Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of t...Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of the gene encoding polycytosine RNA-binding protein 1(PCBP1).Additionally,Ma et al used a lentivirus infection system to express PCBP1.As the authors’method of administration can be improved in terms of stability and cost,we propose delivering PCBP1 to treat type 2 diabetic osteoporosis by encapsulating it in protein nanoparticles.First,PCBP1 is small and druggable.Second,intravenous injection can help deliver PCBP1 across the mucosa while avoiding acid and enzyme-catalyzed degradation.Furthermore,incorporating PCBP1 into nanoparticles prevents its interaction with water or oxygen and protects PCBP1’s structure and activity.Notably,the safety of the protein materials and the industrialization techniques for large-scale production of protein nanoparticles must be comprehensively investigated before clinical application.展开更多
BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progr...BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.展开更多
Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein ...Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.展开更多
Protein-energy malnutrition (PEM) as a result of poor nutrition, especially for deprived resourced households, is a big health concern in the world. According to the World Health Organisation, PEM accounts for 49% of ...Protein-energy malnutrition (PEM) as a result of poor nutrition, especially for deprived resourced households, is a big health concern in the world. According to the World Health Organisation, PEM accounts for 49% of the 10.4 million deaths of children under five that take place in developing countries. The aim of this study was to evaluate the influence of gum Arabic (GA) and texturized soy protein (TSP) and their interactive effect on proximate, functional, and textural properties of the protein-rich snack stick produced from ground green maize, GA powder, and ground TSP. GA varied at 0%, 4%, 8%, and 12%, while TSP varied at 0%, 12%, 24% and 36%. The 5 cm long protein-rich snack sticks were made using a sausage stuffer and baked in an oven at 110˚C for 1 hr 30 minutes. The snack sticks were subjected to proximate, functional and textural analysis using the standard methods. Increasing GA resulted in a significant (p p < 0.05) increased the protein content (32.46%), Ash content (3.6%), fat (11.96%), and moisture content (16.25%) of protein-rich snack sticks. The interactive effect between GA and TSP led to a decrease in fibre and carbohydrates. Results from this study show GA and TSP significantly enhanced the physico-chemical properties of protein-rich snack sticks. A sample with 4% GA and 36% TSP is recommended for the best physico-chemical attributes of the protein-rich snack stick.展开更多
The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enh...The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.展开更多
Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understan...Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.展开更多
The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed...The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.展开更多
BACKGROUND Centromere protein A(CENPA)exhibits an increased expression level in primary human rectal cancer tissues,but its role has not been investigated.AIM To clarify the specific role and mechanism of CENPA in rec...BACKGROUND Centromere protein A(CENPA)exhibits an increased expression level in primary human rectal cancer tissues,but its role has not been investigated.AIM To clarify the specific role and mechanism of CENPA in rectal cancer progression.METHODS CENPA protein expression in rectal cancer tissues and cell lines were detected.CENPA was overexpressed and knocked down in SW837 and SW480 cells,and proliferation,invasion,apoptosis and epithelial-mesenchymal transition(EMT)marker protein levels were examined.O6-methylguanine DNA methyltransferase(MGMT)promoter methylation was assessed with methylation-specific poly-merase chain reaction.Co-immunoprecipitation assay verified the interaction between MGMT and protein tyrosine phosphatase nonreceptor type 4(PTPN4).SW837 cells with CENPA knockdown were injected subcutaneously into mice,and tumor growth was examined.RESULTS CENPA was upregulated in rectal cancer tissues and cell lines.CENPA overex-pression promoted proliferation,invasion and EMT,and inhibited apoptosis in rectal cancer cells.Whereas CENPA knockdown showed the opposite results.Moreover,CENPA inhibited MGMT expression by promoting DNA methyltrans-ferase 1-mediated MGMT promoter methylation.MGMT knockdown abolished the CENPA knockdown-mediated inhibition of rectal cancer cell progression.MGMT increased PTPN4 protein stability by inhibiting PTPN4 ubiquitination degradation via competing with ubiquitin-conjugating enzyme E2O for interacting with PTPN4.PTPN4 knockdown abolished the inhibitory effects of MGMT overexpression on rectal cancer cell progression.Moreover,CENPA knockdown inhibited xenograft tumor growth in vivo.CONCLUSION CENPA knockdown inhibited rectal cancer cell growth and attenuated xenograft tumor growth through regulating the MGMT/PTPN4 axis.展开更多
In the article“Silencing of the long non-coding RNA LINC00265 triggers autophagy and apoptosis in lung cancer by reducing protein stability of SIN3A oncogene”(Oncology Research.2024,Vol.32,No.7,pp.1185–1195.doi:10....In the article“Silencing of the long non-coding RNA LINC00265 triggers autophagy and apoptosis in lung cancer by reducing protein stability of SIN3A oncogene”(Oncology Research.2024,Vol.32,No.7,pp.1185–1195.doi:10.32604/or.2023.030771,https://www.techscience.com/or/v32n7/57163),an inadvertent error occurred during the compilation of Fig.3H.This needed corrections to ensure the accuracy and integrity of the data presented.展开更多
Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode...Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.展开更多
Introduction:Diet intervention,especially supplementation with high-quality protein,is considered to be a critical strategy in sarcopenia.However,different sources and types of protein have different health impacts.Ob...Introduction:Diet intervention,especially supplementation with high-quality protein,is considered to be a critical strategy in sarcopenia.However,different sources and types of protein have different health impacts.Objectives:The aim of this study is to explore the differences in the ameliorative effects and mechanisms of different sources and types of proteins on sarcopenia,providing an optimal path for the prevention and treatment of sarcopenia.Methods:A sarcopenia model was established by intraperitoneal injection of dexamethasone(5 mg/kg).Sixty male C57BL/6 mice(8 months old)were randomly divided into the normal control,sarcopenia,goat whey protein,goat milk casein,bovine whey protein,and bovine milk casein groups.Animals were treated for 8 consecutive weeks.Organism-level and molecular phenotypes,16S rRNA gene sequencing,and untargeted metabolomics profiling based on GC-TOF/MS were employed to investigate the correlation between host metabolism,microbial metabolism,autophagy and inflammation and their influence on sarcopenia in C57BL/6 male mice.Results:All 4 proteins increased muscle mass,and goat whey protein improved muscle strength in sarcopenic mice.Goat and bovine milk proteins promoted muscle regeneration by increasing MyoD1 and MyoG expression,and the former had a more distinct effect in inducing autophagy and decreasing inflammation than the latter.In addition,goat whey protein and casein could modulate hostmicrobial arginine co-metabolism.Notably,goat milk proteins responded well to sarcopenia comorbidities,including sarcopenic obesity,osteosarcopenia,and osteoarthritis.Conclusion:The study confirmed that goat milk proteins were more effective than bovine milk proteins for the control of sarcopenia.Moreover,we found that whey protein and casein could modulate host-microbial arginine co-metabolism,which shows their potential as precision nutritional supplements for the management of sarcopenia.Our study provides theoretical support for the prevention and control of sarcopenia.展开更多
BACKGROUND Ras-related protein Rab24,which belongs to the small GTPase family,plays a crucial role in regulating intracellular protein trafficking.Dysregulation of Rab24 has been recently identified in hepatocellular ...BACKGROUND Ras-related protein Rab24,which belongs to the small GTPase family,plays a crucial role in regulating intracellular protein trafficking.Dysregulation of Rab24 has been recently identified in hepatocellular carcinoma(HCC).However,its clinical significance and tumor related effects remain to be further clarified.AIM To explore the expression pattern of Rab24 and its role in HCC progression.METHODS The expression profile of Rab24 was tested in HCC tissues together with adjacent tissues from transcriptional,mRNA,and protein levels.The prognostic role of Rab24 in HCC was assessed by univariate and multivariate analyses.Clinical outcomes were evaluated by the Kaplan-Meier analysis and log-rank test.The effect of Rab24 on cell proliferation was tested through cellular experiments and xenograft experiments.RESULTS Rab24 expression was elevated in HCC tissues compared to adjacent liver tissues.High expression of Rab24 was significantly associated with larger tumor size and advanced tumor stage.Moreover,HCC patients with high Rab24 expression showed poorer overall survival,and Rab24 was identified as an independent prognosis factor according to multivariate analysis.By using overexpression and shRNA knockdown strategies in HCC cell lines,we found that Rab24 can promote HCC proliferation.Finally,we validated that silencing Rab24 significantly attenuated xenograft growth in vivo.CONCLUSION Our study demonstrated that high expression of Rab24 was significantly correlated with poorer prognosis of HCC patients,indicating the potential of Rab24 as a novel clinical biomarker and therapeutic target.展开更多
BACKGROUND Esophageal cancer(ESCA)is among the most prevalent and lethal tumors globally.While nitric oxide synthase 1(NOS1)is recognized for its important in-volvement in various cancers,its specific function in ESCA...BACKGROUND Esophageal cancer(ESCA)is among the most prevalent and lethal tumors globally.While nitric oxide synthase 1(NOS1)is recognized for its important in-volvement in various cancers,its specific function in ESCA remains unclear.AIM To explore the potential role and underlying mechanisms of NOS1 in ESCA.METHODS Survival rates were analyzed using GeneCards and Gene Expression Profiling Interactive Analysis.The effects and mechanisms of NOS1 on ESCA cells were evaluated via the Cell Counting Kit-8 assay,scratch assay,Transwell assay,flow cytometry,quantitative polymerase chain reaction,western blotting,and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining.The protein interaction network was used to screen the interacting proteins of NOS1 and validate these interactions through co-immuno-precipitation and dual luciferase assays.Additionally,a nude mouse xenograft model was established to evaluate the effect of NOS1 in vivo.RESULTS The survival rate of patients with ESCA with high NOS1 expression was higher than that of patients with low NOS1 expression.NOS1 expression in ESCA cell lines was lower than that in normal esophageal epithelial cells.Overexpression of NOS1(oe-NOS1)inhibited proliferation,invasion,and migration abilities in ESCA cell lines,resulting in decreased autophagy levels and increased apoptosis,pyroptosis,and ferroptosis.Protein interaction studies confirmed the interaction between NOS1 and NOS1 adaptor protein(NOS1AP).Following oe-NOS1 and the silencing of NOS1AP,levels of P62 and microtubule-associated protein 1 light chain 3 beta increased both in vitro and in vivo.Furthermore,the expression levels of E-cadherin,along with the activation of phosphatidylinositol 3-kinase(PI3K)and protein kinase B(AKT),were inhibited in ESCA cell lines.CONCLUSION NOS1 and NOS1 proteins interact to suppress autophagy,activate the PI3K/AKT pathway,and exert anti-cancer effects in ESCA.展开更多
Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal ves...Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.展开更多
BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influen...BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influence of PrPC expression in cholangiocarcinoma(CCA)on patient outcomes following surgical resection.METHODS Patients who underwent curative surgical resection for either intrahepatic or hilar CCA were enrolled in this retrospective study.Based on the immunohistochemical staining results of the surgical specimens,patients were categorized into two groups:The low PrPC group(negative or 1+)and the high PrPC group(2+or 3+).Survival analyses,including overall survival and recurrence-free survival,were conducted using the Kaplan-Meier method and compared using the log-rank test.RESULTS In total,seventy-six patients diagnosed with CCA(39 with intrahepatic and 37 with hilar CCA)underwent curative hepatectomy from January 2011 to November 2021.Among these patients,38(50%)demonstrated high PrPC expression,whereas the remaining 38(50%)showed low expression of PrPC.During a median follow-up period of 31.2 months(range:1 to 137 months),the high PrPC group had a significantly shorter median overall survival than the low PrPC group(40.4 months vs 137.9 months,respectively;P=0.041).Moreover,the high PrPC group had a significantly shorter median recurrence-free survival than the low PrPC group(13.3 months vs 23.8 months,respectively;P=0.026).CONCLUSION PrPC expression is significantly associated with early recurrence and decreased survival period in CCA patients following surgical resection.Thus,PrPC may be used as a prognostic factor in treatment planning.展开更多
BACKGROUND Colon cancer represents a significant malignant neoplasm within the digestive system,characterized by a high incidence rate and substantial disease burden.The F-box protein 22(FBXO22)plays a role in forming...BACKGROUND Colon cancer represents a significant malignant neoplasm within the digestive system,characterized by a high incidence rate and substantial disease burden.The F-box protein 22(FBXO22)plays a role in forming a specific type of ubiquitin ligase subunit,which is expressed abnormally in various malignant neoplasms and shows a notable relationship with prognosis in patients with cancer.Never-theless,the function of FBXO22 in the context of colon cancer remains inade-quately elucidated.AIM To explore the role of FBXO22 in colon cancer by examining FBXO22 expression patterns and analyzing how the protein affects the prognosis in patients who have undergone surgery.METHODS Samples of cancerous and nearby normal tissues from patients with colon cancer were gathered,along with pertinent clinical data.Expression levels of the FBXO22 gene in both cancerous and paracancerous tissues were assessed through immu-nohistochemistry.The median H score served as a criterion for categorizing FBXO22 gene expression into high and low levels in cancerous tissues,and the relationship between these expression levels and various pathologic character-istics of patients,such as age,sex,and clinical stage,was analyzed.Colon cancer cell lines HCT116 and DLD-1 were used and divided into three groups:A blank control group,a negative control group,and a si-FBXO22 group.FBXO22 gene mRNA and protein expression were measured 24 hours post-transfection using real-time fluorescence quantitative polymerase chain reaction and western blotting.The proliferation capabilities of the cells in each group were assessed using the Cell Counting Kit-8 assay and 5-ethynyl-2’-deoxyuridine assay,while cellular migration and invasion abilities were evaluated using scratch healing and Transwell assays.Various online platforms,including the Timer Immune Estimation Resource,were used to analyze pan-cancer expression,promoter methylation levels,and mutation frequencies of the FBXO22 gene in colon cancer patients.Additionally,the correlation between FBXO22 gene expression,patient prognosis,immune cell infiltration,and the expression of immune molecules in the colon cancer microenvironment was investigated.The relationship between FBXO22 gene expression and chemotherapy resistance,along with the potential mechanisms of action of the FBXO22 gene,were analyzed using The Cancer Genome Atlas dataset and the Genomics of Drug Sensitivity in Cancer drug training set via R software.RESULTS Compared with normal colonic tissues,the FBXO22 gene was highly expressed in colon cancer tissues.Post-operative patients with colon cancer elevated FBXO22 reduced survival and exhibited resistance to various chemotherapeutic agents.FBXO22 expression suppresses the infiltration of anti-tumor immune cells.In vitro,FBXO22 knockdown inhibited the proliferation and migration of colon cancer cells.CONCLUSION The FBXO22 gene is a biomarker of poor prognosis in patients with colon cancer and has potential as a target for immunotherapy and overcoming chemotherapy resistance.展开更多
HCLS1-associated protein X-1(HAX1)is a multifunctional mitochondrial protein involved in the regulation of apoptosis,a crucial process of programmed cell death,and mRNA processing.Despite its significance,limited stru...HCLS1-associated protein X-1(HAX1)is a multifunctional mitochondrial protein involved in the regulation of apoptosis,a crucial process of programmed cell death,and mRNA processing.Despite its significance,limited structural data is available for HAX1,hindering a comprehensive understanding of its biological function.Notably,the caseinolytic mitochondrial matrix peptidase chaperone subunit B(CLPB)has been identified as an interacting partner of HAX1,yet the biophysical properties and binding affinity governing their interaction remain poorly defined.In this study,we present a thorough biophysical characterization of full-length human HAX1 and CLPB,accomplished through recombinant expression and purification.By employing size exclusion chromatography,dynamic light scattering,and circular dichroism spectroscopy,we successfully established their biophysical properties,revealing contrasting structural features,with CLPB displaying a-helical content and HAX1 exhibiting a disordered nature.Moreover,we employed solutionstate nuclear magnetic resonance(NMR)spectroscopy to probe their binding affinity.Our findings demonstrate the formation of stable multimeric complexes between HAX1 and CLPB,and we quantified a dissociation constant in the low range of micro-molar for their high affinity interaction.These results lay the foundation for further in-depth investigations into the dynamics and energetics governing the HAX1-CLPB interaction,ultimately contributing to a comprehensive understanding of their functional mechanisms.展开更多
Salmonella enterica serovar Typhimurium,the causative agent of gastroenteritis,is one of the most successful intracellular pathogens.Although certain host factors for Salmonella infection have been unveiled,the factor...Salmonella enterica serovar Typhimurium,the causative agent of gastroenteritis,is one of the most successful intracellular pathogens.Although certain host factors for Salmonella infection have been unveiled,the factors mediating Salmonella entry,particularly the invasion process,remain obscure.Here,we have unearthed β2 integrin,a crucial member of the integrin family,as an important host factor facilitating Salmonella invasion.It is demonstrated that overexpression of β2 integrin promotes Salmonella invasion,while the knockdown of β2 integrin significantly diminishes the extent of invasion.Moreover,Salmonella exhibits specific binding affinity towards β2 integrin,and the block of β2 integrin on cell surface substantially reduces the infection of cells in vitro.The ectodomain soluble protein of β2 integrin neutralized Salmonella infection both in cells(in vitro)and in mice(in vivo).Additionally,Salmonella protein YrbD directly interacts with β2 integrin to facilitate its invasion.To our knowledge,this study showed for the first time that the protein YrbD mediates Salmonella adhesion and internalization into host cells by interacting with β2 integrin.These findings not only broaden our understanding of the mechanisms underlying Salmonella entry,but also identify a prospective target for therapeutic control.展开更多
BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene ma...BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene manipulation for the treatment of osteoarthritis may not produce satisfactory results.Previous studies have shown that nuclear factorκB could promote the inflammatory pathway in osteoarthritic chondrocytes,and bone morphogenetic protein 4(BMP4)could promote cartilage regeneration.OBJECTIVE:To test whether combined application of AAV-p65shRNA and AAV-BMP4 will yield the synergistic effect on chondrocytes regeneration and osteoarthritis treatment.METHODS:Viral particles containing AAV-p65-shRNA and AAV-BMP4 were prepared.Their efficacy in inhibiting inflammation in chondrocytes and promoting chondrogenesis was assessed in vitro and in vivo by transfecting AAV-p65-shRNA or AAV-BMP4 into cells.The experiments were divided into five groups:PBS group;osteoarthritis group;AAV-BMP4 group;AAV-p65shRNA group;and BMP4-p65shRNA 1:1 group.Samples were collected at 4,12,and 24 weeks postoperatively.Tissue staining,including safranin O and Alcian blue,was applied after collecting articular tissue.Then,the optimal ratio between the two types of transfected viral particles was further investigated to improve the chondrogenic potential of mixed cells in vivo.RESULTS AND CONCLUSION:The combined application of AAV-p65shRNA and AAV-BMP4 together showed a synergistic effect on cartilage regeneration and osteoarthritis treatment.Mixed cells transfected with AAV-p65shRNA and AAV-BMP4 at a 1:1 ratio produced the most extracellular matrix synthesis(P<0.05).In vivo results also revealed that the combination of the two viruses had the highest regenerative potential for osteoarthritic cartilage(P<0.05).In the present study,we also discovered that the combined therapy had the maximum effect when the two viruses were administered in equal proportions.Decreasing either p65shRNA or BMP4 transfected cells resulted in less collagen II synthesis.This implies that inhibiting inflammation by p65shRNA and promoting regeneration by BMP4 are equally important for osteoarthritis treatment.These findings provide a new strategy for the treatment of early osteoarthritis by simultaneously inhibiting cartilage inflammation and promoting cartilage repair.展开更多
Edible mushroom proteins are the promising ones with the advantages of complete essential amino acid profile and multiple functional activities.To reinforce their applications in functional food development,this study...Edible mushroom proteins are the promising ones with the advantages of complete essential amino acid profile and multiple functional activities.To reinforce their applications in functional food development,this study comprehensively evaluated the physicochemical and functional properties of protein isolates from 5 mushroom species,i.e.,Pleurotus eryngii(PEP),Pleurotus ostreatus(POP),Lentinula edodes(LEP),Flammulina velutipes(FVP)and Hypsizygus marmoreus(HMP).Results showed that PEP,LEP,FVP,POP and HMP exhibited better protein solubility(PS),water holding capacity(WHC),emulsification activity index(EAI),and foaming capacity(FC)than those of soybean protein and pea protein isolates(PPI).PEP(51.95%)and POP(49.15%)had a higher amount ofβ-sheet structure.Principal component analysis and correlation analysis showed that the seven proteins could be divided into 3 clusters,and WHC,EAI and FC were significantly positively correlated with PS andβ-sheet.The least gelation concentration of PEP(16%)and FVP(16%)at p H 6.0 and 7.0 was similar to PPI,and PEP showed better hardness,springiness and rheological properties than other proteins gels.Overall,our study showed that 5 edible mushroom proteins possessed excellent functionalities(except for gelling capacity),which provided novel insights on unexploited sources of mushroom proteins used as protein-based foods in the food industry.展开更多
文摘Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of the gene encoding polycytosine RNA-binding protein 1(PCBP1).Additionally,Ma et al used a lentivirus infection system to express PCBP1.As the authors’method of administration can be improved in terms of stability and cost,we propose delivering PCBP1 to treat type 2 diabetic osteoporosis by encapsulating it in protein nanoparticles.First,PCBP1 is small and druggable.Second,intravenous injection can help deliver PCBP1 across the mucosa while avoiding acid and enzyme-catalyzed degradation.Furthermore,incorporating PCBP1 into nanoparticles prevents its interaction with water or oxygen and protects PCBP1’s structure and activity.Notably,the safety of the protein materials and the industrialization techniques for large-scale production of protein nanoparticles must be comprehensively investigated before clinical application.
基金Supported by the Fundamental Research Program of Shanxi Province,No.202203021222418Research Program of Shanxi Provincial Health Commission,No.2023061+2 种基金Fundamental Research Cooperation Program of Beijing-Tianjin-Hebei Region of Natural Science Foundation of Tianjin,No.22JCZXJC00140Tianjin Major Science and Technology Project,No.21ZXJBSY00110Tianjin Health and Science and Technology Project,No.TJWJ2024ZK001.
文摘BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.
基金supported by the National Natural Science Foundation of China,Nos.82001178(to LW),81901129(to LH),82001175(to FX)Shanghai Sailing Program,No.20YF1439200(to LW)+1 种基金the Natural Science Foundation of Shanghai,China,No.23ZR1450800(to LH)and the Fundamental Research Funds for the Central Universities,No.YG2023LC15(to ZX)。
文摘Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.
文摘Protein-energy malnutrition (PEM) as a result of poor nutrition, especially for deprived resourced households, is a big health concern in the world. According to the World Health Organisation, PEM accounts for 49% of the 10.4 million deaths of children under five that take place in developing countries. The aim of this study was to evaluate the influence of gum Arabic (GA) and texturized soy protein (TSP) and their interactive effect on proximate, functional, and textural properties of the protein-rich snack stick produced from ground green maize, GA powder, and ground TSP. GA varied at 0%, 4%, 8%, and 12%, while TSP varied at 0%, 12%, 24% and 36%. The 5 cm long protein-rich snack sticks were made using a sausage stuffer and baked in an oven at 110˚C for 1 hr 30 minutes. The snack sticks were subjected to proximate, functional and textural analysis using the standard methods. Increasing GA resulted in a significant (p p < 0.05) increased the protein content (32.46%), Ash content (3.6%), fat (11.96%), and moisture content (16.25%) of protein-rich snack sticks. The interactive effect between GA and TSP led to a decrease in fibre and carbohydrates. Results from this study show GA and TSP significantly enhanced the physico-chemical properties of protein-rich snack sticks. A sample with 4% GA and 36% TSP is recommended for the best physico-chemical attributes of the protein-rich snack stick.
基金supported by the National Natural Science Foundation of China,No.82003965the Science and Technology Research Project of Sichuan Provincial Administration of Traditional Chinese Medicine,No.2024MS167(to LH)+2 种基金the Xinglin Scholar Program of Chengdu University of Traditional Chinese Medicine,No.QJRC2022033(to LH)the Improvement Plan for the'Xinglin Scholar'Scientific Research Talent Program at Chengdu University of Traditional Chinese Medicine,No.XKTD2023002(to LH)the 2023 National Project of the College Students'Innovation and Entrepreneurship Training Program at Chengdu University of Traditional Chinese Medicine,No.202310633028(to FD)。
文摘The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
基金funded by NIH-NIA R01AG061708 (to PHO)Patrick Grange Memorial Foundation (to PHO)+1 种基金A Long Swim (to PHO)CureSPG4 Foundation (to PHO)。
文摘Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.
基金supported by the National Natural Science Foundation of China,Nos.91849115 and U1904207(to YX),81974211 and 82171247(to CS)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No.2020-PT310-01(to YX).
文摘The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.
基金This study was reviewed and approved by the Ethic Committee of Medical College of Henan Vocational University of Science and Technology(Approval No.HVUYL414101416920231017001)all participants signed a written informed consent.
文摘BACKGROUND Centromere protein A(CENPA)exhibits an increased expression level in primary human rectal cancer tissues,but its role has not been investigated.AIM To clarify the specific role and mechanism of CENPA in rectal cancer progression.METHODS CENPA protein expression in rectal cancer tissues and cell lines were detected.CENPA was overexpressed and knocked down in SW837 and SW480 cells,and proliferation,invasion,apoptosis and epithelial-mesenchymal transition(EMT)marker protein levels were examined.O6-methylguanine DNA methyltransferase(MGMT)promoter methylation was assessed with methylation-specific poly-merase chain reaction.Co-immunoprecipitation assay verified the interaction between MGMT and protein tyrosine phosphatase nonreceptor type 4(PTPN4).SW837 cells with CENPA knockdown were injected subcutaneously into mice,and tumor growth was examined.RESULTS CENPA was upregulated in rectal cancer tissues and cell lines.CENPA overex-pression promoted proliferation,invasion and EMT,and inhibited apoptosis in rectal cancer cells.Whereas CENPA knockdown showed the opposite results.Moreover,CENPA inhibited MGMT expression by promoting DNA methyltrans-ferase 1-mediated MGMT promoter methylation.MGMT knockdown abolished the CENPA knockdown-mediated inhibition of rectal cancer cell progression.MGMT increased PTPN4 protein stability by inhibiting PTPN4 ubiquitination degradation via competing with ubiquitin-conjugating enzyme E2O for interacting with PTPN4.PTPN4 knockdown abolished the inhibitory effects of MGMT overexpression on rectal cancer cell progression.Moreover,CENPA knockdown inhibited xenograft tumor growth in vivo.CONCLUSION CENPA knockdown inhibited rectal cancer cell growth and attenuated xenograft tumor growth through regulating the MGMT/PTPN4 axis.
文摘In the article“Silencing of the long non-coding RNA LINC00265 triggers autophagy and apoptosis in lung cancer by reducing protein stability of SIN3A oncogene”(Oncology Research.2024,Vol.32,No.7,pp.1185–1195.doi:10.32604/or.2023.030771,https://www.techscience.com/or/v32n7/57163),an inadvertent error occurred during the compilation of Fig.3H.This needed corrections to ensure the accuracy and integrity of the data presented.
基金supported by the National Institutes of Health,Nos.AA025919,AA025919-03S1,and AA025919-05S1(all to RAF).
文摘Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
基金supported by the Beijing Natural Science Foundation(7232236)the National Key R&D Program of China(2022YFF1100104)。
文摘Introduction:Diet intervention,especially supplementation with high-quality protein,is considered to be a critical strategy in sarcopenia.However,different sources and types of protein have different health impacts.Objectives:The aim of this study is to explore the differences in the ameliorative effects and mechanisms of different sources and types of proteins on sarcopenia,providing an optimal path for the prevention and treatment of sarcopenia.Methods:A sarcopenia model was established by intraperitoneal injection of dexamethasone(5 mg/kg).Sixty male C57BL/6 mice(8 months old)were randomly divided into the normal control,sarcopenia,goat whey protein,goat milk casein,bovine whey protein,and bovine milk casein groups.Animals were treated for 8 consecutive weeks.Organism-level and molecular phenotypes,16S rRNA gene sequencing,and untargeted metabolomics profiling based on GC-TOF/MS were employed to investigate the correlation between host metabolism,microbial metabolism,autophagy and inflammation and their influence on sarcopenia in C57BL/6 male mice.Results:All 4 proteins increased muscle mass,and goat whey protein improved muscle strength in sarcopenic mice.Goat and bovine milk proteins promoted muscle regeneration by increasing MyoD1 and MyoG expression,and the former had a more distinct effect in inducing autophagy and decreasing inflammation than the latter.In addition,goat whey protein and casein could modulate hostmicrobial arginine co-metabolism.Notably,goat milk proteins responded well to sarcopenia comorbidities,including sarcopenic obesity,osteosarcopenia,and osteoarthritis.Conclusion:The study confirmed that goat milk proteins were more effective than bovine milk proteins for the control of sarcopenia.Moreover,we found that whey protein and casein could modulate host-microbial arginine co-metabolism,which shows their potential as precision nutritional supplements for the management of sarcopenia.Our study provides theoretical support for the prevention and control of sarcopenia.
文摘BACKGROUND Ras-related protein Rab24,which belongs to the small GTPase family,plays a crucial role in regulating intracellular protein trafficking.Dysregulation of Rab24 has been recently identified in hepatocellular carcinoma(HCC).However,its clinical significance and tumor related effects remain to be further clarified.AIM To explore the expression pattern of Rab24 and its role in HCC progression.METHODS The expression profile of Rab24 was tested in HCC tissues together with adjacent tissues from transcriptional,mRNA,and protein levels.The prognostic role of Rab24 in HCC was assessed by univariate and multivariate analyses.Clinical outcomes were evaluated by the Kaplan-Meier analysis and log-rank test.The effect of Rab24 on cell proliferation was tested through cellular experiments and xenograft experiments.RESULTS Rab24 expression was elevated in HCC tissues compared to adjacent liver tissues.High expression of Rab24 was significantly associated with larger tumor size and advanced tumor stage.Moreover,HCC patients with high Rab24 expression showed poorer overall survival,and Rab24 was identified as an independent prognosis factor according to multivariate analysis.By using overexpression and shRNA knockdown strategies in HCC cell lines,we found that Rab24 can promote HCC proliferation.Finally,we validated that silencing Rab24 significantly attenuated xenograft growth in vivo.CONCLUSION Our study demonstrated that high expression of Rab24 was significantly correlated with poorer prognosis of HCC patients,indicating the potential of Rab24 as a novel clinical biomarker and therapeutic target.
基金Supported by the National Natural Science Foundation of China,No.81000201.
文摘BACKGROUND Esophageal cancer(ESCA)is among the most prevalent and lethal tumors globally.While nitric oxide synthase 1(NOS1)is recognized for its important in-volvement in various cancers,its specific function in ESCA remains unclear.AIM To explore the potential role and underlying mechanisms of NOS1 in ESCA.METHODS Survival rates were analyzed using GeneCards and Gene Expression Profiling Interactive Analysis.The effects and mechanisms of NOS1 on ESCA cells were evaluated via the Cell Counting Kit-8 assay,scratch assay,Transwell assay,flow cytometry,quantitative polymerase chain reaction,western blotting,and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining.The protein interaction network was used to screen the interacting proteins of NOS1 and validate these interactions through co-immuno-precipitation and dual luciferase assays.Additionally,a nude mouse xenograft model was established to evaluate the effect of NOS1 in vivo.RESULTS The survival rate of patients with ESCA with high NOS1 expression was higher than that of patients with low NOS1 expression.NOS1 expression in ESCA cell lines was lower than that in normal esophageal epithelial cells.Overexpression of NOS1(oe-NOS1)inhibited proliferation,invasion,and migration abilities in ESCA cell lines,resulting in decreased autophagy levels and increased apoptosis,pyroptosis,and ferroptosis.Protein interaction studies confirmed the interaction between NOS1 and NOS1 adaptor protein(NOS1AP).Following oe-NOS1 and the silencing of NOS1AP,levels of P62 and microtubule-associated protein 1 light chain 3 beta increased both in vitro and in vivo.Furthermore,the expression levels of E-cadherin,along with the activation of phosphatidylinositol 3-kinase(PI3K)and protein kinase B(AKT),were inhibited in ESCA cell lines.CONCLUSION NOS1 and NOS1 proteins interact to suppress autophagy,activate the PI3K/AKT pathway,and exert anti-cancer effects in ESCA.
基金National Natural Science Foundation of China(Grant Nos.32070838 and 82301874)Open Fund of State Key Laboratory of Reproductive Medicine,Nanjing Medical University(Grant No.SKLRM K202102)。
文摘Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.
基金Supported by National Research Foundation of Korea Grant Funded by the Korea Government,No.RS-2023-00213951.
文摘BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influence of PrPC expression in cholangiocarcinoma(CCA)on patient outcomes following surgical resection.METHODS Patients who underwent curative surgical resection for either intrahepatic or hilar CCA were enrolled in this retrospective study.Based on the immunohistochemical staining results of the surgical specimens,patients were categorized into two groups:The low PrPC group(negative or 1+)and the high PrPC group(2+or 3+).Survival analyses,including overall survival and recurrence-free survival,were conducted using the Kaplan-Meier method and compared using the log-rank test.RESULTS In total,seventy-six patients diagnosed with CCA(39 with intrahepatic and 37 with hilar CCA)underwent curative hepatectomy from January 2011 to November 2021.Among these patients,38(50%)demonstrated high PrPC expression,whereas the remaining 38(50%)showed low expression of PrPC.During a median follow-up period of 31.2 months(range:1 to 137 months),the high PrPC group had a significantly shorter median overall survival than the low PrPC group(40.4 months vs 137.9 months,respectively;P=0.041).Moreover,the high PrPC group had a significantly shorter median recurrence-free survival than the low PrPC group(13.3 months vs 23.8 months,respectively;P=0.026).CONCLUSION PrPC expression is significantly associated with early recurrence and decreased survival period in CCA patients following surgical resection.Thus,PrPC may be used as a prognostic factor in treatment planning.
基金The study was reviewed and approved by institutional ethics board of Affiliated Hospital of Hebei Engineering University(No.:2024[K]005-01).
文摘BACKGROUND Colon cancer represents a significant malignant neoplasm within the digestive system,characterized by a high incidence rate and substantial disease burden.The F-box protein 22(FBXO22)plays a role in forming a specific type of ubiquitin ligase subunit,which is expressed abnormally in various malignant neoplasms and shows a notable relationship with prognosis in patients with cancer.Never-theless,the function of FBXO22 in the context of colon cancer remains inade-quately elucidated.AIM To explore the role of FBXO22 in colon cancer by examining FBXO22 expression patterns and analyzing how the protein affects the prognosis in patients who have undergone surgery.METHODS Samples of cancerous and nearby normal tissues from patients with colon cancer were gathered,along with pertinent clinical data.Expression levels of the FBXO22 gene in both cancerous and paracancerous tissues were assessed through immu-nohistochemistry.The median H score served as a criterion for categorizing FBXO22 gene expression into high and low levels in cancerous tissues,and the relationship between these expression levels and various pathologic character-istics of patients,such as age,sex,and clinical stage,was analyzed.Colon cancer cell lines HCT116 and DLD-1 were used and divided into three groups:A blank control group,a negative control group,and a si-FBXO22 group.FBXO22 gene mRNA and protein expression were measured 24 hours post-transfection using real-time fluorescence quantitative polymerase chain reaction and western blotting.The proliferation capabilities of the cells in each group were assessed using the Cell Counting Kit-8 assay and 5-ethynyl-2’-deoxyuridine assay,while cellular migration and invasion abilities were evaluated using scratch healing and Transwell assays.Various online platforms,including the Timer Immune Estimation Resource,were used to analyze pan-cancer expression,promoter methylation levels,and mutation frequencies of the FBXO22 gene in colon cancer patients.Additionally,the correlation between FBXO22 gene expression,patient prognosis,immune cell infiltration,and the expression of immune molecules in the colon cancer microenvironment was investigated.The relationship between FBXO22 gene expression and chemotherapy resistance,along with the potential mechanisms of action of the FBXO22 gene,were analyzed using The Cancer Genome Atlas dataset and the Genomics of Drug Sensitivity in Cancer drug training set via R software.RESULTS Compared with normal colonic tissues,the FBXO22 gene was highly expressed in colon cancer tissues.Post-operative patients with colon cancer elevated FBXO22 reduced survival and exhibited resistance to various chemotherapeutic agents.FBXO22 expression suppresses the infiltration of anti-tumor immune cells.In vitro,FBXO22 knockdown inhibited the proliferation and migration of colon cancer cells.CONCLUSION The FBXO22 gene is a biomarker of poor prognosis in patients with colon cancer and has potential as a target for immunotherapy and overcoming chemotherapy resistance.
基金supported by grants from the Special Foundation of President of the Chinese Academy of Sciences(Grant No.,YZJJ2020QN27,YZJJ2021QN33)Anhui Provincial Natural Science Foundation(Grant No.,2108085MC79).
文摘HCLS1-associated protein X-1(HAX1)is a multifunctional mitochondrial protein involved in the regulation of apoptosis,a crucial process of programmed cell death,and mRNA processing.Despite its significance,limited structural data is available for HAX1,hindering a comprehensive understanding of its biological function.Notably,the caseinolytic mitochondrial matrix peptidase chaperone subunit B(CLPB)has been identified as an interacting partner of HAX1,yet the biophysical properties and binding affinity governing their interaction remain poorly defined.In this study,we present a thorough biophysical characterization of full-length human HAX1 and CLPB,accomplished through recombinant expression and purification.By employing size exclusion chromatography,dynamic light scattering,and circular dichroism spectroscopy,we successfully established their biophysical properties,revealing contrasting structural features,with CLPB displaying a-helical content and HAX1 exhibiting a disordered nature.Moreover,we employed solutionstate nuclear magnetic resonance(NMR)spectroscopy to probe their binding affinity.Our findings demonstrate the formation of stable multimeric complexes between HAX1 and CLPB,and we quantified a dissociation constant in the low range of micro-molar for their high affinity interaction.These results lay the foundation for further in-depth investigations into the dynamics and energetics governing the HAX1-CLPB interaction,ultimately contributing to a comprehensive understanding of their functional mechanisms.
基金supported by the National Key R&D Program of China(2022YFF0710500)the the National Natural Science Foundation,China(31802192,32172853 and 32373013)+2 种基金the Natural Science Foundation of Heilongjiang Province of China(C2018070)China Postdoctoral Science Foundation(2017M620076)the Central Public-interest Scientific Institution Basal Research Fund,China(1610302022001)。
文摘Salmonella enterica serovar Typhimurium,the causative agent of gastroenteritis,is one of the most successful intracellular pathogens.Although certain host factors for Salmonella infection have been unveiled,the factors mediating Salmonella entry,particularly the invasion process,remain obscure.Here,we have unearthed β2 integrin,a crucial member of the integrin family,as an important host factor facilitating Salmonella invasion.It is demonstrated that overexpression of β2 integrin promotes Salmonella invasion,while the knockdown of β2 integrin significantly diminishes the extent of invasion.Moreover,Salmonella exhibits specific binding affinity towards β2 integrin,and the block of β2 integrin on cell surface substantially reduces the infection of cells in vitro.The ectodomain soluble protein of β2 integrin neutralized Salmonella infection both in cells(in vitro)and in mice(in vivo).Additionally,Salmonella protein YrbD directly interacts with β2 integrin to facilitate its invasion.To our knowledge,this study showed for the first time that the protein YrbD mediates Salmonella adhesion and internalization into host cells by interacting with β2 integrin.These findings not only broaden our understanding of the mechanisms underlying Salmonella entry,but also identify a prospective target for therapeutic control.
文摘BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene manipulation for the treatment of osteoarthritis may not produce satisfactory results.Previous studies have shown that nuclear factorκB could promote the inflammatory pathway in osteoarthritic chondrocytes,and bone morphogenetic protein 4(BMP4)could promote cartilage regeneration.OBJECTIVE:To test whether combined application of AAV-p65shRNA and AAV-BMP4 will yield the synergistic effect on chondrocytes regeneration and osteoarthritis treatment.METHODS:Viral particles containing AAV-p65-shRNA and AAV-BMP4 were prepared.Their efficacy in inhibiting inflammation in chondrocytes and promoting chondrogenesis was assessed in vitro and in vivo by transfecting AAV-p65-shRNA or AAV-BMP4 into cells.The experiments were divided into five groups:PBS group;osteoarthritis group;AAV-BMP4 group;AAV-p65shRNA group;and BMP4-p65shRNA 1:1 group.Samples were collected at 4,12,and 24 weeks postoperatively.Tissue staining,including safranin O and Alcian blue,was applied after collecting articular tissue.Then,the optimal ratio between the two types of transfected viral particles was further investigated to improve the chondrogenic potential of mixed cells in vivo.RESULTS AND CONCLUSION:The combined application of AAV-p65shRNA and AAV-BMP4 together showed a synergistic effect on cartilage regeneration and osteoarthritis treatment.Mixed cells transfected with AAV-p65shRNA and AAV-BMP4 at a 1:1 ratio produced the most extracellular matrix synthesis(P<0.05).In vivo results also revealed that the combination of the two viruses had the highest regenerative potential for osteoarthritic cartilage(P<0.05).In the present study,we also discovered that the combined therapy had the maximum effect when the two viruses were administered in equal proportions.Decreasing either p65shRNA or BMP4 transfected cells resulted in less collagen II synthesis.This implies that inhibiting inflammation by p65shRNA and promoting regeneration by BMP4 are equally important for osteoarthritis treatment.These findings provide a new strategy for the treatment of early osteoarthritis by simultaneously inhibiting cartilage inflammation and promoting cartilage repair.
基金supported by the special fund of Jiangsu Province for the transformation of scientific and technological achievements(BA2021062)Jiangsu agricultural science and technology independent innovation fund(CX(22)2007)。
文摘Edible mushroom proteins are the promising ones with the advantages of complete essential amino acid profile and multiple functional activities.To reinforce their applications in functional food development,this study comprehensively evaluated the physicochemical and functional properties of protein isolates from 5 mushroom species,i.e.,Pleurotus eryngii(PEP),Pleurotus ostreatus(POP),Lentinula edodes(LEP),Flammulina velutipes(FVP)and Hypsizygus marmoreus(HMP).Results showed that PEP,LEP,FVP,POP and HMP exhibited better protein solubility(PS),water holding capacity(WHC),emulsification activity index(EAI),and foaming capacity(FC)than those of soybean protein and pea protein isolates(PPI).PEP(51.95%)and POP(49.15%)had a higher amount ofβ-sheet structure.Principal component analysis and correlation analysis showed that the seven proteins could be divided into 3 clusters,and WHC,EAI and FC were significantly positively correlated with PS andβ-sheet.The least gelation concentration of PEP(16%)and FVP(16%)at p H 6.0 and 7.0 was similar to PPI,and PEP showed better hardness,springiness and rheological properties than other proteins gels.Overall,our study showed that 5 edible mushroom proteins possessed excellent functionalities(except for gelling capacity),which provided novel insights on unexploited sources of mushroom proteins used as protein-based foods in the food industry.
