To elucidate the intracellular signaling pathways for VLDL-induced VLDLR transcription, Western blot analysis was used to examine phosphorylated ERK1/2 protein. It was found that that VLDL induced an increase in ERK1/...To elucidate the intracellular signaling pathways for VLDL-induced VLDLR transcription, Western blot analysis was used to examine phosphorylated ERK1/2 protein. It was found that that VLDL induced an increase in ERK1/2 activity in a protein kinase C (PKC)-dependent manner in murine RAW264. 7 macrophages. By using different protein kinases inhibitors or activators it was observed that the effect of VLDL-induced VLDL receptor transcription, which is monitored by RT-PCR analysis of VLDL receptor mRNA, was not affected by the inhibitor of p38 kinase and cAMP analog, but completely abolished by pretreatment of the cells with PD 98059, an inhibitor of MEK and GF 109203X, an inhibitor of PKC. These results demonstrated that the PKC/ERK1/2 cascade is the essential signaling pathway by which VLDL activates VLDL receptor mRNA expression.展开更多
The ligand-binding domain of VLDL receptor contains eight imperfectly similar repeats. To discuss the contribution of each repeat to ligand binding, the RT-PCR technique was used to clone the VLDLR-cDNA from the heart...The ligand-binding domain of VLDL receptor contains eight imperfectly similar repeats. To discuss the contribution of each repeat to ligand binding, the RT-PCR technique was used to clone the VLDLR-cDNA from the heart muscle of Chinese people. Two recombinants were further constructed, which contained the full-length cDNA of VLDLR and the mutant lacking repeats 1-5. CHO cell line was transfected with two recombinants. The expression of VLDLR gene could be detected by RT-PCR from the CHO cells transfected with pCD-VR. The results of binding experiments showed that the ability of the CHO cells transfected with the full-length cDNA of VLDL-R binding DiI-labeled β-VLDL was higher than that of the CHO cells transfected with the mutant. Our findings indicated that human VLDL-R gene could be expressed effectively on CHO cells, and the receptor was almost inactivated when repeats1-5 were deleted.展开更多
We previously reported that Dai-saiko-to (Da-Chai-Hu-Tang), a traditional Japanese kampo medicine, increased LDL receptor mRNA expression in the liver of the hypercholesterolemic rabbits. In this study, we focused on ...We previously reported that Dai-saiko-to (Da-Chai-Hu-Tang), a traditional Japanese kampo medicine, increased LDL receptor mRNA expression in the liver of the hypercholesterolemic rabbits. In this study, we focused on LDL receptor gene expression in a human hepatoma cell line (HepG2) treated with Dai-saiko-to extract and the extracts of eight herbs presented in Dai-saiko-to. Dai-saiko-to extract significantly increased LDL receptor gene and SREBP2 gene expression compared with the control. The extracts of four herbs, Bupleurum root, Pinellia tuber, Scutellaria root and Peony root significantly increased the LDL receptor gene expression. Whereas, Jujube, Immature orange, Ginger and Rhubarb extracts did not change the gene expression. These results suggest that Dai-saiko-to increased the expression of the cholesterol transport gene (LDL receptor) regulated by SREBP2 gene in the human hepatoma cell line. The pharmacological activity of Dai-saiko-to against hypercholesterolemia and atheromatous lesions related for these four herbal components.展开更多
Ongoing insulin therapy maintains LDL receptors at highly expressed state in Type-1 diabetic people;yet Type-1 diabetics are liable of having higher plasma LDL level. This disparity has raised doubt on the probability...Ongoing insulin therapy maintains LDL receptors at highly expressed state in Type-1 diabetic people;yet Type-1 diabetics are liable of having higher plasma LDL level. This disparity has raised doubt on the probability of existence of functionally active LDL receptor in such people. Confocal microscopy and immunoprecipitation have made it evident that a portion of insulin and LDL receptors remain together in a co-localized mode, which only gets freed in presence of insulin. The findings of this study have shown that insulin therapy protects Type-1 diabetic people from the pathogenesis of atherosclerosis by decimating the inactivity of the co-localized LDL receptors in addition to its regular effect of having increased glucose tolerance. The existence of co-localized state of these two receptors and their dependence on insulin for independent activity has, at least, presented a reason for developing hypercholesterolemia and advanced coronary atherosclerotic lesion in chronic Type-1 diabetic subjects.展开更多
By means of radioligand binding assay, both receptors of the malondialdehyde modified low density lipoprotein (MDA-LDL) and the oxidatively modified LDL(o-LDL) on the mouse's peritoneal macrophage (MPM) were studi...By means of radioligand binding assay, both receptors of the malondialdehyde modified low density lipoprotein (MDA-LDL) and the oxidatively modified LDL(o-LDL) on the mouse's peritoneal macrophage (MPM) were studied. The results show that there were high affinity receptors for MDA-LDL and o-LDL on the MPM and both receptors had multiplicity of configuration based on the competitive-inhibition curve or parameters IC50 and Ki, and the acetylated LDL (Ac-LDL) and dextran sulfate can both competitively inhibit MDA-LDL or oLDL binding to these receptors in some degree.It is meanful to study the scavenger receptor multiplicity and its relationship to the genesis, protection and treamtent of atherosclerosis.展开更多
Summary: The polyclonal antibodies against VLDL receptor were prepared and identified. Rabbits were immunized with polypeptide fragment of VLDL receptor as antigen. The collected blood serum of the immunized rabbits w...Summary: The polyclonal antibodies against VLDL receptor were prepared and identified. Rabbits were immunized with polypeptide fragment of VLDL receptor as antigen. The collected blood serum of the immunized rabbits was analyzed and identified by using ELISA and Western Blot. The results showed that the rabbit against mouse and human VLDL receptor antibodies were obtained with high titer and could recognize the natural VLDL receptors through Western blot. The prepared polyclonal antibodies against VLDL receptor provide a new tool to study the protein of VLDL receptor.展开更多
The role of very low density lipoprotein receptor (LVLDR) in the process of foam cell formation was investigated. After the primary cultured mouse peritoneal macrophages were incubated with VLDL, β VLDL or low densi...The role of very low density lipoprotein receptor (LVLDR) in the process of foam cell formation was investigated. After the primary cultured mouse peritoneal macrophages were incubated with VLDL, β VLDL or low density lipoprotein (LDL), respectively for 24 h and 48 h, foam cells formation was identified by oil red O staining and cellular contents of triglyceride (TG) and total cholesterol (TC) were determined. The mRNA levels of LDLR, LDLR related protein (LRP) and VLDLR were detected by semi quantitative RT PCR. The results demonstrated that VLDL, β VLDL and LDL could increase the contents of TG and TC in macrophages. Cells treated with VLDL or β VLDL showed markedly increased expression of VLDLR and decreased expression of LDLR, whereas LRP was up regulated slightly. For identifying the effect of VLDL receptor on cellular lipid accumulation, ldl A7 VR cells, which expresses VLDLR and trace amount of LRP without functional LDLR, was used to incubate with lipoproteins for further examination. The results elucidated that the uptake of triglyceride rich lipoprotein mediated by VLDLR plays an important role in accumulation of lipid and the formation of foam cells.展开更多
Sugars are one of the major metabolites and are essential for nucleic acid synthesis and energy production.In addition,sugars can act as signaling molecules.To study sugar signaling at the systemic level,there is an u...Sugars are one of the major metabolites and are essential for nucleic acid synthesis and energy production.In addition,sugars can act as signaling molecules.To study sugar signaling at the systemic level,there is an urgent need to systematically identify sugar-sensing proteins and nucleic acids.I propose the terms“swodkoreceptor”and“swodkocrine signaling,”derived from the Polish word“slodki”meaning“sweet,”to comprise all sugar-sensing proteins and signaling events,respectively,regardless of their cellular location and signaling domains.This proposal is intended to facilitate the inclusion of proteins such as the Escherichia coli Lac I repressor as an allolactose receptor,human glucokinase regulatory protein(GCKR)as a fructose receptor,and other sugar-binding based allosterically regulated enzymes and transcription factors as sugar-sensing receptors.In addition,enzyme-interacting proteins whose interaction state is regulated by sugar binding have also been proposed as sugar receptors.The systemic study of protein-and nucleic-acid-based swodkoreceptors may help to identify organelle-specific swodkoreceptors and to also address receptor duality.The study of intra-and inter-organism swodkocrine signaling and its crosstalk with gasocrine signaling may help to understand the etiology of diseases due to dysregulation in sugar homeostasis and signaling.展开更多
This study examined the effect of insulin on the expression of very low density lipoprotein receptor (VLDLR) subtypes of SGC7901 cells and discussed its biological implication.In vitro, moderately or poorly-differenti...This study examined the effect of insulin on the expression of very low density lipoprotein receptor (VLDLR) subtypes of SGC7901 cells and discussed its biological implication.In vitro, moderately or poorly-differentiated human gastric adenocarcinoma cell line SGC7901 was incubated with insulin for different lengths of time, and then the expression of protein and RNA level in VLDLR subtypes were detected by Western blotting and real-time PCR, respectively.The results showed that, at certain time interval, insulin could down-regulate expression of type Ⅰ VLDLR and up-regulate the expression of type Ⅱ VLDLR in SGC7901 cells, at both protein and RNA level.We are led to conclude that insulin serves as a regulator in maintaining the balance between glucose and lipid metabolism in vivo, possibly through its effect on the differential expression of VLDLR subtypes.展开更多
AIM: To investigated the status of low-density lipoprotein (LDL)-receptor and angiotensionogen gene expression in rats treated chronically with ethanol followed by binge administration, a model that mimics the human s...AIM: To investigated the status of low-density lipoprotein (LDL)-receptor and angiotensionogen gene expression in rats treated chronically with ethanol followed by binge administration, a model that mimics the human scenario. METHODS: Rats were chronically treated with ethanol in liquid diet for 4 wk followed by a single binge mode of ethanol administration (5 mg/kg body weight). Samples were processed 4 h after binge ethanol administration (chronic ethanol binge). Control rats were fed isocaloric diet. In the control for binge, ethanol was replaced by water. Expression of mRNA for angioten-sinogen, c-fos and LDL-receptor, and nuclear accumulation of phospho-extracellular regulated kinases (ERK)1/2 and ERK1/2 protein were examined. RESULTS: Binge ethanol administration in chronically treated rats caused increase in steatosis and necrosis. Chronic ethanol alone had negligible effect on mRNA levels of LDL-receptor, or on the levels of nuclear ERK1/2 and phospho-ERK1/2. But, chronic ethanol followed by binge caused a decrease in LDL-receptor mRNA, and also decreased the levels of ERK1/2 and phospho-ERK1/2 in the nuclear compartment. On the other hand, chronic ethanol-binge increased mRNA expression of angiotensinogen and c-fos. CONCLUSION: Binge ethanol after chronic exposure, causes transcriptional dysregulation of LDL-receptor and angiotensinogen genes, both cardiovascular risk factors.展开更多
Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic...Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.展开更多
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well ...Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.展开更多
Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Int...Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Interaction(DTI)prediction methods(including those based on heterogeneous information networks)have shown promise,they remain limited in their ability to fully capture the nature of DTIs and often lack interpretability.To overcome these limitations,this study introduces a novel hybrid optimization model termed MDBO-RF,which integrates a Modified Dung Beetle Optimizer(MDBO)with Random Forest(RF).The key innovation lies in the enhancement of the DBO algorithm through a quaternion-based learning mechanism and the Cauchy mutation strategy,specifically designed to overcome the slow convergence and susceptibility to local optima that plague traditional metaheuristic algorithms used for hyperparameter tuning.The model leverages commonly used molecular descriptors to enhance the prediction of Tyrosine Kinase(TK)inhibitory activity and enable efficient compound screening.Our results demonstrate that MDBO-RF achieves a 3.41%increase in prediction accuracy compared to the standard RF model and outperforms several other contemporary machine learning approaches.The model effectively streamlines the RTK inhibitor screening process by improving prediction accuracy in multi-target competitive binding scenarios and reducing false-positive screening due to off-target effects.This work underscores the value of hybrid optimization strategies in bioinformatics and provides a robust,interpretable tool for accelerating drug discovery.展开更多
Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential ...Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential benefits by reducing metabolic demands and protecting organs,but its application in HS is challenged by cooling difficulties and side effects.This study introduces a novel nasal gel formulation of N6-cyclohexyladenosine(CHA),an adenosine A1 receptor agonist,designed to enhance brain delivery while minimizing peripheral side effects.In a mouse model of HS,administration of CHA nasal gel significantly improved survival rates,reduced metabolic rates,and protected major organs without worsening coagulopathy.Metabolomics analysis revealed a shift towards fatty acid oxidation and increased antioxidant capacity.These findings demonstrate that CHA nasal gel effectively induces TH,offering a safe and innovative treatment strategy for HS,particularly in resource-limited environments.展开更多
Phytomelatonin,an emerging plant hormone,plays vital roles in plant growth,development,and stress adaptation(Arnao et al.,2022;Ullah et al.,2024).It acts both as a direct antioxidant and a signaling molecule,engaging ...Phytomelatonin,an emerging plant hormone,plays vital roles in plant growth,development,and stress adaptation(Arnao et al.,2022;Ullah et al.,2024).It acts both as a direct antioxidant and a signaling molecule,engaging complex networks and interacting with other phytohormones(Liu et al.,2022;Khan et al.,2023).Although phytomelatonin receptors(PMTRs)have been identified in many plants(Wei et al.,2018;Wang et al.,2022;Liu et al.,2025),the downstream signaling mechanisms,particularly receptor-mediated protein modifications and transcriptional regulation,remain poorly characterized.展开更多
Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown t...Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.展开更多
Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote i...Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.展开更多
Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor...Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.展开更多
基金This project was supported by a grant from National Natural Sciences Foundation of China(Serial No.39970307).
文摘To elucidate the intracellular signaling pathways for VLDL-induced VLDLR transcription, Western blot analysis was used to examine phosphorylated ERK1/2 protein. It was found that that VLDL induced an increase in ERK1/2 activity in a protein kinase C (PKC)-dependent manner in murine RAW264. 7 macrophages. By using different protein kinases inhibitors or activators it was observed that the effect of VLDL-induced VLDL receptor transcription, which is monitored by RT-PCR analysis of VLDL receptor mRNA, was not affected by the inhibitor of p38 kinase and cAMP analog, but completely abolished by pretreatment of the cells with PD 98059, an inhibitor of MEK and GF 109203X, an inhibitor of PKC. These results demonstrated that the PKC/ERK1/2 cascade is the essential signaling pathway by which VLDL activates VLDL receptor mRNA expression.
文摘The ligand-binding domain of VLDL receptor contains eight imperfectly similar repeats. To discuss the contribution of each repeat to ligand binding, the RT-PCR technique was used to clone the VLDLR-cDNA from the heart muscle of Chinese people. Two recombinants were further constructed, which contained the full-length cDNA of VLDLR and the mutant lacking repeats 1-5. CHO cell line was transfected with two recombinants. The expression of VLDLR gene could be detected by RT-PCR from the CHO cells transfected with pCD-VR. The results of binding experiments showed that the ability of the CHO cells transfected with the full-length cDNA of VLDL-R binding DiI-labeled β-VLDL was higher than that of the CHO cells transfected with the mutant. Our findings indicated that human VLDL-R gene could be expressed effectively on CHO cells, and the receptor was almost inactivated when repeats1-5 were deleted.
文摘We previously reported that Dai-saiko-to (Da-Chai-Hu-Tang), a traditional Japanese kampo medicine, increased LDL receptor mRNA expression in the liver of the hypercholesterolemic rabbits. In this study, we focused on LDL receptor gene expression in a human hepatoma cell line (HepG2) treated with Dai-saiko-to extract and the extracts of eight herbs presented in Dai-saiko-to. Dai-saiko-to extract significantly increased LDL receptor gene and SREBP2 gene expression compared with the control. The extracts of four herbs, Bupleurum root, Pinellia tuber, Scutellaria root and Peony root significantly increased the LDL receptor gene expression. Whereas, Jujube, Immature orange, Ginger and Rhubarb extracts did not change the gene expression. These results suggest that Dai-saiko-to increased the expression of the cholesterol transport gene (LDL receptor) regulated by SREBP2 gene in the human hepatoma cell line. The pharmacological activity of Dai-saiko-to against hypercholesterolemia and atheromatous lesions related for these four herbal components.
文摘Ongoing insulin therapy maintains LDL receptors at highly expressed state in Type-1 diabetic people;yet Type-1 diabetics are liable of having higher plasma LDL level. This disparity has raised doubt on the probability of existence of functionally active LDL receptor in such people. Confocal microscopy and immunoprecipitation have made it evident that a portion of insulin and LDL receptors remain together in a co-localized mode, which only gets freed in presence of insulin. The findings of this study have shown that insulin therapy protects Type-1 diabetic people from the pathogenesis of atherosclerosis by decimating the inactivity of the co-localized LDL receptors in addition to its regular effect of having increased glucose tolerance. The existence of co-localized state of these two receptors and their dependence on insulin for independent activity has, at least, presented a reason for developing hypercholesterolemia and advanced coronary atherosclerotic lesion in chronic Type-1 diabetic subjects.
文摘By means of radioligand binding assay, both receptors of the malondialdehyde modified low density lipoprotein (MDA-LDL) and the oxidatively modified LDL(o-LDL) on the mouse's peritoneal macrophage (MPM) were studied. The results show that there were high affinity receptors for MDA-LDL and o-LDL on the MPM and both receptors had multiplicity of configuration based on the competitive-inhibition curve or parameters IC50 and Ki, and the acetylated LDL (Ac-LDL) and dextran sulfate can both competitively inhibit MDA-LDL or oLDL binding to these receptors in some degree.It is meanful to study the scavenger receptor multiplicity and its relationship to the genesis, protection and treamtent of atherosclerosis.
基金ThisprojectwassupportedbyagrantfromNationalNaturalSciencesFoundationofChina (No .39970 30 7)
文摘Summary: The polyclonal antibodies against VLDL receptor were prepared and identified. Rabbits were immunized with polypeptide fragment of VLDL receptor as antigen. The collected blood serum of the immunized rabbits was analyzed and identified by using ELISA and Western Blot. The results showed that the rabbit against mouse and human VLDL receptor antibodies were obtained with high titer and could recognize the natural VLDL receptors through Western blot. The prepared polyclonal antibodies against VLDL receptor provide a new tool to study the protein of VLDL receptor.
文摘The role of very low density lipoprotein receptor (LVLDR) in the process of foam cell formation was investigated. After the primary cultured mouse peritoneal macrophages were incubated with VLDL, β VLDL or low density lipoprotein (LDL), respectively for 24 h and 48 h, foam cells formation was identified by oil red O staining and cellular contents of triglyceride (TG) and total cholesterol (TC) were determined. The mRNA levels of LDLR, LDLR related protein (LRP) and VLDLR were detected by semi quantitative RT PCR. The results demonstrated that VLDL, β VLDL and LDL could increase the contents of TG and TC in macrophages. Cells treated with VLDL or β VLDL showed markedly increased expression of VLDLR and decreased expression of LDLR, whereas LRP was up regulated slightly. For identifying the effect of VLDL receptor on cellular lipid accumulation, ldl A7 VR cells, which expresses VLDLR and trace amount of LRP without functional LDLR, was used to incubate with lipoproteins for further examination. The results elucidated that the uptake of triglyceride rich lipoprotein mediated by VLDLR plays an important role in accumulation of lipid and the formation of foam cells.
基金supported by the National Science Centre grants,Grant/Award Number:SONATA-BIS 2020/38/E/NZ3/00090 and SONATA 2021/43/D/NZ3/01798。
文摘Sugars are one of the major metabolites and are essential for nucleic acid synthesis and energy production.In addition,sugars can act as signaling molecules.To study sugar signaling at the systemic level,there is an urgent need to systematically identify sugar-sensing proteins and nucleic acids.I propose the terms“swodkoreceptor”and“swodkocrine signaling,”derived from the Polish word“slodki”meaning“sweet,”to comprise all sugar-sensing proteins and signaling events,respectively,regardless of their cellular location and signaling domains.This proposal is intended to facilitate the inclusion of proteins such as the Escherichia coli Lac I repressor as an allolactose receptor,human glucokinase regulatory protein(GCKR)as a fructose receptor,and other sugar-binding based allosterically regulated enzymes and transcription factors as sugar-sensing receptors.In addition,enzyme-interacting proteins whose interaction state is regulated by sugar binding have also been proposed as sugar receptors.The systemic study of protein-and nucleic-acid-based swodkoreceptors may help to identify organelle-specific swodkoreceptors and to also address receptor duality.The study of intra-and inter-organism swodkocrine signaling and its crosstalk with gasocrine signaling may help to understand the etiology of diseases due to dysregulation in sugar homeostasis and signaling.
基金supported by grants from National Natural Sciences Foundation of China (No.39970307)Hubei Provincial Natural Sciences Foundation of China (No.2005ABA092)
文摘This study examined the effect of insulin on the expression of very low density lipoprotein receptor (VLDLR) subtypes of SGC7901 cells and discussed its biological implication.In vitro, moderately or poorly-differentiated human gastric adenocarcinoma cell line SGC7901 was incubated with insulin for different lengths of time, and then the expression of protein and RNA level in VLDLR subtypes were detected by Western blotting and real-time PCR, respectively.The results showed that, at certain time interval, insulin could down-regulate expression of type Ⅰ VLDLR and up-regulate the expression of type Ⅱ VLDLR in SGC7901 cells, at both protein and RNA level.We are led to conclude that insulin serves as a regulator in maintaining the balance between glucose and lipid metabolism in vivo, possibly through its effect on the differential expression of VLDLR subtypes.
文摘AIM: To investigated the status of low-density lipoprotein (LDL)-receptor and angiotensionogen gene expression in rats treated chronically with ethanol followed by binge administration, a model that mimics the human scenario. METHODS: Rats were chronically treated with ethanol in liquid diet for 4 wk followed by a single binge mode of ethanol administration (5 mg/kg body weight). Samples were processed 4 h after binge ethanol administration (chronic ethanol binge). Control rats were fed isocaloric diet. In the control for binge, ethanol was replaced by water. Expression of mRNA for angioten-sinogen, c-fos and LDL-receptor, and nuclear accumulation of phospho-extracellular regulated kinases (ERK)1/2 and ERK1/2 protein were examined. RESULTS: Binge ethanol administration in chronically treated rats caused increase in steatosis and necrosis. Chronic ethanol alone had negligible effect on mRNA levels of LDL-receptor, or on the levels of nuclear ERK1/2 and phospho-ERK1/2. But, chronic ethanol followed by binge caused a decrease in LDL-receptor mRNA, and also decreased the levels of ERK1/2 and phospho-ERK1/2 in the nuclear compartment. On the other hand, chronic ethanol-binge increased mRNA expression of angiotensinogen and c-fos. CONCLUSION: Binge ethanol after chronic exposure, causes transcriptional dysregulation of LDL-receptor and angiotensinogen genes, both cardiovascular risk factors.
基金National Natural Science Foundation of China,Grant/Award Number:82260007Jilin Province Health Commission,Grant/Award Number:2024A062+1 种基金Jilin Provincial Department of Education,Grant/Award Number:JJKH20240698KJJilin Province Science and Technology Department,Grant/Award Number:20240404025ZP and 20240602100RC。
文摘Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.
基金Supported by Fondo per gli Investimenti della Ricerca di Base(FIRB)(RBAP10MY35_002)by Ente Cassa di Risparmio di Firenzeby FiorGen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
基金National Key Research and Development Program of China(No.2022YFD1802104).
文摘Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Interaction(DTI)prediction methods(including those based on heterogeneous information networks)have shown promise,they remain limited in their ability to fully capture the nature of DTIs and often lack interpretability.To overcome these limitations,this study introduces a novel hybrid optimization model termed MDBO-RF,which integrates a Modified Dung Beetle Optimizer(MDBO)with Random Forest(RF).The key innovation lies in the enhancement of the DBO algorithm through a quaternion-based learning mechanism and the Cauchy mutation strategy,specifically designed to overcome the slow convergence and susceptibility to local optima that plague traditional metaheuristic algorithms used for hyperparameter tuning.The model leverages commonly used molecular descriptors to enhance the prediction of Tyrosine Kinase(TK)inhibitory activity and enable efficient compound screening.Our results demonstrate that MDBO-RF achieves a 3.41%increase in prediction accuracy compared to the standard RF model and outperforms several other contemporary machine learning approaches.The model effectively streamlines the RTK inhibitor screening process by improving prediction accuracy in multi-target competitive binding scenarios and reducing false-positive screening due to off-target effects.This work underscores the value of hybrid optimization strategies in bioinformatics and provides a robust,interpretable tool for accelerating drug discovery.
基金supported by grants from the National Natural Science Foundation of China(No.81981340417 to LiSu)Natural Science Foundation of Jiangsu Province Outstanding Youth Fund(No.BK20240134 to Yuanqing Gao).
文摘Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential benefits by reducing metabolic demands and protecting organs,but its application in HS is challenged by cooling difficulties and side effects.This study introduces a novel nasal gel formulation of N6-cyclohexyladenosine(CHA),an adenosine A1 receptor agonist,designed to enhance brain delivery while minimizing peripheral side effects.In a mouse model of HS,administration of CHA nasal gel significantly improved survival rates,reduced metabolic rates,and protected major organs without worsening coagulopathy.Metabolomics analysis revealed a shift towards fatty acid oxidation and increased antioxidant capacity.These findings demonstrate that CHA nasal gel effectively induces TH,offering a safe and innovative treatment strategy for HS,particularly in resource-limited environments.
基金supported by the grants from the Key Research and Development Program of Xinjiang Uygur autonomous region in China(Grant No.2023B02017)the National Key Research and Development Program of China(Grant No.2024YFD2300703)+1 种基金the financial support from the Beijing Rural Revitalization Agricultural Science and Technology Project(Grant No.NY2401080000),BAIC01-2025the 2115 Talent Development Program of China Agricultural University.
文摘Phytomelatonin,an emerging plant hormone,plays vital roles in plant growth,development,and stress adaptation(Arnao et al.,2022;Ullah et al.,2024).It acts both as a direct antioxidant and a signaling molecule,engaging complex networks and interacting with other phytohormones(Liu et al.,2022;Khan et al.,2023).Although phytomelatonin receptors(PMTRs)have been identified in many plants(Wei et al.,2018;Wang et al.,2022;Liu et al.,2025),the downstream signaling mechanisms,particularly receptor-mediated protein modifications and transcriptional regulation,remain poorly characterized.
基金supported by grants from Tianjin Scientific Research Project in Key Areas of Traditional Chinese Medicine,Tianjin Municipal Health Commission,No.2024012(to JL)Tianjin Municipal Education Commission Project,No.2021KJ217(to CS)。
文摘Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.
基金supported by the National Natural Science Foundation of China(Grant No.82060479)Key Research and Development Program of Ningxia Hui Autonomous Region(Grant No.2021BEG03062)Ningxia Natural Science Fund Key Project(Grant No.2024AAC02080).
文摘Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.
文摘Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.
