BACKGROUND RPF2 is a crucial factor in ribosome synthesis,which has been linked to the development of several cancers.However,the mechanism of RPF2 in gastric carcinogenesis is unclear.AIM To explore the role and mech...BACKGROUND RPF2 is a crucial factor in ribosome synthesis,which has been linked to the development of several cancers.However,the mechanism of RPF2 in gastric carcinogenesis is unclear.AIM To explore the role and mechanism of RPF2 in the pathogenesis of Helicobacter pylori(H.pylori)infection.METHODS GES-1 was co-cultured with H.pylori in vitro to detect changes in the expression of RPF2.Overexpression and silencing of RPF2 were performed.Quantitative realtime polymerase chain reaction(q-PCR)and Western blot(WB)were used to determine mRNA and protein expression of RPF2,protein kinase B(AKT)/mammalian target of rapamycin(mTOR),and epithelial-mesenchymal transitionrelated factors MMP2 and MMP9;cell counting kit 8 and wound healing assays were utilized to evaluate cell viability and migratory capacity;q-PCR,WB,and immunohistochemistry were employed to establish RPF2 expression in cancer tissues.RESULTS H.pylori facilitated RPF2 expression and triggered AKT/mTOR signaling pathway.Functional experiments showed that RPF2 overexpression could promote a series of malignant transformations such as cell proliferation,cell migration and invasion,and further enhance AKT/mTOR signaling pathway activation.RPF2 knockdown had the opposite effect.In addition,RPF2 expression was higher in gastric cancer tissues than in adjacent tissues.CONCLUSION RPF2 plays a significant role in the pathogenic mechanism of H.pylori infection and may be useful in the detection and management of gastric cancer caused by H.pylori infection.展开更多
The mammalian target of rapamycin （mTOR） pathway plays an important role in neuronal growth, proliferation and differentiation. To better understand the role of mTOR pathway involved in the induction of spinal cord ...The mammalian target of rapamycin （mTOR） pathway plays an important role in neuronal growth, proliferation and differentiation. To better understand the role of mTOR pathway involved in the induction of spinal cord injury, rat models of spinal cord injury were established by modified Allen＇s stall method and interfered for 7 days by intraperitoneal administration of mTOR activator adenosine triphosphate and mTOR kinase inhibitor rapamycin. At 1-4 weeks after spinal cord injury induction, the Basso, Beattie and Bresnahan locomotor rating scale was used to evaluate rat locomotor function, and immunohistochemical staining and western blot analysis were used to detect the expression of nestin （neural stem cell marker）, neuronal nuclei （neuronal marker）, neuron specific enolase, neurofilament protein 200 （axonal marker）, glial fibrillary acidic protein （astrocyte marker）, Akt, mTOR and signal transduction and activator of transcription 3 （STAT3）. Results showed that adenosine triphosphate-mediated Akt/mTOR/STAT3 pathway increased endogenous neural stem cells, induced neurogenesis and axonal growth, inhibited excessive astrogliosis and improved the locomotor function of rats with spinal cord injury.展开更多
BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) a...BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma(HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHPassociated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS). Cellbased experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP(0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay.Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction(RT-qPCR), respectively.Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway.Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry:Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose-and timedependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract(0.625mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins(e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3.Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.展开更多
Objective Our previous studies established that microRNA(miR)-451 from human umbilical cord mesenchymal stem cell-derived exosomes(hUC-MSC-Exos)alleviates acute lung injury(ALI).This study aims to elucidate the mechan...Objective Our previous studies established that microRNA(miR)-451 from human umbilical cord mesenchymal stem cell-derived exosomes(hUC-MSC-Exos)alleviates acute lung injury(ALI).This study aims to elucidate the mechanisms by which miR-451 in hUC-MSC-Exos reduces ALI by modulating macrophage autophagy.Methods Exosomes were isolated from hUC-MSCs.Severe burn-induced ALI rat models were treated with hUC-MSC-Exos carrying the miR-451 inhibitor.Hematoxylin-eosin staining evaluated inflammatory injury.Enzyme-linked immunosorbnent assay measured lipopolysaccharide(LPS),tumor necrosis factor-α,and interleukin-1βlevels.qRT-PCR detected miR-451 and tuberous sclerosis complex 1(TSC1)expressions.The regulatory role of miR-451 on TSC1 was determined using a dual-luciferase reporter system.Western blotting determined TSC1 and proteins related to the mammalian target of rapamycin(mTOR)pathway and autophagy.Immunofluorescence analysis was conducted to examine exosomes phagocytosis in alveolar macrophages and autophagy level.Results hUC-MSC-Exos with miR-451 inhibitor reduced burn-induced ALI and promoted macrophage autophagy.MiR-451 could be transferred from hUC-MSCs to alveolar macrophages via exosomes and directly targeted TSC1.Inhibiting miR-451 in hUC-MSC-Exos elevated TSC1 expression and inactivated the mTOR pathway in alveolar macrophages.Silencing TSC1 activated mTOR signaling and inhibited autophagy,while TSC1 knockdown reversed the autophagy from the miR-451 inhibitor-induced.Conclusion miR-451 from hUC-MSC exosomes improves ALI by suppressing alveolar macrophage autophagy through modulation of the TSC1/mTOR pathway,providing a potential therapeutic strategy for ALI.展开更多
Objective:To obtain the relevant information of pathway and gene by using the database of DAVID,analyze the function and distribution of important genes,screen out the target genes related to Ulcerative Colitis and pr...Objective:To obtain the relevant information of pathway and gene by using the database of DAVID,analyze the function and distribution of important genes,screen out the target genes related to Ulcerative Colitis and promote the study of the pathogenesis of UC and the development of new drugs.Methods:The Ulcerative Colitis was used to search UC related genes in TTD,Drugbank,DisGeNET database.The obtained gene data was input to the database of Daved,and the data of gene enriched pathway was obtained 87 genes were Significant enriched in the first 20 KEGG pathways.The 87 genes were input to the string database to make the interaction network diagram,and the key genes enriched in the pathway were also made the network diagram,and the two network diagrams were compared.Results:RELA,TNF,IL1B,NFKB1,IL6 and IL10 were among the highest ranked genes in two network diagrams.Conclusion:The study of RELA,TNF,IL1B,NFKB1,IL6 and IL10 is necessary for us to study further.The pathogenesis of UC was associated with multiple pathways such as NF-kappa B signaling pathway,Jak-STAT signaling pathway,TNF signaling pathway and so on.It is helpful to understand the pathogenesis of disease and provide a reliable target for the development of new drugs by analyzing the pathway and the network diagram of the interaction between genes and disease related genes.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors.Osteopontin(OPN)is thought to be closely related to the occurrence,metastasis and prognosis of many types of tumors.AIM To investigate the effect...BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors.Osteopontin(OPN)is thought to be closely related to the occurrence,metastasis and prognosis of many types of tumors.AIM To investigate the effects of OPN on the proliferation,invasion and migration of GC cells and its possible mechanism.METHODS The mRNA and protein expression of OPN in the GC cells were analyzed by realtime quantitative-reverse transcription polymerase chain reaction and western blotting,and observe the effect of varying degree expression OPN on the proliferation and other behaviors of GC.Next,the effects of OPN knockdown on GC cells migration and invasion were examined.The short hairpin RNA(shRNA)and negative control shRNA targeting OPN-shRNA were transfected into the cells according to the manufacturer’s instructions.Non transfected cells were classified as control in the identical transfecting process.24 h after RNA transfection cell proliferation activity was detected by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay,and cell invasiveness and migration were detected by Trans well assay.Meanwhile,the expression of protein kinase B(AKT),matrix metalloproteinase 2(MMP-2)and vascular endothelial growth factor(VEGF)in the human GC cell lines was detected by reverse transcription polymerase chain reaction and western blotting.RESULTS The results of this study revealed that OPN mRNA and protein expression levels were highly expressed in SGC-7901 cells.OPN knockdown by specific shRNA noticeably reduced the capabilities of proliferation,invasion and migration of SGC-7901 cells.Moreover,in the experiments of investigating the underlying mechanism,results showed that OPN knockdown could down-regulated the expression of MMP-2 and VEGF,it also decreased the phosphorylation of AKT.Meanwhile,the protein expression levels of MMP-2,VEGF and phosphorylated AKT was noticeable lower than that in control group in the GC cells after they were added to phosphatidylinositol-3-kinase(PI3K)inhibitor(LY294002).CONCLUSION These results suggested that OPN though PI3K/AKT/mammalian target of rapamycin signal pathway to upregulate MMP-2 and VEGF expression,which contribute SGC-7901 cells to proliferation,invasion and migration.Thus,our results demonstrate that OPN may serve as a novel prognostic biomarkers as well as a potential therapeutic targets for GC.展开更多
Neurodegeneration is characterized by the progressive and permanent loss of neurons.Degeneration typically results in a debilitating loss of function in an otherwise healthy person.Neurodegenerative diseases have enor...Neurodegeneration is characterized by the progressive and permanent loss of neurons.Degeneration typically results in a debilitating loss of function in an otherwise healthy person.Neurodegenerative diseases have enormous direct health care costs,with some estimates for diseases.展开更多
This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulato...This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.展开更多
The mechanistic target of rapamycin(mTOR)integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth,proliferation and survival.A regulatory network with multiple feedback loo...The mechanistic target of rapamycin(mTOR)integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth,proliferation and survival.A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division.Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate.Multiple genetic alterations are involved in colorectal carcinogenesis,including oncogenic Ras activation,phosphatidylinositol 3-kinase pathway hyperactivation,p 53 mutation,and dysregulation of wnt pathway.Many oncogenic pathways activate the mTOR pathway.mTOR has emerged as an effective target for colorectal cancer therapy.In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives.However,the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest,especially in advanced metastatic colorectal cancer.Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy,inhibitors of vascular endothelial growth factor,epidermal growth factor receptor and Mitogen-activated protein kinase kinase(MEK)inhibitors are being intensively studied and appear to be promising.Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens.In this paper,oncogenic gene alterations in colorectal cancer,as well as their interaction with the mTOR pathway,are systematically summarized.The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed.New players in mTOR signaling pathway,such as nonsteroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.展开更多
Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulatio...Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.展开更多
The study was conducted to investigate the effect and mechanism of dietary quercetin supplementation on protein utilization of Arbor Acres(AA)broilers.A total of 2401-day-old AA broilers were randomly allocated to fou...The study was conducted to investigate the effect and mechanism of dietary quercetin supplementation on protein utilization of Arbor Acres(AA)broilers.A total of 2401-day-old AA broilers were randomly allocated to four treatments with six replicates,comprising 10 broilers each replicate(60 broilers per treatment).Birds were fed either a corn-soybean meal basal diet without quercetin(control)or a basal diet supplemented with 0.2,0.4 or 0.6 g of quercetin per kg feed,and the trial lasted 42 days.Dietary quercetin supplementation tended to increase the apparent metabolic rate of protein(p=0.076)and the content of serum albumin(p=0.062)in AA broilers.Compared with the control,dietary quercetin supplementation increased the contents of protein in breast muscle(p<0.05)and in thigh muscle(p=0.053).In addition,quercetin up-regulated mRNA expression of insulin-like growth factor 1(IGF-1),phosphatidylinositol 3-kinase(PI3K),target of rapamycin(TOR),ribosomal protein S6 kinase 1(S6K1),eukaryotic translation initiation factor 4E(eIF4E),eukaryotic translation initiation factor 4G(eIF4G),eukaryotic elongation factor 2(eEF2)and eukaryotic translation initiation factor 4B(eIF4B)genes and down-regulated mRNA expression of eukaryotic elongation factor 2 kinase(eEF2K)and eukaryotic initiation factor 4E binding protein1(4E-BP1)genes in breast muscle,thigh muscle and liver of AA broilers(p<0.05).The present results suggested that dietary quercetin supplementation enhanced protein utilization in broilers by activating TOR signaling pathway.展开更多
We study the problem of detecting a target that moves between a hiding area and an operating area over multiple fixed routes. The research is carried out with one or more cookie-cutter sensors with stochastic intermis...We study the problem of detecting a target that moves between a hiding area and an operating area over multiple fixed routes. The research is carried out with one or more cookie-cutter sensors with stochastic intermission, which turn on and off stochastically governed by an on-rate and an off-rate. A cookie-cutter sensor, when it is on, can detect the target instantly once the target comes within the detection radius of the sensor. In the hiding area, the target is shielded from being detected. The residence times of the target, respectively, in the hiding area and in the operating area, are exponentially distributed and are governed by rates of transitions between the two areas. On each travel between the two areas and in each travel direction, the target selects a route randomly according to a probability distribution. Previously, we analyzed the simple case where the sensors have no intermission (i.e., they stay on all the time). In the current study, the sensors are stochastically intermittent and are synchronized (i.e., they turn on or off simultaneously). This happens when all sensors are affected by the same environmental factors. We derive asymptotic expansions for the mean time to detection when the on-rate and off-rate of the sensors are large in comparison with the rates of the target traveling between the two areas. Based on the mean time to detection, we evaluate the performance of placing the sensor(s) to monitor various travel route(s) or to scan the operating area.展开更多
BACKGROUND Ischemic heart disease ranks among the foremost contributors to mortality worldwide.Myocardial infarction injury poses a prevalent challenge in current therapies.Studies have shown that mesenchymal stem cel...BACKGROUND Ischemic heart disease ranks among the foremost contributors to mortality worldwide.Myocardial infarction injury poses a prevalent challenge in current therapies.Studies have shown that mesenchymal stem cell transplantation increases cytokine release,reduces myocardial cell necrosis,and improves left ventricular function;thus,it can be used to understand protective mechanisms.Fat extract(FE)derived from mesenchymal stem cell therapy contains high levels of paracrine factors.AIM To study the effects of FE on myocardial injury and its mechanism of action.METHODS A mouse model of myocardial infarction and a hypoxic model of neonatal rat cardiomyocytes(CMs)were established to evaluate the effects of FE.RESULTS FE exhibited an inhibitory effect on CM apoptosis and improved left ventricular function.This protective effect of FE on CMs was mediated,in part,by the activation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway.CONCLUSION Our findings showed that FE could be a new treatment to protect CMs in ischemic heart disease.展开更多
Myosin heavy chain 9(MYH9),a non-muscle myosin heavy chain protein,has been identified as a significant factor in gastrointestinal(GI)oncology,with its overexpression in various GI malignancies such as esophageal,gast...Myosin heavy chain 9(MYH9),a non-muscle myosin heavy chain protein,has been identified as a significant factor in gastrointestinal(GI)oncology,with its overexpression in various GI malignancies such as esophageal,gastric,and co-lorectal cancers being associated with poor prognosis and playing a role in tumor invasion and metastasis.This comprehensive review synthesizes the current body of knowledge regarding MYH9’s role in GI tumors,focusing on its molecular mechanisms,including its interaction with key signaling pathways like the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin axis,which suggests a role in cancer cell survival,proliferation,and epithelial-mesenchymal transition.The review also explores MYH9’s potential as a therapeutic target,with preclinical models demonstrating promising results in inhibiting tumor growth and enhancing chemosensitivity.The evidence suggests that MYH9 is a multifaceted protein with significant implications in GI tumor biology,warranting further research to elucidate its mechanisms of action and develop targeted therapies that could improve patient outcomes.展开更多
Liver cancer,particularly hepatocellular carcinoma,remains a formidable challenge in medical research and requires a deeper understanding of its molecular underpinnings.In a fascinating recent study published in Milit...Liver cancer,particularly hepatocellular carcinoma,remains a formidable challenge in medical research and requires a deeper understanding of its molecular underpinnings.In a fascinating recent study published in Military Medical Research,Xiong et al.[1]revealed the complex roles of F-box and leucine-rich repeat 6(FBXL6)and Kirsten rat sarcoma(KRAS)^(G12D) in the pathogenesis of liver cancer.This research offers critical insights into how these proteins contribute to hepatocellular carcinoma development and progression,potentially paving the way for targeted therapeutic strategies.This commentary analyzes the key findings from this study and their broader implications in oncology.展开更多
BACKGROUND： Liver regeneration is a complex process. micro RNAs（mi RNAs） are short, single-stranded RNAs that modify gene expression at the post-transcriptional level. Recent investigations have revealed that mi RN...BACKGROUND： Liver regeneration is a complex process. micro RNAs（mi RNAs） are short, single-stranded RNAs that modify gene expression at the post-transcriptional level. Recent investigations have revealed that mi RNAs are closely linked to liver regeneration.DATA SOURCES： All included studies were obtained from Pub Med, Embase, the Science Direct databases and Web of Science, with no limitation on publication year. Only studies published in English were considered.RESULTS： We grouped studies that involved mi RNA and liver regeneration into two groups： mi RNAs as promoters and as inhibitors of liver regeneration. We summarized the relevant mi RNAs separately from the related pathways.CONCLUSIONS： Blocking or stimulating the pathways of mi RNAs in liver regeneration may be novel therapeutic strategies in future regeneration-related liver managements. We may discover additional chemotherapy targets of mi RNA.展开更多
Osteosarcoma is the most common primary malignant ＇bone sarcoma, and occurs predominantly in childrenand young adults. The overall survival of patients with osteosarcoma remains low at approximately 60%.1 The prognos...Osteosarcoma is the most common primary malignant ＇bone sarcoma, and occurs predominantly in childrenand young adults. The overall survival of patients with osteosarcoma remains low at approximately 60%.1 The prognosis of osteosarcoma patients is highly associated with response to chemotherapy. Although multiple chemotherapy regimens have improved the outcome of patients with osteosarcoma, resistance to current regimens has been reported in more than 30% of patients,2 highlighting the need for novel, targeted therapies.展开更多
BACKGROUND Mesenchymal stem cells(MSCs)are a type of stem cells that possess relevant regenerative abilities and can be used to treat many chronic diseases.Diabetes mellitus(DM)is a frequently diagnosed chronic diseas...BACKGROUND Mesenchymal stem cells(MSCs)are a type of stem cells that possess relevant regenerative abilities and can be used to treat many chronic diseases.Diabetes mellitus(DM)is a frequently diagnosed chronic disease characterized by hyperglycemia which initiates many multisystem complications in the long-run.DM patients can benefit from MSCs transplantation to curb down the pathological consequences associated with hyperglycemia persistence and restore the function of damaged tissues.MSCs therapeutic outcomes are found to last for short period of time and ultimately these regenerative cells are eradicated and died in DM disease model.AIM To investigate the impact of high glucose or hyperglycemia on the cellular and molecular characteristics of MSCs.METHODS Human adipose tissue-derived MSCs(hAD-MSCs)were seeded in low(5.6 mmol/L of glucose)and high glucose(25 mmol/L of glucose)for 7 d.Cytotoxicity,viability,mitochondrial dynamics,and apoptosis were deplored using specific kits.Western blotting was performed to measure the protein expression of phosphatidylinositol 3-kinase(PI3K),TSC1,and mammalian target of rapamycin(mTOR)in these cells.RESULTS hAD-MSCs cultured in high glucose for 7 d demonstrated marked decrease in their viability,as shown by a significant increase in lactate dehydrogenase(P<0.01)and a significant decrease in Trypan blue(P<0.05)in these cells compared to low glucose control.Mitochondrial membrane potential,indicated by tetramethylrhodamine ethyl ester(TMRE)fluorescence intensity,and nicotinamide adenine dinucleotide(NAD+)/NADH ratio were significantly dropped(P<0.05 for TMRE and P<0.01 for NAD+/NADH)in high glucose exposed hAD-MSCs,indicating disturbed mitochondrial function.PI3K protein expression significantly decreased in high glucose culture MSCs(P<0.05 compared to low glucose)and it was coupled with significant upregulation in TSC1(P<0.05)and downregulation in mTOR protein expression(P<0.05).Mitochondrial complexes I,IV,and V were downregulated profoundly in high glucose(P<0.05 compared to low glucose).Apoptosis was induced as a result of mitochondrial impairment and explained the poor survival of MSCs in high glucose.CONCLUSION High glucose impaired the mitochondrial dynamics and regulatory proteins in hAD-MSCs ensuing their poor survival and high apoptosis rate in hyperglycemic microenvironment.展开更多
This review revises the reclassification of the mem-branoproliferative glomerulonephritis （MPGN） after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and patho-genes...This review revises the reclassification of the mem-branoproliferative glomerulonephritis （MPGN） after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and patho-genesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized： The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecifc treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in fnding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.展开更多
Background:TopoisomeraseⅡalpha(TOP2A)has been reported to play a crucial role in the tumorigenesis of various cancer types.However,the biological role of TOP2A in gallbladder cancer(GBC)remains unknown.The current st...Background:TopoisomeraseⅡalpha(TOP2A)has been reported to play a crucial role in the tumorigenesis of various cancer types.However,the biological role of TOP2A in gallbladder cancer(GBC)remains unknown.The current study aimed to explore the function and potential mechanism of TOP2A in GBC.Methods:Based on Gene Expression Profiling Interactive Analysis data,we found TOP2A was significantly up-regulated in GBC tissues and resulting in shorter overall survival.Quantitative real-time polymerase chain reaction and immunohistochemistry were conducted to detect the expression of TOP2A in 45 pairs of GBC tissues and adjacent non-tumor tissues.In vitro,cell proliferation,migration,and invasion ability were examined by cell counting kit-8 and transwell assay,respectively.Epithelial-mesenchymal transition(EMT)related and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway-related markers were measured by Western blotting.Xenograft model assay was performed to evaluate the effect of TOP2A in vivo.Results:TOP2A was found up-regulated in GBC(tumor vs.normal,12.62 vs.0.34)and correlated with the late tumor node metastasis stage(P=0.0032),present of lymph node metastasis(P=0.0273),and poor prognosis in GBC patients(log-rank P=0.028).In vitro and in vivo assays showed that knockdown of TOP2A notably inhibited cell proliferation,migration,invasion,EMT process,and tumor growth in GBC.In addition,TOP2A down-regulation significantly decreased the protein levels of phosphor(p)-PI3K,p-Akt,and p-mTOR.Conclusion:Our study demonstrates that TOP2A was overexpressed in GBC and associated with poor prognosis in GBC patients.TOP2A promotes GBC cell proliferation,migration,invasion,EMT process,and tumor growth through activating PI3K/Akt/mTOR signaling pathway,and may serve as a novel prognostic biomarker and therapeutic target for GBC.展开更多
基金Supported by the National Natural Science Foundation of China,No.82160634.
文摘BACKGROUND RPF2 is a crucial factor in ribosome synthesis,which has been linked to the development of several cancers.However,the mechanism of RPF2 in gastric carcinogenesis is unclear.AIM To explore the role and mechanism of RPF2 in the pathogenesis of Helicobacter pylori(H.pylori)infection.METHODS GES-1 was co-cultured with H.pylori in vitro to detect changes in the expression of RPF2.Overexpression and silencing of RPF2 were performed.Quantitative realtime polymerase chain reaction(q-PCR)and Western blot(WB)were used to determine mRNA and protein expression of RPF2,protein kinase B(AKT)/mammalian target of rapamycin(mTOR),and epithelial-mesenchymal transitionrelated factors MMP2 and MMP9;cell counting kit 8 and wound healing assays were utilized to evaluate cell viability and migratory capacity;q-PCR,WB,and immunohistochemistry were employed to establish RPF2 expression in cancer tissues.RESULTS H.pylori facilitated RPF2 expression and triggered AKT/mTOR signaling pathway.Functional experiments showed that RPF2 overexpression could promote a series of malignant transformations such as cell proliferation,cell migration and invasion,and further enhance AKT/mTOR signaling pathway activation.RPF2 knockdown had the opposite effect.In addition,RPF2 expression was higher in gastric cancer tissues than in adjacent tissues.CONCLUSION RPF2 plays a significant role in the pathogenic mechanism of H.pylori infection and may be useful in the detection and management of gastric cancer caused by H.pylori infection.
文摘The mammalian target of rapamycin （mTOR） pathway plays an important role in neuronal growth, proliferation and differentiation. To better understand the role of mTOR pathway involved in the induction of spinal cord injury, rat models of spinal cord injury were established by modified Allen＇s stall method and interfered for 7 days by intraperitoneal administration of mTOR activator adenosine triphosphate and mTOR kinase inhibitor rapamycin. At 1-4 weeks after spinal cord injury induction, the Basso, Beattie and Bresnahan locomotor rating scale was used to evaluate rat locomotor function, and immunohistochemical staining and western blot analysis were used to detect the expression of nestin （neural stem cell marker）, neuronal nuclei （neuronal marker）, neuron specific enolase, neurofilament protein 200 （axonal marker）, glial fibrillary acidic protein （astrocyte marker）, Akt, mTOR and signal transduction and activator of transcription 3 （STAT3）. Results showed that adenosine triphosphate-mediated Akt/mTOR/STAT3 pathway increased endogenous neural stem cells, induced neurogenesis and axonal growth, inhibited excessive astrogliosis and improved the locomotor function of rats with spinal cord injury.
基金Supported by National Natural Science Foundation of China, No. U20A20408 and No. 82074450Natural Science Foundation of Hunan Province, No. 2020JJ4066+4 种基金Hunan Province"Domestic First-class Cultivation Discipline"Integrated Traditional Chinese and Western Medicine Open Fund Project, No. 2020ZXYJH34 and No. 2020ZXYJH35Hunan Graduate Scientific Research Innovation Project, No. QL20210173 and No. CX20210730Hunan Province Science and Technology Innovation Talents Plan College Students Science and Technology Innovation and Entrepreneurship Project, No. 2020RC1004Guangzhou Health Science and Technology Project, No. 20221A011102Hunan Traditional Chinese Medicine Scientific Research Project, No. 202101
文摘BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin(PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills(XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma(HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHPassociated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS). Cellbased experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP(0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay.Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction(RT-qPCR), respectively.Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway.Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry:Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose-and timedependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract(0.625mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins(e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3.Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.
基金supported by the tenth batch of"3221"industrial innovation and scientific research projects in Bengbu City(beng talent[2020]No.8)the 2021 Bengbu Medical College Science and Technology Project[Natural Science,Project Number:2021byzd217].
文摘Objective Our previous studies established that microRNA(miR)-451 from human umbilical cord mesenchymal stem cell-derived exosomes(hUC-MSC-Exos)alleviates acute lung injury(ALI).This study aims to elucidate the mechanisms by which miR-451 in hUC-MSC-Exos reduces ALI by modulating macrophage autophagy.Methods Exosomes were isolated from hUC-MSCs.Severe burn-induced ALI rat models were treated with hUC-MSC-Exos carrying the miR-451 inhibitor.Hematoxylin-eosin staining evaluated inflammatory injury.Enzyme-linked immunosorbnent assay measured lipopolysaccharide(LPS),tumor necrosis factor-α,and interleukin-1βlevels.qRT-PCR detected miR-451 and tuberous sclerosis complex 1(TSC1)expressions.The regulatory role of miR-451 on TSC1 was determined using a dual-luciferase reporter system.Western blotting determined TSC1 and proteins related to the mammalian target of rapamycin(mTOR)pathway and autophagy.Immunofluorescence analysis was conducted to examine exosomes phagocytosis in alveolar macrophages and autophagy level.Results hUC-MSC-Exos with miR-451 inhibitor reduced burn-induced ALI and promoted macrophage autophagy.MiR-451 could be transferred from hUC-MSCs to alveolar macrophages via exosomes and directly targeted TSC1.Inhibiting miR-451 in hUC-MSC-Exos elevated TSC1 expression and inactivated the mTOR pathway in alveolar macrophages.Silencing TSC1 activated mTOR signaling and inhibited autophagy,while TSC1 knockdown reversed the autophagy from the miR-451 inhibitor-induced.Conclusion miR-451 from hUC-MSC exosomes improves ALI by suppressing alveolar macrophage autophagy through modulation of the TSC1/mTOR pathway,providing a potential therapeutic strategy for ALI.
文摘Objective:To obtain the relevant information of pathway and gene by using the database of DAVID,analyze the function and distribution of important genes,screen out the target genes related to Ulcerative Colitis and promote the study of the pathogenesis of UC and the development of new drugs.Methods:The Ulcerative Colitis was used to search UC related genes in TTD,Drugbank,DisGeNET database.The obtained gene data was input to the database of Daved,and the data of gene enriched pathway was obtained 87 genes were Significant enriched in the first 20 KEGG pathways.The 87 genes were input to the string database to make the interaction network diagram,and the key genes enriched in the pathway were also made the network diagram,and the two network diagrams were compared.Results:RELA,TNF,IL1B,NFKB1,IL6 and IL10 were among the highest ranked genes in two network diagrams.Conclusion:The study of RELA,TNF,IL1B,NFKB1,IL6 and IL10 is necessary for us to study further.The pathogenesis of UC was associated with multiple pathways such as NF-kappa B signaling pathway,Jak-STAT signaling pathway,TNF signaling pathway and so on.It is helpful to understand the pathogenesis of disease and provide a reliable target for the development of new drugs by analyzing the pathway and the network diagram of the interaction between genes and disease related genes.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors.Osteopontin(OPN)is thought to be closely related to the occurrence,metastasis and prognosis of many types of tumors.AIM To investigate the effects of OPN on the proliferation,invasion and migration of GC cells and its possible mechanism.METHODS The mRNA and protein expression of OPN in the GC cells were analyzed by realtime quantitative-reverse transcription polymerase chain reaction and western blotting,and observe the effect of varying degree expression OPN on the proliferation and other behaviors of GC.Next,the effects of OPN knockdown on GC cells migration and invasion were examined.The short hairpin RNA(shRNA)and negative control shRNA targeting OPN-shRNA were transfected into the cells according to the manufacturer’s instructions.Non transfected cells were classified as control in the identical transfecting process.24 h after RNA transfection cell proliferation activity was detected by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay,and cell invasiveness and migration were detected by Trans well assay.Meanwhile,the expression of protein kinase B(AKT),matrix metalloproteinase 2(MMP-2)and vascular endothelial growth factor(VEGF)in the human GC cell lines was detected by reverse transcription polymerase chain reaction and western blotting.RESULTS The results of this study revealed that OPN mRNA and protein expression levels were highly expressed in SGC-7901 cells.OPN knockdown by specific shRNA noticeably reduced the capabilities of proliferation,invasion and migration of SGC-7901 cells.Moreover,in the experiments of investigating the underlying mechanism,results showed that OPN knockdown could down-regulated the expression of MMP-2 and VEGF,it also decreased the phosphorylation of AKT.Meanwhile,the protein expression levels of MMP-2,VEGF and phosphorylated AKT was noticeable lower than that in control group in the GC cells after they were added to phosphatidylinositol-3-kinase(PI3K)inhibitor(LY294002).CONCLUSION These results suggested that OPN though PI3K/AKT/mammalian target of rapamycin signal pathway to upregulate MMP-2 and VEGF expression,which contribute SGC-7901 cells to proliferation,invasion and migration.Thus,our results demonstrate that OPN may serve as a novel prognostic biomarkers as well as a potential therapeutic targets for GC.
文摘Neurodegeneration is characterized by the progressive and permanent loss of neurons.Degeneration typically results in a debilitating loss of function in an otherwise healthy person.Neurodegenerative diseases have enormous direct health care costs,with some estimates for diseases.
基金Supported by Hubei Provincial Natural Science Foundation,No.2025AFB845Graduate Innovation and Entrepreneurship Fund of Wuhan University of Science and Technology,No.JCX2024044.
文摘This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.
基金Supported by National Nature Science Foundation,No.81270035International Cooperation Grant,No.11410708100
文摘The mechanistic target of rapamycin(mTOR)integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth,proliferation and survival.A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division.Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate.Multiple genetic alterations are involved in colorectal carcinogenesis,including oncogenic Ras activation,phosphatidylinositol 3-kinase pathway hyperactivation,p 53 mutation,and dysregulation of wnt pathway.Many oncogenic pathways activate the mTOR pathway.mTOR has emerged as an effective target for colorectal cancer therapy.In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives.However,the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest,especially in advanced metastatic colorectal cancer.Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy,inhibitors of vascular endothelial growth factor,epidermal growth factor receptor and Mitogen-activated protein kinase kinase(MEK)inhibitors are being intensively studied and appear to be promising.Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens.In this paper,oncogenic gene alterations in colorectal cancer,as well as their interaction with the mTOR pathway,are systematically summarized.The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed.New players in mTOR signaling pathway,such as nonsteroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.
文摘Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.
基金Supported by the National Natural Science Foundation of China(31872377)。
文摘The study was conducted to investigate the effect and mechanism of dietary quercetin supplementation on protein utilization of Arbor Acres(AA)broilers.A total of 2401-day-old AA broilers were randomly allocated to four treatments with six replicates,comprising 10 broilers each replicate(60 broilers per treatment).Birds were fed either a corn-soybean meal basal diet without quercetin(control)or a basal diet supplemented with 0.2,0.4 or 0.6 g of quercetin per kg feed,and the trial lasted 42 days.Dietary quercetin supplementation tended to increase the apparent metabolic rate of protein(p=0.076)and the content of serum albumin(p=0.062)in AA broilers.Compared with the control,dietary quercetin supplementation increased the contents of protein in breast muscle(p<0.05)and in thigh muscle(p=0.053).In addition,quercetin up-regulated mRNA expression of insulin-like growth factor 1(IGF-1),phosphatidylinositol 3-kinase(PI3K),target of rapamycin(TOR),ribosomal protein S6 kinase 1(S6K1),eukaryotic translation initiation factor 4E(eIF4E),eukaryotic translation initiation factor 4G(eIF4G),eukaryotic elongation factor 2(eEF2)and eukaryotic translation initiation factor 4B(eIF4B)genes and down-regulated mRNA expression of eukaryotic elongation factor 2 kinase(eEF2K)and eukaryotic initiation factor 4E binding protein1(4E-BP1)genes in breast muscle,thigh muscle and liver of AA broilers(p<0.05).The present results suggested that dietary quercetin supplementation enhanced protein utilization in broilers by activating TOR signaling pathway.
文摘We study the problem of detecting a target that moves between a hiding area and an operating area over multiple fixed routes. The research is carried out with one or more cookie-cutter sensors with stochastic intermission, which turn on and off stochastically governed by an on-rate and an off-rate. A cookie-cutter sensor, when it is on, can detect the target instantly once the target comes within the detection radius of the sensor. In the hiding area, the target is shielded from being detected. The residence times of the target, respectively, in the hiding area and in the operating area, are exponentially distributed and are governed by rates of transitions between the two areas. On each travel between the two areas and in each travel direction, the target selects a route randomly according to a probability distribution. Previously, we analyzed the simple case where the sensors have no intermission (i.e., they stay on all the time). In the current study, the sensors are stochastically intermittent and are synchronized (i.e., they turn on or off simultaneously). This happens when all sensors are affected by the same environmental factors. We derive asymptotic expansions for the mean time to detection when the on-rate and off-rate of the sensors are large in comparison with the rates of the target traveling between the two areas. Based on the mean time to detection, we evaluate the performance of placing the sensor(s) to monitor various travel route(s) or to scan the operating area.
基金Supported by National Natural Science Foundation of China,No.82200270and the Vascular Disease Discipline Cluster,No.SKQJS202402.
文摘BACKGROUND Ischemic heart disease ranks among the foremost contributors to mortality worldwide.Myocardial infarction injury poses a prevalent challenge in current therapies.Studies have shown that mesenchymal stem cell transplantation increases cytokine release,reduces myocardial cell necrosis,and improves left ventricular function;thus,it can be used to understand protective mechanisms.Fat extract(FE)derived from mesenchymal stem cell therapy contains high levels of paracrine factors.AIM To study the effects of FE on myocardial injury and its mechanism of action.METHODS A mouse model of myocardial infarction and a hypoxic model of neonatal rat cardiomyocytes(CMs)were established to evaluate the effects of FE.RESULTS FE exhibited an inhibitory effect on CM apoptosis and improved left ventricular function.This protective effect of FE on CMs was mediated,in part,by the activation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway.CONCLUSION Our findings showed that FE could be a new treatment to protect CMs in ischemic heart disease.
文摘Myosin heavy chain 9(MYH9),a non-muscle myosin heavy chain protein,has been identified as a significant factor in gastrointestinal(GI)oncology,with its overexpression in various GI malignancies such as esophageal,gastric,and co-lorectal cancers being associated with poor prognosis and playing a role in tumor invasion and metastasis.This comprehensive review synthesizes the current body of knowledge regarding MYH9’s role in GI tumors,focusing on its molecular mechanisms,including its interaction with key signaling pathways like the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin axis,which suggests a role in cancer cell survival,proliferation,and epithelial-mesenchymal transition.The review also explores MYH9’s potential as a therapeutic target,with preclinical models demonstrating promising results in inhibiting tumor growth and enhancing chemosensitivity.The evidence suggests that MYH9 is a multifaceted protein with significant implications in GI tumor biology,warranting further research to elucidate its mechanisms of action and develop targeted therapies that could improve patient outcomes.
基金supported by the National Natural Science Foundation of China(82271518,81971158,and 81671306)the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University(JCRCFZ-2022-030)the Guiding Projects of Traditional Chinese Medicine in 2023–2024 by Hubei Provincial Administration of Traditional Chinese Medicine(ZY2023F038).
文摘Liver cancer,particularly hepatocellular carcinoma,remains a formidable challenge in medical research and requires a deeper understanding of its molecular underpinnings.In a fascinating recent study published in Military Medical Research,Xiong et al.[1]revealed the complex roles of F-box and leucine-rich repeat 6(FBXL6)and Kirsten rat sarcoma(KRAS)^(G12D) in the pathogenesis of liver cancer.This research offers critical insights into how these proteins contribute to hepatocellular carcinoma development and progression,potentially paving the way for targeted therapeutic strategies.This commentary analyzes the key findings from this study and their broader implications in oncology.
文摘BACKGROUND： Liver regeneration is a complex process. micro RNAs（mi RNAs） are short, single-stranded RNAs that modify gene expression at the post-transcriptional level. Recent investigations have revealed that mi RNAs are closely linked to liver regeneration.DATA SOURCES： All included studies were obtained from Pub Med, Embase, the Science Direct databases and Web of Science, with no limitation on publication year. Only studies published in English were considered.RESULTS： We grouped studies that involved mi RNA and liver regeneration into two groups： mi RNAs as promoters and as inhibitors of liver regeneration. We summarized the relevant mi RNAs separately from the related pathways.CONCLUSIONS： Blocking or stimulating the pathways of mi RNAs in liver regeneration may be novel therapeutic strategies in future regeneration-related liver managements. We may discover additional chemotherapy targets of mi RNA.
基金This study was supported by a grant from the National Natural Science Foundation of China （No. 81172550）
文摘Osteosarcoma is the most common primary malignant ＇bone sarcoma, and occurs predominantly in childrenand young adults. The overall survival of patients with osteosarcoma remains low at approximately 60%.1 The prognosis of osteosarcoma patients is highly associated with response to chemotherapy. Although multiple chemotherapy regimens have improved the outcome of patients with osteosarcoma, resistance to current regimens has been reported in more than 30% of patients,2 highlighting the need for novel, targeted therapies.
文摘BACKGROUND Mesenchymal stem cells(MSCs)are a type of stem cells that possess relevant regenerative abilities and can be used to treat many chronic diseases.Diabetes mellitus(DM)is a frequently diagnosed chronic disease characterized by hyperglycemia which initiates many multisystem complications in the long-run.DM patients can benefit from MSCs transplantation to curb down the pathological consequences associated with hyperglycemia persistence and restore the function of damaged tissues.MSCs therapeutic outcomes are found to last for short period of time and ultimately these regenerative cells are eradicated and died in DM disease model.AIM To investigate the impact of high glucose or hyperglycemia on the cellular and molecular characteristics of MSCs.METHODS Human adipose tissue-derived MSCs(hAD-MSCs)were seeded in low(5.6 mmol/L of glucose)and high glucose(25 mmol/L of glucose)for 7 d.Cytotoxicity,viability,mitochondrial dynamics,and apoptosis were deplored using specific kits.Western blotting was performed to measure the protein expression of phosphatidylinositol 3-kinase(PI3K),TSC1,and mammalian target of rapamycin(mTOR)in these cells.RESULTS hAD-MSCs cultured in high glucose for 7 d demonstrated marked decrease in their viability,as shown by a significant increase in lactate dehydrogenase(P<0.01)and a significant decrease in Trypan blue(P<0.05)in these cells compared to low glucose control.Mitochondrial membrane potential,indicated by tetramethylrhodamine ethyl ester(TMRE)fluorescence intensity,and nicotinamide adenine dinucleotide(NAD+)/NADH ratio were significantly dropped(P<0.05 for TMRE and P<0.01 for NAD+/NADH)in high glucose exposed hAD-MSCs,indicating disturbed mitochondrial function.PI3K protein expression significantly decreased in high glucose culture MSCs(P<0.05 compared to low glucose)and it was coupled with significant upregulation in TSC1(P<0.05)and downregulation in mTOR protein expression(P<0.05).Mitochondrial complexes I,IV,and V were downregulated profoundly in high glucose(P<0.05 compared to low glucose).Apoptosis was induced as a result of mitochondrial impairment and explained the poor survival of MSCs in high glucose.CONCLUSION High glucose impaired the mitochondrial dynamics and regulatory proteins in hAD-MSCs ensuing their poor survival and high apoptosis rate in hyperglycemic microenvironment.
文摘This review revises the reclassification of the mem-branoproliferative glomerulonephritis （MPGN） after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and patho-genesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized： The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecifc treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in fnding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.
文摘Background:TopoisomeraseⅡalpha(TOP2A)has been reported to play a crucial role in the tumorigenesis of various cancer types.However,the biological role of TOP2A in gallbladder cancer(GBC)remains unknown.The current study aimed to explore the function and potential mechanism of TOP2A in GBC.Methods:Based on Gene Expression Profiling Interactive Analysis data,we found TOP2A was significantly up-regulated in GBC tissues and resulting in shorter overall survival.Quantitative real-time polymerase chain reaction and immunohistochemistry were conducted to detect the expression of TOP2A in 45 pairs of GBC tissues and adjacent non-tumor tissues.In vitro,cell proliferation,migration,and invasion ability were examined by cell counting kit-8 and transwell assay,respectively.Epithelial-mesenchymal transition(EMT)related and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR)pathway-related markers were measured by Western blotting.Xenograft model assay was performed to evaluate the effect of TOP2A in vivo.Results:TOP2A was found up-regulated in GBC(tumor vs.normal,12.62 vs.0.34)and correlated with the late tumor node metastasis stage(P=0.0032),present of lymph node metastasis(P=0.0273),and poor prognosis in GBC patients(log-rank P=0.028).In vitro and in vivo assays showed that knockdown of TOP2A notably inhibited cell proliferation,migration,invasion,EMT process,and tumor growth in GBC.In addition,TOP2A down-regulation significantly decreased the protein levels of phosphor(p)-PI3K,p-Akt,and p-mTOR.Conclusion:Our study demonstrates that TOP2A was overexpressed in GBC and associated with poor prognosis in GBC patients.TOP2A promotes GBC cell proliferation,migration,invasion,EMT process,and tumor growth through activating PI3K/Akt/mTOR signaling pathway,and may serve as a novel prognostic biomarker and therapeutic target for GBC.
