Insomnia is associated with neurotransmitters and intestinal dysbiosis.Though studies have demonstrated the ameliorative effects of milk hydrolysates on insomnia,the underlying mechanisms require further exploration.I...Insomnia is associated with neurotransmitters and intestinal dysbiosis.Though studies have demonstrated the ameliorative effects of milk hydrolysates on insomnia,the underlying mechanisms require further exploration.In this study,we investigated how papain hydrolysates of goat casein(CPH)and whey protein(WPH)affected mice's sleeplessness.Here,we show that CPH effectively improved the total sleep time in 12 h and restoring neurotransmitters(5-hydroxytryptamine(5-HT),γ-aminobutyric acid(GABA),dopamine(DA),and norepinephrine(NE))in mice.Further gut microbiota analysis revealed a significant increase in the relative abundance of Helicobacter and Escherichia-Shigella and a decrease in the relative abundance of Lactobacillus in the insomnia model mice(Model).Compared to the Model group,both CPH and WPH significantly increased the relative abundance of Akkermansia and Lactobacillus while lowering the relative abundance of Helicobacter and Escherichia-Shigella.Notably,while diazepam(DZP)increased mouse sleep duration,it also increased the relative abundance of Colidextribacter,Parasutterella,Muribaculaceae,and Prevotella.Additionally,the gene expression and protein expression of GABA_A receptor,cAMP-response element binding protein(CREB),and brain-derived neurotrophic factor(BDNF)were upregulated in the hypothalamus.We also discovered a link between intestinal gut microbiota and neurotransmitters.Overall,our results suggest that goat milk hydrolysates,especially CPH,can effectively improve insomnia,providing a theoretical basis for further experimentation and individualized designs.展开更多
Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadia...Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.展开更多
In this study,two series of foams based on tannic acid(TA),furfuryl alcohol(FA),soybean protein isolate(SPI),and casein(CA),namely TA–FA–SPI(TS series)and TA–FA–CA(TC series)were developed,and their properties wer...In this study,two series of foams based on tannic acid(TA),furfuryl alcohol(FA),soybean protein isolate(SPI),and casein(CA),namely TA–FA–SPI(TS series)and TA–FA–CA(TC series)were developed,and their properties were enhanced by adding poplar fibers(WF).From the samples produced,a complete set of characterization was performed including possible crosslinking reactions,morphology,mechanical properties,flame retardancy,thermal insulation and thermal stability.Fourier-transform infrared spectroscopy(FTIR)revealed possible covalent crosslinking among the components and hydrogen bonding between WF and the matrix.Viscosity results indicated that lower prepolymer viscosity led to lower apparent density,while WF addition reduced even more the density.Mechanical tests showed that the maximum compressive strengths were good,while WF improved the compressive strength by up to 56%.Scanning electron microscopy(SEM)showed uniform cell structures,but small open pores were observed.Two-dimensional(2D)CT scan images confirmed the good compatibility between WF and the matrix,with low anisotropy in the material.Friability tests indicated that WF decreased the pulverization ratio of the materials by up to 42%.Thermogravimetric analysis(TGA)showed good thermal stability of the materials up to 328°C.Vertical burning tests showed that the materials were self-extinguishing without residue(dripping).The lowest thermal conductivity was 0.04 W/m·K.These results suggest that these novel formaldehyde-free,high biomass content(95%–96%)foams and composite foams have high potential to replace traditional phenolic foams(PF)in applications such as construction,transportation,packaging,and thermal insulation.展开更多
Immunosuppressants currently approved for the treatment of autoimmune diseases and organ transplant rejection present diverse adverse effects that impair the life quality of patients.Therefore,the development of novel...Immunosuppressants currently approved for the treatment of autoimmune diseases and organ transplant rejection present diverse adverse effects that impair the life quality of patients.Therefore,the development of novel immunomodulators with high efficiency and low toxicity is essential.Ellagic acid(EA),a natural polyphenol compound widely distributed in berries,is metabolically transformed by gut microbiome to exert systemic health benefits.Here,we identified that intraperitoneal administration of EA with no cytotoxicity,beyond its wellknown oral metabolic fate,effectively decreased clinical severity and central nervous system(CNS)inflammation/demyelination in experimental autoimmune encephalomyelitis,a mouse model of an autoimmune disease multiple sclerosis.Interestingly,intraperitoneal EA administration at incredibly low doses(0.1 mg/(kg·day))is dose-sparing with fingolimod(FTY720),the first FDA-approved oral drug for MS.In addition,intraperitoneal EA also ameliorated the brain damage in a neuromyelitis optica(NMO)model,and significantly prevented the immune rejection of allograft skin graft.Evidence from pharmacological studies combined with RNA-seq indicate that prototype EA functions by a mechanism that involves direct inhibition of casein kinase II(CKII)to suppress the expression of IL-17 and promote the expression of Cpt1a to regulate T helper cell 17 differentiation.In conclusion,our study demonstrates that the prototype EA entering the blood circulation acts as a novel therapeutic immunomodulator for the treatment of autoimmune diseases and transplant rejection through the CKII-mediated Janus kinase/signal transducer and activator of transcription 3 Cpt1a signaling pathway.展开更多
Intraocular pressure elevation can induce retinal ganglion cell death and is a clinically reversible risk factor for glaucoma,the leading cause of irreversible blindness.We previously demonstrated that casein kinase-2...Intraocular pressure elevation can induce retinal ganglion cell death and is a clinically reversible risk factor for glaucoma,the leading cause of irreversible blindness.We previously demonstrated that casein kinase-2 inhibition can promote retinal ganglion cell survival and axonal regeneration in rats after optic nerve injury.To investigate the underlying mechanism,in the current study we increased the intraocular pressure of adult rats to 75 mmHg for 2 hours and then administered a casein kinase-2 inhibitor(4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole)by intravitreal injection.We found that intravitreal injection of 4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole promoted retinal ganglion cell survival and reduced the number of infiltrating macrophages.Transcriptomic analysis showed that the mitogen activated protein kinase signaling pathway was involved in the response to intraocular pressure elevation but was not modulated by the casein kinase-2 inhibitors.Furthermore,casein kinase-2 inhibition downregulated the expression of genes(Cck,Htrsa,Nef1,Htrlb,Prph,Chat,Slc18a3,Slc5a7,Scn1b,Crybb2,Tsga10ip,and Vstm21)involved in intraocular pressure elevation.Our data indicate that inhibition of casein kinase-2 can enhance retinal ganglion cell survival in rats after acute intraocular pressure elevation via macrophage inactivation.展开更多
Tiller number and grain size are important agronomic traits that determine grain yield in rice.Here,we demonstrate that DEFECTIVE TILLER GROWTH 1(DTG1),a member of the casein kinase 1 protein family,exerts a co-regula...Tiller number and grain size are important agronomic traits that determine grain yield in rice.Here,we demonstrate that DEFECTIVE TILLER GROWTH 1(DTG1),a member of the casein kinase 1 protein family,exerts a co-regulatory effect on tiller number and grain size.We identified a single amino acid substitution in DTG1(I357K)that caused a decrease in tiller number and an increase in grain size in NIL-dtg1.Genetic analyses revealed that DTG1 plays a pivotal role in regulation of tillering and grain size.The DTG1^(I357K) allelic variant exhibited robust functionality in suppressing tillering.We show that DTG1 is preferentially expressed in tiller buds and young panicles,and negatively regulates grain size by restricting cell proliferation in spikelet hulls.We further confirm that DTG1 functioned in grain size regulation by directly interacting with Grain Width 2(GW2),a critical grain size regulator in rice.The CRISPR/Cas9-mediated elimination of DTG1 significantly enhanced tiller number and grain size,thereby increasing rice grain yield under field conditions,thus highlighting potential value of DTG1 in rice breeding.展开更多
Introduction:The regulation of thyroid-stimulating hormone(TSH)synthesis involves neurotransmitters,with melatonin being a subject of ongoing debate.TSH transcription,synthesis,and secretion from the pituitary pars di...Introduction:The regulation of thyroid-stimulating hormone(TSH)synthesis involves neurotransmitters,with melatonin being a subject of ongoing debate.TSH transcription,synthesis,and secretion from the pituitary pars distalis(PD)is primarily regulated in a photoperiodic manner by thyrotropin-releasing hormone(TRH).In contrast,in the pituitary pars tuberalis(PT),mRNA transcription and alpha/beta chain synthesis,but not secretion,of a TSHlike product is regulated by melatonin.Conversely,non-photoperiodic melatonin might also affect the secretion of a TSH-like product from the PT.Nevertheless,the impact of exogenous melatonin on the underlying PD-TSH synthesis remains unclear.Casein kinase 1α(CK1α)plays a negative regulatory role in TSH synthesis in the mouse pituitary.Objective:We investigated whether non-photoperiodic melatonin affects PD-TSH synthesis through its interaction with CK1α.Methods:Immunohistochemistry and immunofluorescence staining detected the colocalization of the melatonin receptor MT1 with CK1αand TSH-βin the PD.RT-qPCR,western blotting,and ELISA revealed the effect of melatonin on Tshb mRNA,MTNR1A mRNA,Csnk1a1 mRNA,CK1αprotein,MT1 protein,and TSH levels.Results:Robust colocalization of the melatonin receptor MT1 with CK1αand TSH-βin the PD.Tshb mRNA and CK1αprotein expression levels peaked at opposite phases of the 24-h light:dark cycle.Exogenous melatonin administration promoted pituitary TSH synthesis,while concurrently inhibiting CK1αactivity.The upregulation of endogenous CK1αactivity in primary pituitary cells significantly blunted the melatonin stimulatory impact on Tshb mRNA and TSH levels.Mechanistically,the CK1αagonist pyrvinium abrogated melatonin-induced activation of p-PKC and p-CREB expression in vitro.Conclusion:The CK1α/PKC signaling pathway mediates the regulation of melatonin in pituitary TSH synthesis.We demonstrate an important theoretical and experimental basis for understanding the mechanism of endocrine system diseases caused by abnormal TSH synthesis in the pituitary.展开更多
Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene pr...Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The precise mechanism of the MJD/SCA3 pathogenesis remains unclear. A growing body of evidence demonstrates that phosphorylation plays an important role in the pathogenesis of many neurodegenerative diseases. However, few kinases are known to phosphorylate ataxin-3. The present study is to explore whether ataxin-3 is a substrate of casein kinase 2 （CK2）. Methods The interaction between ataxin-3 and CK2 was identified by glutathione S-transferase （GST） pull-down assay and co-immunoprecipition assay. The phosphorylation of ataxin-3 by CK2 was measured by in vitro phosphorylation assays. Results （1） Both wild type and expanded ataxin-3 interacted with CK2α and CK2β in vitro. （2） In 293 cells, both wild type and expanded ataxin-3 interacted with CK2β, but not CK2α. （3） CK2 phosphorylated wild type and expanded ataxin-3. Conclusion Ataxin-3 is a substrate of protein kinase CK2.展开更多
The kinetics of casein tryptic hydrolysis to prepare activepeptides was investigated. Taking into account the reaction mechanismincluding single substrate hydrolysis, irreversible enzymeinactivation, and substrate inh...The kinetics of casein tryptic hydrolysis to prepare activepeptides was investigated. Taking into account the reaction mechanismincluding single substrate hydrolysis, irreversible enzymeinactivation, and substrate inhibition, a set of exponentialequations was established to characterize the enzymatic hydrolysiscurves. The verification was carried out by a series of experimentalresults and indicated that the average regressive error was less than5/100. According to the proposed kinetic model, the kinetic constantsand thermodynamic constants of the reaction system were alsocalculated.展开更多
Background:High-protein diets can increase the colonic health risks.A moderate reduction of dietary crude-protein(CP)level can improve the colonic bacterial community and mucosal immunity of pigs.However,greatly reduc...Background:High-protein diets can increase the colonic health risks.A moderate reduction of dietary crude-protein(CP)level can improve the colonic bacterial community and mucosal immunity of pigs.However,greatly reducing the dietary CP level,even supplemented with all amino acids(AAs),detrimentally affects the colonic health,which may be due to the lack of protein-derived peptides.Therefore,this study evaluated the effects of supplementation of casein hydrolysate(peptide source)in low-protein(LP)diets,in comparison with AAs supplementation,on the colonic microbiota,microbial metabolites and mucosal immunity in pigs,aiming to determine whether a supplementation of casein hydrolysate can improve colonic health under very LP level.Twenty-one pigs(initial BW 19.90±1.00 kg,63±1 days of age)were assigned to three groups and fed with control diet(16%CP),LP diets(13%CP)supplemented with free AAs(LPA)or casein hydrolysate(LPC)for 4 weeks.Results:Compared with control diet,LPA and LPC diet decreased the relative abundance of Streptococcus and Escherichia coli,and LPC diet further decreased the relative abundance of Proteobacteria.LPC diet also increased the relative abundance of Lactobacillus reuteri.Both LP diets decreased concentrations of ammonia and cadaverine,and LPC diet also reduced concentrations of putrescine,phenol and indole.Moreover,LPC diet increased total short-chain fatty acid concentration.In comparison with control diet,both LP diets decreased protein expressions of Toll-like receptor-4,nuclear factor-κB,interleukin-1βand tumor necrosis factor-α,and LPC diet further decreased protein expressions of nucleotide-binding oligomerization domain protein-1 and interferon-γ.LPC diet also increased protein expressions of G-protein coupled receptor-43,interleukin-4,transforming growth factor-β,immunoglobulin A and mucin-4,which are indicators for mucosal defense activity.Conclusions:The results showed that supplementing casein hydrolysate showed beneficial effects on the colonic microbiota and mucosal immunity and barrier function in comparison with supplementing free AAs in LP diets.These findings may provide new framework for future nutritional interventions for colon health in pigs.展开更多
Whey protein concentrate (WPC 80) and sodium caseinate were hydrolyzed by Protamex to 5%, 10%, 15%, and 20% degree of hydrolysis (DH). WPC 80, sodium caseinate and their hydrolysates were then analyzed, compared and e...Whey protein concentrate (WPC 80) and sodium caseinate were hydrolyzed by Protamex to 5%, 10%, 15%, and 20% degree of hydrolysis (DH). WPC 80, sodium caseinate and their hydrolysates were then analyzed, compared and evaluated for their nutritional qualities. Their chemical composition, protein solubility, amino acid composition, essential amino acid index (EAA index), biological value (BV), nutritional index (NI), chemical score, enzymic protein efficiency ratio (E-PER) and in vitro protein digestibility (IVPD) were determined. The results indicated that the enzymatic hydrolysis of WPC 80 and sodium caseinate by Protamex improved the solubility and IVPD of their hydrolysates. WPC 80, sodium caseinate and their hydrolysates were high-quality proteins and had a surplus of essential amino acids compared with the FAO/WHO/UNU (1985) reference standard. The nutritive value of WPC 80 and its hydrolysates was superior to that of sodium caseinate and its hydrolysates as indicated by some nutritional parameters such as the amino acid composition, chemical score, EAA index and predicted BV. However, the E-PER was lower for the WPC hydrolysates as compared to unhydrolyzed WPC 80 but sodium caseinate and its hydrolysates did not differ significantly. The nutritional qualities of WPC 80, sodium caseinate and their hydrolysates were good and make them appropriate for food formulations or as nutritional supplements.展开更多
There is no study on food-derived peptide with both anticoagulant and angiotensin I-converting enzyme inhibitory (ACEI) activities yet. In this work, the anticoagulant and ACEI activities of the casein hydrolysates re...There is no study on food-derived peptide with both anticoagulant and angiotensin I-converting enzyme inhibitory (ACEI) activities yet. In this work, the anticoagulant and ACEI activities of the casein hydrolysates released by pepsin digestion were evaluated for the first time to the best of our knowledge. Results indicated that the casein hydrolysate exhibited potent anticoagulant activity by prolonging the thrombin time (TT) and the activated partial thromboplastin time (APTT). Compared with control samples, at 10 mg/mL, the TT and APTT of casein hydrolysate were 186.0 % ± 6.6 % and 163.5 % ± 7.4 %, respectively. The casein hydrolysate also showed a strong ACEI activity with an IC50 value of 1.775 mg/mL. The components of the bioactive casein hydrolysate were analyzed by nanoscale liquid chromatography quadrupole time-of-flight tandem mass spectrometry (NanoLC-Q-TOF-MS/MS). Total of 115 peptides were identified, among which 34, 9, 55 and 17 peptides were derived from α_(s1-), α_(s2-), β-, and κ-casein, respectively. The results of PeptideRanker and PepSite 2 analysis showed that 6 peptides (FRQFYQL, NENLLRF, NPWDQVKR, PVVVPPFLQ, PVRGPFPIIV, and ARHPHPHLSF) have both ACEI and anticoagulant activities by binding to the active sites of ACE and thrombin. This study indicated that casein is a potential functional food supplement that can be used for medical purposes.展开更多
Casein kinase I is a group of ubiquitous Serine/Threonine kinases that have been implicated in both normal cellular functions and several pathological conditions including Alzheimer's disease and cancer.Recent fin...Casein kinase I is a group of ubiquitous Serine/Threonine kinases that have been implicated in both normal cellular functions and several pathological conditions including Alzheimer's disease and cancer.Recent findings in colon and pancreatic cancer have brought tremendous attention to these molecules as potential therapeutic targets in treatment of digestive cancers.In this review,we summarize up to date what is known about this family of kinases and their involvement in carcinogenesis and other pathological conditions.Our emphasis is on their implications in digestive cancers and their potential for cancer screening and therapy.展开更多
The aim of this work was to develop an alginate-casein composite microsphere as a bioaetive vehicle for oral administration of nutrients by a simple extrusion dripping method. Riboflavin was selected as a model drug, ...The aim of this work was to develop an alginate-casein composite microsphere as a bioaetive vehicle for oral administration of nutrients by a simple extrusion dripping method. Riboflavin was selected as a model drug, and the microencapsulation efficiency was raised to 97.94% after optimizing the preparation conditions by response surface methodology. In vitro release studies showed that riboflavin was released completely from alginate-casein microspheres in simulated intestinal fluids. Meanwhile, the morphology, structure and interaction between alginate and casein were characterized by scanning electron microscopy （SEM） and Fourier transform infrared （FTIR） spectra.展开更多
基金supported by the National First-class Discipline Program of Food Science and Technology(JUFSTR20180204)。
文摘Insomnia is associated with neurotransmitters and intestinal dysbiosis.Though studies have demonstrated the ameliorative effects of milk hydrolysates on insomnia,the underlying mechanisms require further exploration.In this study,we investigated how papain hydrolysates of goat casein(CPH)and whey protein(WPH)affected mice's sleeplessness.Here,we show that CPH effectively improved the total sleep time in 12 h and restoring neurotransmitters(5-hydroxytryptamine(5-HT),γ-aminobutyric acid(GABA),dopamine(DA),and norepinephrine(NE))in mice.Further gut microbiota analysis revealed a significant increase in the relative abundance of Helicobacter and Escherichia-Shigella and a decrease in the relative abundance of Lactobacillus in the insomnia model mice(Model).Compared to the Model group,both CPH and WPH significantly increased the relative abundance of Akkermansia and Lactobacillus while lowering the relative abundance of Helicobacter and Escherichia-Shigella.Notably,while diazepam(DZP)increased mouse sleep duration,it also increased the relative abundance of Colidextribacter,Parasutterella,Muribaculaceae,and Prevotella.Additionally,the gene expression and protein expression of GABA_A receptor,cAMP-response element binding protein(CREB),and brain-derived neurotrophic factor(BDNF)were upregulated in the hypothalamus.We also discovered a link between intestinal gut microbiota and neurotransmitters.Overall,our results suggest that goat milk hydrolysates,especially CPH,can effectively improve insomnia,providing a theoretical basis for further experimentation and individualized designs.
文摘Casein kinase 1(CK1)is an important member of the serine/threonine protein kinase family,playing a crucial role in various cellular processes,including cell cycle regulation,signal transduction,DNA repair,and circadian rhythm control.CK1 is also essential in the nervous system,where it regulates neuronal growth,differentiation,and synaptic plasticity.Studies have shown that CK1δ phosphorylates neuron-specific proteins to regulate axonal growth and synaptogenesis.Primary cilia are non-motile microtubule structures present on the surface of most mammalian cells.Recent studies have revealed their multiple roles in cellular physiology and development,and dysfunction of cilia can impact the development and function of the nervous system.CK1 has an important role in the formation and function of primary cilia.By regulating various signaling pathways and the phosphorylation status of proteins,CK1 affects the generation,maintenance,and signaling transduction of cilia.In this review,the relationship between CK1,primary cilia,and the nervous system was explored,focusing on how CK1 influences cilia to regulate the structure and function of the nervous system.
基金funded by the Natural Sciences and Engineering Research Council of Canada(NSERC)for financial support,Grant Nos.CG125664 and GF136078.
文摘In this study,two series of foams based on tannic acid(TA),furfuryl alcohol(FA),soybean protein isolate(SPI),and casein(CA),namely TA–FA–SPI(TS series)and TA–FA–CA(TC series)were developed,and their properties were enhanced by adding poplar fibers(WF).From the samples produced,a complete set of characterization was performed including possible crosslinking reactions,morphology,mechanical properties,flame retardancy,thermal insulation and thermal stability.Fourier-transform infrared spectroscopy(FTIR)revealed possible covalent crosslinking among the components and hydrogen bonding between WF and the matrix.Viscosity results indicated that lower prepolymer viscosity led to lower apparent density,while WF addition reduced even more the density.Mechanical tests showed that the maximum compressive strengths were good,while WF improved the compressive strength by up to 56%.Scanning electron microscopy(SEM)showed uniform cell structures,but small open pores were observed.Two-dimensional(2D)CT scan images confirmed the good compatibility between WF and the matrix,with low anisotropy in the material.Friability tests indicated that WF decreased the pulverization ratio of the materials by up to 42%.Thermogravimetric analysis(TGA)showed good thermal stability of the materials up to 328°C.Vertical burning tests showed that the materials were self-extinguishing without residue(dripping).The lowest thermal conductivity was 0.04 W/m·K.These results suggest that these novel formaldehyde-free,high biomass content(95%–96%)foams and composite foams have high potential to replace traditional phenolic foams(PF)in applications such as construction,transportation,packaging,and thermal insulation.
基金supported by the Chinese National Natural Science Foundation(92268118,82071396,82271199)the Shaanxi Provincial Key R&D Foundation(2021ZDLSF03-09)+3 种基金the Scientific Research Program Funded by Shaanxi Provincial Education Department(22JK0550)the Fundamental Research Funds for the Central Universities(GK202201013,GK202202006,GK202305001)the Excellent Graduate Training Program of Shaanxi Normal University(LHRCYB23003)Tian Jiabing Scholar Program.
文摘Immunosuppressants currently approved for the treatment of autoimmune diseases and organ transplant rejection present diverse adverse effects that impair the life quality of patients.Therefore,the development of novel immunomodulators with high efficiency and low toxicity is essential.Ellagic acid(EA),a natural polyphenol compound widely distributed in berries,is metabolically transformed by gut microbiome to exert systemic health benefits.Here,we identified that intraperitoneal administration of EA with no cytotoxicity,beyond its wellknown oral metabolic fate,effectively decreased clinical severity and central nervous system(CNS)inflammation/demyelination in experimental autoimmune encephalomyelitis,a mouse model of an autoimmune disease multiple sclerosis.Interestingly,intraperitoneal EA administration at incredibly low doses(0.1 mg/(kg·day))is dose-sparing with fingolimod(FTY720),the first FDA-approved oral drug for MS.In addition,intraperitoneal EA also ameliorated the brain damage in a neuromyelitis optica(NMO)model,and significantly prevented the immune rejection of allograft skin graft.Evidence from pharmacological studies combined with RNA-seq indicate that prototype EA functions by a mechanism that involves direct inhibition of casein kinase II(CKII)to suppress the expression of IL-17 and promote the expression of Cpt1a to regulate T helper cell 17 differentiation.In conclusion,our study demonstrates that the prototype EA entering the blood circulation acts as a novel therapeutic immunomodulator for the treatment of autoimmune diseases and transplant rejection through the CKII-mediated Janus kinase/signal transducer and activator of transcription 3 Cpt1a signaling pathway.
基金supported by the National Natural Science Foundation of China,Nos.81570849,81100931the Natural Science Foundation of Guangdong Province of China,Nos.2015A030313446,2020A1515011413(all to LPC).
文摘Intraocular pressure elevation can induce retinal ganglion cell death and is a clinically reversible risk factor for glaucoma,the leading cause of irreversible blindness.We previously demonstrated that casein kinase-2 inhibition can promote retinal ganglion cell survival and axonal regeneration in rats after optic nerve injury.To investigate the underlying mechanism,in the current study we increased the intraocular pressure of adult rats to 75 mmHg for 2 hours and then administered a casein kinase-2 inhibitor(4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole)by intravitreal injection.We found that intravitreal injection of 4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole promoted retinal ganglion cell survival and reduced the number of infiltrating macrophages.Transcriptomic analysis showed that the mitogen activated protein kinase signaling pathway was involved in the response to intraocular pressure elevation but was not modulated by the casein kinase-2 inhibitors.Furthermore,casein kinase-2 inhibition downregulated the expression of genes(Cck,Htrsa,Nef1,Htrlb,Prph,Chat,Slc18a3,Slc5a7,Scn1b,Crybb2,Tsga10ip,and Vstm21)involved in intraocular pressure elevation.Our data indicate that inhibition of casein kinase-2 can enhance retinal ganglion cell survival in rats after acute intraocular pressure elevation via macrophage inactivation.
基金supported by the Sichuan Science and Technology Support Project (2022ZDZX0012,2021YFYZ0016,2023YFN0007,2021YFYZ0027)the National Natural Science Foundation of China (32171966,U23A20180).
文摘Tiller number and grain size are important agronomic traits that determine grain yield in rice.Here,we demonstrate that DEFECTIVE TILLER GROWTH 1(DTG1),a member of the casein kinase 1 protein family,exerts a co-regulatory effect on tiller number and grain size.We identified a single amino acid substitution in DTG1(I357K)that caused a decrease in tiller number and an increase in grain size in NIL-dtg1.Genetic analyses revealed that DTG1 plays a pivotal role in regulation of tillering and grain size.The DTG1^(I357K) allelic variant exhibited robust functionality in suppressing tillering.We show that DTG1 is preferentially expressed in tiller buds and young panicles,and negatively regulates grain size by restricting cell proliferation in spikelet hulls.We further confirm that DTG1 functioned in grain size regulation by directly interacting with Grain Width 2(GW2),a critical grain size regulator in rice.The CRISPR/Cas9-mediated elimination of DTG1 significantly enhanced tiller number and grain size,thereby increasing rice grain yield under field conditions,thus highlighting potential value of DTG1 in rice breeding.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Introduction:The regulation of thyroid-stimulating hormone(TSH)synthesis involves neurotransmitters,with melatonin being a subject of ongoing debate.TSH transcription,synthesis,and secretion from the pituitary pars distalis(PD)is primarily regulated in a photoperiodic manner by thyrotropin-releasing hormone(TRH).In contrast,in the pituitary pars tuberalis(PT),mRNA transcription and alpha/beta chain synthesis,but not secretion,of a TSHlike product is regulated by melatonin.Conversely,non-photoperiodic melatonin might also affect the secretion of a TSH-like product from the PT.Nevertheless,the impact of exogenous melatonin on the underlying PD-TSH synthesis remains unclear.Casein kinase 1α(CK1α)plays a negative regulatory role in TSH synthesis in the mouse pituitary.Objective:We investigated whether non-photoperiodic melatonin affects PD-TSH synthesis through its interaction with CK1α.Methods:Immunohistochemistry and immunofluorescence staining detected the colocalization of the melatonin receptor MT1 with CK1αand TSH-βin the PD.RT-qPCR,western blotting,and ELISA revealed the effect of melatonin on Tshb mRNA,MTNR1A mRNA,Csnk1a1 mRNA,CK1αprotein,MT1 protein,and TSH levels.Results:Robust colocalization of the melatonin receptor MT1 with CK1αand TSH-βin the PD.Tshb mRNA and CK1αprotein expression levels peaked at opposite phases of the 24-h light:dark cycle.Exogenous melatonin administration promoted pituitary TSH synthesis,while concurrently inhibiting CK1αactivity.The upregulation of endogenous CK1αactivity in primary pituitary cells significantly blunted the melatonin stimulatory impact on Tshb mRNA and TSH levels.Mechanistically,the CK1αagonist pyrvinium abrogated melatonin-induced activation of p-PKC and p-CREB expression in vitro.Conclusion:The CK1α/PKC signaling pathway mediates the regulation of melatonin in pituitary TSH synthesis.We demonstrate an important theoretical and experimental basis for understanding the mechanism of endocrine system diseases caused by abnormal TSH synthesis in the pituitary.
基金the National Natural Sciences Foundation of China (No. 30770664)a grant from Educational Committee of Anhui Province, China (No. ZD2008008-2).
文摘Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The precise mechanism of the MJD/SCA3 pathogenesis remains unclear. A growing body of evidence demonstrates that phosphorylation plays an important role in the pathogenesis of many neurodegenerative diseases. However, few kinases are known to phosphorylate ataxin-3. The present study is to explore whether ataxin-3 is a substrate of casein kinase 2 （CK2）. Methods The interaction between ataxin-3 and CK2 was identified by glutathione S-transferase （GST） pull-down assay and co-immunoprecipition assay. The phosphorylation of ataxin-3 by CK2 was measured by in vitro phosphorylation assays. Results （1） Both wild type and expanded ataxin-3 interacted with CK2α and CK2β in vitro. （2） In 293 cells, both wild type and expanded ataxin-3 interacted with CK2β, but not CK2α. （3） CK2 phosphorylated wild type and expanded ataxin-3. Conclusion Ataxin-3 is a substrate of protein kinase CK2.
基金Supported by National Natural Science Foundation of China (No. 20276052) and Tianjin Science & Technology Commission (No. 023105411).
文摘The kinetics of casein tryptic hydrolysis to prepare activepeptides was investigated. Taking into account the reaction mechanismincluding single substrate hydrolysis, irreversible enzymeinactivation, and substrate inhibition, a set of exponentialequations was established to characterize the enzymatic hydrolysiscurves. The verification was carried out by a series of experimentalresults and indicated that the average regressive error was less than5/100. According to the proposed kinetic model, the kinetic constantsand thermodynamic constants of the reaction system were alsocalculated.
基金supported by National Key Basic Research Program of China(2013CB127300)Natural Science Foundation of China(31430082).
文摘Background:High-protein diets can increase the colonic health risks.A moderate reduction of dietary crude-protein(CP)level can improve the colonic bacterial community and mucosal immunity of pigs.However,greatly reducing the dietary CP level,even supplemented with all amino acids(AAs),detrimentally affects the colonic health,which may be due to the lack of protein-derived peptides.Therefore,this study evaluated the effects of supplementation of casein hydrolysate(peptide source)in low-protein(LP)diets,in comparison with AAs supplementation,on the colonic microbiota,microbial metabolites and mucosal immunity in pigs,aiming to determine whether a supplementation of casein hydrolysate can improve colonic health under very LP level.Twenty-one pigs(initial BW 19.90±1.00 kg,63±1 days of age)were assigned to three groups and fed with control diet(16%CP),LP diets(13%CP)supplemented with free AAs(LPA)or casein hydrolysate(LPC)for 4 weeks.Results:Compared with control diet,LPA and LPC diet decreased the relative abundance of Streptococcus and Escherichia coli,and LPC diet further decreased the relative abundance of Proteobacteria.LPC diet also increased the relative abundance of Lactobacillus reuteri.Both LP diets decreased concentrations of ammonia and cadaverine,and LPC diet also reduced concentrations of putrescine,phenol and indole.Moreover,LPC diet increased total short-chain fatty acid concentration.In comparison with control diet,both LP diets decreased protein expressions of Toll-like receptor-4,nuclear factor-κB,interleukin-1βand tumor necrosis factor-α,and LPC diet further decreased protein expressions of nucleotide-binding oligomerization domain protein-1 and interferon-γ.LPC diet also increased protein expressions of G-protein coupled receptor-43,interleukin-4,transforming growth factor-β,immunoglobulin A and mucin-4,which are indicators for mucosal defense activity.Conclusions:The results showed that supplementing casein hydrolysate showed beneficial effects on the colonic microbiota and mucosal immunity and barrier function in comparison with supplementing free AAs in LP diets.These findings may provide new framework for future nutritional interventions for colon health in pigs.
文摘Whey protein concentrate (WPC 80) and sodium caseinate were hydrolyzed by Protamex to 5%, 10%, 15%, and 20% degree of hydrolysis (DH). WPC 80, sodium caseinate and their hydrolysates were then analyzed, compared and evaluated for their nutritional qualities. Their chemical composition, protein solubility, amino acid composition, essential amino acid index (EAA index), biological value (BV), nutritional index (NI), chemical score, enzymic protein efficiency ratio (E-PER) and in vitro protein digestibility (IVPD) were determined. The results indicated that the enzymatic hydrolysis of WPC 80 and sodium caseinate by Protamex improved the solubility and IVPD of their hydrolysates. WPC 80, sodium caseinate and their hydrolysates were high-quality proteins and had a surplus of essential amino acids compared with the FAO/WHO/UNU (1985) reference standard. The nutritive value of WPC 80 and its hydrolysates was superior to that of sodium caseinate and its hydrolysates as indicated by some nutritional parameters such as the amino acid composition, chemical score, EAA index and predicted BV. However, the E-PER was lower for the WPC hydrolysates as compared to unhydrolyzed WPC 80 but sodium caseinate and its hydrolysates did not differ significantly. The nutritional qualities of WPC 80, sodium caseinate and their hydrolysates were good and make them appropriate for food formulations or as nutritional supplements.
基金The China Postdoctoral Science Foundation(2019M661072)the Basic Research Program of Liaoning Education Department(2017J080)the National Natural Science Foundation of China(31771926)funded this study.
文摘There is no study on food-derived peptide with both anticoagulant and angiotensin I-converting enzyme inhibitory (ACEI) activities yet. In this work, the anticoagulant and ACEI activities of the casein hydrolysates released by pepsin digestion were evaluated for the first time to the best of our knowledge. Results indicated that the casein hydrolysate exhibited potent anticoagulant activity by prolonging the thrombin time (TT) and the activated partial thromboplastin time (APTT). Compared with control samples, at 10 mg/mL, the TT and APTT of casein hydrolysate were 186.0 % ± 6.6 % and 163.5 % ± 7.4 %, respectively. The casein hydrolysate also showed a strong ACEI activity with an IC50 value of 1.775 mg/mL. The components of the bioactive casein hydrolysate were analyzed by nanoscale liquid chromatography quadrupole time-of-flight tandem mass spectrometry (NanoLC-Q-TOF-MS/MS). Total of 115 peptides were identified, among which 34, 9, 55 and 17 peptides were derived from α_(s1-), α_(s2-), β-, and κ-casein, respectively. The results of PeptideRanker and PepSite 2 analysis showed that 6 peptides (FRQFYQL, NENLLRF, NPWDQVKR, PVVVPPFLQ, PVRGPFPIIV, and ARHPHPHLSF) have both ACEI and anticoagulant activities by binding to the active sites of ACE and thrombin. This study indicated that casein is a potential functional food supplement that can be used for medical purposes.
基金Supported by The Merit Review grant (the Department of Veterans Affairs of the United States) and the Grant-in-Aid (the American Heart Association) to Dr. Chai
文摘Casein kinase I is a group of ubiquitous Serine/Threonine kinases that have been implicated in both normal cellular functions and several pathological conditions including Alzheimer's disease and cancer.Recent findings in colon and pancreatic cancer have brought tremendous attention to these molecules as potential therapeutic targets in treatment of digestive cancers.In this review,we summarize up to date what is known about this family of kinases and their involvement in carcinogenesis and other pathological conditions.Our emphasis is on their implications in digestive cancers and their potential for cancer screening and therapy.
基金Supported by the National High Technology Research and Development Program of China("863"Program,No.2013AA102204)National Natural Science Foundation of China(No.31071509)+2 种基金program of Ministry of Science and Technology of China(No.2012YQ090194)Program of Beiyang Young Scholar of Tianjin University(2012)Program of Introducing Talents of Discipline to Universities of China(No.B06006)
文摘The aim of this work was to develop an alginate-casein composite microsphere as a bioaetive vehicle for oral administration of nutrients by a simple extrusion dripping method. Riboflavin was selected as a model drug, and the microencapsulation efficiency was raised to 97.94% after optimizing the preparation conditions by response surface methodology. In vitro release studies showed that riboflavin was released completely from alginate-casein microspheres in simulated intestinal fluids. Meanwhile, the morphology, structure and interaction between alginate and casein were characterized by scanning electron microscopy （SEM） and Fourier transform infrared （FTIR） spectra.
