RIP2 transcription,while it reduced the expression of RIP2 protein.Detailed analysis showed that FMDV 2B,2C,3C^(pro),and L^(pro) proteins were responsible for inducing the reduction of RIP2 protein.3C^(pro) and L^(pro) are viral proteinases that can induce the cleavage or reduction of many host proteins and block host protein synthesis.The carboxyl terminal 105-C114 and 135-C144 regions of 2B were essential for reduction of RIP2.Our results also showed that the N terminal 1-61 region of 2C were essential for the reduction of RIP2.The 2C-induced reduction of RIP2 was dependent on inducing the reduction of poly(A)-binding protein 1(PABPC1).The interaction between RIP2 and 2C was observed in the context of viral infection,and the residues 1-61 were required for the interaction.These data clarify novel mechanisms of reduction of RIP2 mediated by FMDV.展开更多
Subject Code:H06 With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Zou Weiguo(邹卫国)from the Institute of Biochemistry and Cell Biology,Shanghai Institutes...Subject Code:H06 With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Zou Weiguo(邹卫国)from the Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,CAS demonstrates that E3ligase SMURF2maintains bone展开更多
Background Receptor interacting protein 1 （RIP1）, which plays a key role in apoptosis, cell survival and programmed cell necrosis, is one of the most important proteins in the RIP family. The purpose of this study w...Background Receptor interacting protein 1 （RIP1）, which plays a key role in apoptosis, cell survival and programmed cell necrosis, is one of the most important proteins in the RIP family. The purpose of this study was to investigate the roles of RIP1 in the apoptosis, the generation of reactive oxygen species （ROS） and the expression of matrix metalloproteinases （MMPs） induced by ultraviolet B （UVB） in fibroblasts. Methods siRNA targeting RIP1 was used to silence RIP1 expression in the NIH3T3 fibroblasts. The mRNA and protein levels of MMP-1 and MMP-3, caspase-3 and -8 activities, and ROS activities were determined by reverse transcriptasequantitative polymerase chain reaction （RT-qPCR）, immunoblotting, caspase activity assay, immunofiuorescence, and flow cytometry. Results The mRNA and protein expressions of MMP-1 and MMP-3 were significantly increased in RIP1 deficient NIH3T3 cells at 24 hours after UVB treatment. At 24 hours after exposure to UVB, RIP1 deficient NIH3T3 cells presented apoptotic morphology, and the apoptosis rate was significantly increased accompanied by pronounced increase in caspase-8 and -3 activities. ROS production was inhibited by UVB at 12 hours in RIP1 deficient NIH3T3 cells. Conclusion RIP1 is involved in NIH3T3 cell damage induced by UVB via participating in the apoptosis, expression of MMPs and ROS production.展开更多
Gastric cancer peritoneal metastasis(GCPM)typically indicates a poor clinical prognosis and is frequently observed in diffuse gastric cancer(GC)patients with CDH1 loss of function.GCPM characterized for its aggressive...Gastric cancer peritoneal metastasis(GCPM)typically indicates a poor clinical prognosis and is frequently observed in diffuse gastric cancer(GC)patients with CDH1 loss of function.GCPM characterized for its aggressiveness and resistance to chemotherapy,most notably paclitaxel(PTX),poses significant treatment challenges.Previously,no mouse gastric adenocarcinoma(MGA)cell lines with Trp53(encoding mouse p53)and Cdh1(encoding mouse E-cadherin)mutations and a high potential for peritoneal metastasis in mice have been established.Here,we derived a mouse GC cell line,called MTC,from subcutaneously transplanted mouse Trp53^(−/−)Cdh1^(−/−)GC organoids.Through matching the short tandem repeat profile of MTC with those in current cell banks,we verified the uniqueness of MTC.Furtherly,we confirmed the features of MTC by detecting the expression of p53,E-cadherin,and pan-CK.After long-term exposure of the original MTC line to PTX,we developed a more aggressive,PTX-resistant cell line,termed MTC-R.Compared with MTC,MTC-R demonstrated enhanced tumorigenicity and high potential for peritoneal metastasis in subcutaneous and intraperitoneal tumour models both in BALB/c nude mice and C57BL/6 J mice.Transcriptome analysis revealed the ECM‒receptor interaction pathway activation during the development of PTX resistance,and dasatinib(DASA)was identified as a potential drug targeting this pathway.DASA showed promise in ameliorating disease progression and improving overall survival in MTC-R GCPM model in C57BL/6 J mice.Overall,we established a novel MGA cell line with Trp53 and Cdh1 mutations and its PTX-resistant variant and demonstrated the efficacy of DASA in treating PTX-resistant GCPM.展开更多
Hepatocellular carcinoma(HCC)was characterized as being hypervascular.In the present study,we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed ...Hepatocellular carcinoma(HCC)was characterized as being hypervascular.In the present study,we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73(GP73)HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development.Specifically,we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc,lactate,Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway,and endoplasmic reticulum stress(ERS)signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo.Mechanistically,we found that GP73,the pivotal hub gene,was activated by histone lactylation and c-Myc,which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78(GRP78)-induced ERS.STAT3 potentiates GP73-mediated pro-angiogenic functions.Clinically,serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy.Taken together,the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.展开更多
The human body is one of the most sophisticated material systems.It is still a considerable challenge to biomimic the“life-design”process to construct a part of“life”in vivo.Herein,we mimicked the natural fibronec...The human body is one of the most sophisticated material systems.It is still a considerable challenge to biomimic the“life-design”process to construct a part of“life”in vivo.Herein,we mimicked the natural fibronectin(FN)fibrillogenesis system using ligand–receptor interaction-induced self-assembly to construct in situ artificial fibrous FN in vivo,based on exogenous FN mimic peptide(FNMP).We performed the in vivo study with a tumor-bearing mouse model,to which the particle formulated FNMP raw materials were delivered with high efficiency to the tumor site through intravenous(iv)administration.In the tumor,the presence of overexpressed integrin receptors on the cell surface induced the self-assembly of the FNMP into fibrous structures,thereby,creating an artificial fibrous FN.However,the FNMP-based artificial fibrous FN showed different biological functionality from the natural fibrous FN,inhibiting the growth and migration of cells,making our constructed FN able to inhibit tumor growth,invasion,and metastasis.Thus,this study opens an avenue for the precise construction of biomimetic materials for in vivo biomedical applications.展开更多
文摘Regulation of the number of aetivin receptors that are present in the cell membrane plays a key role in the modulation of cellular responses to activin. In order to find the regulators, a novel protein ARIPzip, interacting with activin type II receptors, was searched and identified by using yeast two-hybrid screening. ARIPzip is a splicing variant of ARIP2. This has been discussed previously. ARIPzip can specifically interact with ActR Ⅱ A, and is widely distributed in mouse tissues. Overexpression of ARIPzip can cause the activin-induced transcriptional activities to increase in a dose-dependent manner while the overexpression of ARIV2 can decrease these activities. These data suggest that the C-terminal rezions of ARIP2 and ARIPzip are involved in the regulation of activin signaling.
基金supported by the National Basic Research Development Program(973 Program)of China(2013CB530902)the National Natural Science Foundation of China(91132712,81571125,81221003 and 81300979)+2 种基金the Natural Science Foundation of Zhejiang Province,China(LR12C09001 and Q13C090002)the Fundamental Research Funds for the Central Universities of China(2014FZA7008)partly supported by a Chinese Postdoctoral Science Foundation grant(2015M570501)
文摘Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine（DA）system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4（TLR4）, an important pattern-recognition receptor in the innate immune system,can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient（TLR4^（-/-））and wild-type（WT） mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed,large spaces. We found that TLR4^（-/-）mice exhibitedreduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4^（-/-）mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4^（-/-）mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly,the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell（NAc Sh） in TLR4^（-/-）mice than in WT mice. Partially inactivating the NAc Sh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4^（-/-）mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAc Sh may contribute to this phenomenon.
基金supported by the grants from the National Natural Science Foundation of China(82404638)the Xingdian Talent Plan of Yunnan Province(XDYC-QNRC-2023-0427 and XDYC-YLXZ-2022-0025)the Natural Science Foundation of Yunnan Province(202101BD070001-034,202101BD070001-049,202201AT070267,and 202201AU070183).
文摘Tumor necrosis factor-α(TNF-α)is a key player in the pathogenesis of rheumatoid arthritis(RA)and considered a promising target for therapeutic drug development.Activation of the nuclear factor-kappa B(NF-κB)pathway upon TNF-αbinding to its receptor is crucial for progression of RA.Stephanine(SA),an isoquinoline aporphine-type alkaloid recently identified in Stephania plants,exhibits anti-inflammatory properties,but its underlying mechanisms of action are unknown at present.In this study,we explored whether SA could ameliorate RA through inhibition of the NF-κB signaling pathway in association with TNF-αactivity.Our experiments revealed a binding affinity(K_(D))of SA for TNF-αof 2.934×10^(-6)mol/L.Additionally,SA at a concentration of 10μmol/L effectively hindered the binding of TNF-αto its receptors tumor necrosis factor receptor 1(TNFR1)and TNFR2.In vitro,SA prevented TNF-α-induced death of L929 cells and blocked NF-κB activation triggered by TNF-αin 293-TNF-αresponsive,as well as human fibroblast-like synoviocytes(HFLS)and human RA fibroblast-like synoviocytes(MH7A)cell lines.Furthermore,in a collagen-induced arthritis(CIA)mouse model,SA alleviated the symptoms of RA through suppression of NF-κB signaling.Our collective findings support the therapeutic efficacy of SA,a natural compound targeting TNF-α,in the management of RA.
基金Science and Technology Commission Shanghai Municipality:Exploring the Mechanism of Qushi Huayu Formula in Treating Non-alcoholic Fatty Liver Disease from the Perspective of Intestinal Barrier Function(17PJ1408900)Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine:“Si Ming”Scholar(SGXZ-201911)。
文摘OBJECTIVE:To evaluate the effects of Sanren Tang(SRT,三仁汤)on a high-fat diet(HFD)-induced non-alcoholic fatty liver disease(NAFLD)in mice and to investigate the hepatic transcriptome regulated by SRT.METHODS:The primary SRT components were identified using ultra-high-performance liquid chromatography-high-resolution accurate mass spectrometry.The SRT-induced pharmacological effects on HFD-induced NAFLD were evaluated in mice for 16 weeks.Obeticholic acid was used as a control drug.Body weight,food intake,and homeostatic model assessment for insulin resistance(HOMA-IR)index were analysed.Hepatic histological changes were observed in haematoxylin and eosin-stained sections and quantified using the NAFLD activity score(NAS).Serum alanine aminotransferase(ALT)and hepatic triglyceride(TG)levels were measured.Lipids in hepatocytes were visualised by Oil red staining.RNA-sequencing was performed to determine the transcriptome profile of the liver tissue.The differentially expressed genes were validated using real-time polymerase chain reaction and Western blotting.RESULTS:Four principal compounds were identified in the SRT:adenosine,amygdalin,luteoloside,and magnolol.SRT ameliorated hepatic histology and lipid deposition in the NAFLD mice,and decreased HOMA-IR,NAS and ALT,and hepatic TG levels.Hepatic transcriptome analysis revealed 232 HFD-regulated genes that were reversed by SRT simultaneously.Retinol metabolism,cytokine-cytokine receptor interaction,and peroxisome proliferator-activated receptor(PPAR)γsignalling were the top three SRT-regulated pathways in NAFLD.CONCLUSIONS:SRT significantly ameliorated HFD-induced NAFLD,which was correlated with the regulation of genes enriched in the retinol metabolism,cytokine-cytokine receptor interaction,and PPARγsignalling pathways.
基金supported by the National Natural Science Foundation of China(32150410366,31972338,and32372639)the earmarked fund for China Agriculture Research System(CARS-02-26)+1 种基金the National Key Research and Development Program of China(2021YFD1400700)the Special Grant of China Postdoctoral Science Foundation(2022T150712)。
文摘The mirid bug Apolygus lucorum(Hemiptera:Miridae)is a polyphagous pest that affects a wide range of host plants.Its control remains challenging mainly due to its rapid reproduction,necessitating an understanding of sex pheromone communication.The recognition of sex pheromones is vital for courtship and mating behaviors,and is mediated by various chemosensory-associated proteins.Among these,sensory neuron membrane protein(SNMP),a CD36-related protein,is suggested to play crucial roles in detecting sex pheromones.In this study,we employed transcriptomic and genomic data from A.lucorum and phylogenetic approaches,and identified four putative SNMP genes(AlucSNMP1a,AlucSNMP1b,AlucSNMP2a,and AlucSNMP2b)with full open reading frames.Expression analysis revealed the ubiquitous presence of AlucSNMP transcripts in multiple tissues,with only AlucSNMP1a exhibiting male-biased expression in the antennae,suggesting its potential role in male chemosensation.Functional analysis using the Xenopus oocyte expression system,coupled with two-electrode voltage clamp recording,demonstrated that the co-expression of AlucSNMP1a with specific pheromone receptors(PRs)and the Odorant receptor co-receptor(Orco)significantly enhanced electrophysiological responses to sex pheromones compared to the co-expression of PRs and Orco alone.Moreover,the results indicated that the presence of AlucSNMP1a not only affected the responsiveness to sex pheromones but also influenced the kinetics(activation and inactivation)of the induced signals.In contrast,the co-expression of AlucSNMP1b with AlucPR/Orco complexes had no impact on the inward currents induced by two pheromone compounds.An examination of the selective pressures on SNMP1 genes across 20 species indicated strong purifying selection,implying potential functional conservation in various insects.These findings highlight the crucial role of AlucSNMP1a in the response to sex pheromones.
基金Supported by State Administration of Traditional Chinese Medicine of Heilongjiang Province,No.ZHY16-027Harbin Municipal Science and Technology BureauYouth Reserve Talent Project,No.2017RAQXJ170
文摘BACKGROUND Receptor interacting protein kinase 1(RIPK1)-mediated cell death,including apoptosis and necroptosis,belongs to programmed cell death.It has been reported that RIPK1-mediated necroptosis exists in lesions of cerebral hemorrhage(CH).Electroacupuncture,a treatment derived from traditional Chinese medicine,could improve neurological impairment in patients with brain injury.AIM To investigate the protective role of cross electro-nape acupuncture(CENA)in CH,and clarify the potential mechanism.METHODS CH rat models were established,and CENA was applied to the experimental rats.Neurological functions and encephaledema were then measured.Necrotic cells in the brain of rats with CH were evaluated by propidium iodide staining.Necroptosis was assessed by immunofluorescence.Activation of the necroptosisrelated pathway was detected by western blot.Extraction of brain tissue,cerebrospinal fluid and serum samples was conducted to measure the expression and secretion of inflammatory cytokines by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay.RESULTS The necroptotic marker p-MLKL was detectable in the brains of rats with CH.Next,we found that CENA could ameliorate neurological functions in rat models of CH.Moreover,the upregulation of RIPK1-mediated necroptosis-related molecules in the brains of rats with CH were inhibited by CENA.Further investigation revealed that CENA partially blocked the interaction between RIPK1 and RIPK3.Finally,in vivo assays showed that CENA decreased the expression of the inflammatory cytokines tumor necrosis factor-α,interleukin-6 and interleukin-8 in CH rat models.CONCLUSION These findings revealed that CENA exerts a protective role in CH models by inhibiting RIPK1-mediated necroptosis.
基金Supported by Medical Science Research Foundation of Health Bureau of Zhejiang Province,No.WKJ-ZJ-1516
文摘Guo-Qiang XuFor a long time, it was believed that apoptosis and necrosis were the main pathways for cell death, but a growing body of research has shown that there are other pathways. Among these, necroptosis, a regulatory caspase-independent, programmed cell death pathway, is supposed to be of importance in the pathogenesis of many diseases. The mechanism of regulating, in-ducing and blocking necroptosis is a complex process that involves expression and regulation of a series of molecules including receptor interacting protein kinase 1 （RIPK1）, RIPK3, and mixed lineage kinase like protein. By blocking or downregulating expression of key molecules in the necroptotic pathway, intestinal inflammation can be affected to some extent. In this paper, we introduce the concept of necroptosis, its main pathway, and its impact on the pathogenesis ofinfammatory bowel disease （IBD） and other intestinal diseases, to explore new drug targets for intestinal diseases, including IBD.
基金This work was supported by Grants from the National Key R&D Programme of China(No.2017YFD0501103 and 2017YFD0501800)the Key Development and Research Foundation of Yunnan(No.2018BB004)the Chinese Academy of Agricultural Science and Technology Innovation Project(CAAS-XTCX2016011-01 and Y2017JC55).
文摘Receptors interaction protein 2(RIP2)is a specific adaptor molecule in the downstream of NOD2.The role of RIP2 during foot-and-mouth disease virus(FMDV)infection remains unknown.Here,our results showed that RIP2 inhibited FMDV replication and played an important role in the activation of IFN-βand NF-κB signal pathways during FMDV infection.FMDV infection triggered RIP2 transcription,while it reduced the expression of RIP2 protein.Detailed analysis showed that FMDV 2B,2C,3C^(pro),and L^(pro) proteins were responsible for inducing the reduction of RIP2 protein.3C^(pro) and L^(pro) are viral proteinases that can induce the cleavage or reduction of many host proteins and block host protein synthesis.The carboxyl terminal 105-C114 and 135-C144 regions of 2B were essential for reduction of RIP2.Our results also showed that the N terminal 1-61 region of 2C were essential for the reduction of RIP2.The 2C-induced reduction of RIP2 was dependent on inducing the reduction of poly(A)-binding protein 1(PABPC1).The interaction between RIP2 and 2C was observed in the context of viral infection,and the residues 1-61 were required for the interaction.These data clarify novel mechanisms of reduction of RIP2 mediated by FMDV.
文摘Subject Code:H06 With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Zou Weiguo(邹卫国)from the Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,CAS demonstrates that E3ligase SMURF2maintains bone
基金This work was supported by a grant from the National Natural Science Foundation of China （No. 81000702）. The authors have no conflicts of interest to declare.
文摘Background Receptor interacting protein 1 （RIP1）, which plays a key role in apoptosis, cell survival and programmed cell necrosis, is one of the most important proteins in the RIP family. The purpose of this study was to investigate the roles of RIP1 in the apoptosis, the generation of reactive oxygen species （ROS） and the expression of matrix metalloproteinases （MMPs） induced by ultraviolet B （UVB） in fibroblasts. Methods siRNA targeting RIP1 was used to silence RIP1 expression in the NIH3T3 fibroblasts. The mRNA and protein levels of MMP-1 and MMP-3, caspase-3 and -8 activities, and ROS activities were determined by reverse transcriptasequantitative polymerase chain reaction （RT-qPCR）, immunoblotting, caspase activity assay, immunofiuorescence, and flow cytometry. Results The mRNA and protein expressions of MMP-1 and MMP-3 were significantly increased in RIP1 deficient NIH3T3 cells at 24 hours after UVB treatment. At 24 hours after exposure to UVB, RIP1 deficient NIH3T3 cells presented apoptotic morphology, and the apoptosis rate was significantly increased accompanied by pronounced increase in caspase-8 and -3 activities. ROS production was inhibited by UVB at 12 hours in RIP1 deficient NIH3T3 cells. Conclusion RIP1 is involved in NIH3T3 cell damage induced by UVB via participating in the apoptosis, expression of MMPs and ROS production.
基金supported by grants from the National Natural Science Foundation of China(Grant No.81972228,No.82002527,and No.82073098)the Interdisciplinary Program of Shanghai Jiao Tong University(YG2022QN086).
文摘Gastric cancer peritoneal metastasis(GCPM)typically indicates a poor clinical prognosis and is frequently observed in diffuse gastric cancer(GC)patients with CDH1 loss of function.GCPM characterized for its aggressiveness and resistance to chemotherapy,most notably paclitaxel(PTX),poses significant treatment challenges.Previously,no mouse gastric adenocarcinoma(MGA)cell lines with Trp53(encoding mouse p53)and Cdh1(encoding mouse E-cadherin)mutations and a high potential for peritoneal metastasis in mice have been established.Here,we derived a mouse GC cell line,called MTC,from subcutaneously transplanted mouse Trp53^(−/−)Cdh1^(−/−)GC organoids.Through matching the short tandem repeat profile of MTC with those in current cell banks,we verified the uniqueness of MTC.Furtherly,we confirmed the features of MTC by detecting the expression of p53,E-cadherin,and pan-CK.After long-term exposure of the original MTC line to PTX,we developed a more aggressive,PTX-resistant cell line,termed MTC-R.Compared with MTC,MTC-R demonstrated enhanced tumorigenicity and high potential for peritoneal metastasis in subcutaneous and intraperitoneal tumour models both in BALB/c nude mice and C57BL/6 J mice.Transcriptome analysis revealed the ECM‒receptor interaction pathway activation during the development of PTX resistance,and dasatinib(DASA)was identified as a potential drug targeting this pathway.DASA showed promise in ameliorating disease progression and improving overall survival in MTC-R GCPM model in C57BL/6 J mice.Overall,we established a novel MGA cell line with Trp53 and Cdh1 mutations and its PTX-resistant variant and demonstrated the efficacy of DASA in treating PTX-resistant GCPM.
基金granted by Guangxi Key Research and Development Plan(no.GUIKEAB19245002)National Natural Science Foundation of China(nos.82060427 and 82103297)+2 种基金Guangxi Natural Science Foundation(nos.2024GXNSFDA010046 and 2024GXNSFAA010401)Advanced Innovation Teams and Xinghu Scholars Program of Guangxi Medical University,Guangxi Medical University Outstanding Young Talents Training Program,Guangxi Scholarship Fund of Guangxi Education Department,Nanning Qingxiu District Science and Technology Project(nos.2020037,2020038,2021007,2021010,and 2021012)Guangxi Medical and health key discipline construction project,and Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer.
文摘Hepatocellular carcinoma(HCC)was characterized as being hypervascular.In the present study,we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73(GP73)HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development.Specifically,we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc,lactate,Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway,and endoplasmic reticulum stress(ERS)signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo.Mechanistically,we found that GP73,the pivotal hub gene,was activated by histone lactylation and c-Myc,which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78(GRP78)-induced ERS.STAT3 potentiates GP73-mediated pro-angiogenic functions.Clinically,serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy.Taken together,the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.
基金supported by the National Natural Science Foundation of China(51890891,21807020,51573031,and 51573032)the National Science Fund for Distinguished Young Scholars(51725302)+2 种基金Science Fund for Creative Research Groups of the National Natural Science Foundation of China(11621505)CAS Interdisciplinary Innovation Team,and Jilin Province Key Laboratory of Organic Functional Molecular Design&Synthesis(130028911)Fundamental Research Funds for the Central Universities(CZD19014).
文摘The human body is one of the most sophisticated material systems.It is still a considerable challenge to biomimic the“life-design”process to construct a part of“life”in vivo.Herein,we mimicked the natural fibronectin(FN)fibrillogenesis system using ligand–receptor interaction-induced self-assembly to construct in situ artificial fibrous FN in vivo,based on exogenous FN mimic peptide(FNMP).We performed the in vivo study with a tumor-bearing mouse model,to which the particle formulated FNMP raw materials were delivered with high efficiency to the tumor site through intravenous(iv)administration.In the tumor,the presence of overexpressed integrin receptors on the cell surface induced the self-assembly of the FNMP into fibrous structures,thereby,creating an artificial fibrous FN.However,the FNMP-based artificial fibrous FN showed different biological functionality from the natural fibrous FN,inhibiting the growth and migration of cells,making our constructed FN able to inhibit tumor growth,invasion,and metastasis.Thus,this study opens an avenue for the precise construction of biomimetic materials for in vivo biomedical applications.
