Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 41
Filter
Add more filters

Country/Region as subject
Publication year range
1.
Acta Pharmacol Sin ; 45(2): 366-377, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37770579

ABSTRACT

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , Humans , Mice , Animals , Sirtuin 1/metabolism , Diabetic Nephropathies/pathology , Acetyl Coenzyme A/metabolism , Acetyl Coenzyme A/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Molecular Docking Simulation , Kidney/pathology , Transcription Factors/metabolism , Lipid Metabolism , Glucose/metabolism , Fatty Acids/metabolism , Inflammation/metabolism , Ligases/metabolism , Lipids
2.
Ann Noninvasive Electrocardiol ; 28(1): e12988, 2023 01.
Article in English | MEDLINE | ID: mdl-35809079

ABSTRACT

Even though patients with pulmonary embolism usually present with respiratory distress and tachycardia, the patient presented with syncope only. Typical ECG changes associated with PE include right axis deviation, right bundle-branch block, S1Q3T3 pattern, arrhythmia, nonspecific ST-segment changes, QR pattern in lead V1, Brugada ECG pattern, and T-wave inversions in the precordial leads. However, his electrocardiogram showed QT-interval prolongation and simultaneous T-wave inversions in the inferior and anterior leads. This ECG pattern is crucial for diagnosing PE. The patient underwent computed tomography-pulmonary angiography, which revealed pulmonary embolism. At the same time, these ECG changes should be differentiated from those of long QT syndrome, myocardial ischemia, Takotsubo cardiomyopathy, post-pacing T-wave memory, hypertrophic cardiomyopathy, and subarachnoid hemorrhage.


Subject(s)
Long QT Syndrome , Pulmonary Embolism , Humans , Electrocardiography , Arrhythmias, Cardiac/complications , Syncope/etiology , Syncope/complications , Pulmonary Embolism/diagnosis
3.
Acta Neuropsychiatr ; : 1-13, 2023 Aug 18.
Article in English | MEDLINE | ID: mdl-37592805

ABSTRACT

OBJECTIVE: We previously reported that dual injections of lipopolysaccharide (LPS) in mice constitute a valuable tool for investigating the contribution of inflammation to psychotic disorders. The present study investigated how immune activation affects the kynurenine pathway and rat behaviour of relevance for psychotic disorders. METHODS: Male Sprague Dawley rats were treated with either dual injections of LPS (0.5 mg/kg + 0.5 mg/kg, i.p.) or dual injections of saline. Twenty-four hours after the second injection, behavioural tests were carried out, including locomotor activity test, fear conditioning test, spontaneous alternation Y-maze test, and novel object recognition test. In a separate batch of animals, in vivo striatal microdialysis was performed, and tryptophan, kynurenine, quinolinic acid, and kynurenic acid (KYNA) in the dialysate were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Dual-LPS treatment decreased spontaneous locomotion, exaggerated d-amphetamine-induced locomotor activity, and impaired recognition memory in male Sprague-Dawley rats. In vivo microdialysis showed that dual-LPS treatment elicited metabolic disturbances in the kynurenine pathway with increased extracellular levels of kynurenine and KYNA in the striatum. CONCLUSION: The present study further supports the feasibility of using the dual-LPS model to investigate inflammation-related psychotic disorders and cognitive impairments.

4.
Phytother Res ; 36(3): 1103-1114, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35023220

ABSTRACT

Epidemiological studies indicate that higher intakes of flavonoids are associated with reduced stroke risk, however, which subtypes play significant roles to protect against stroke remain unclear. A systematic literature search in PubMed and Web of Science databases was performed up to Oct. 2021. Flavonoids or their subtypes (flavanol, flavanone, flavone, flavan-3-ol, isoflavone, or anthocyanin) were paired with stoke as the search term. Multivariate-adjusted relative risks (RRs) with 95% confidence intervals (CIs) for the highest versus the lowest category were pooled by using a random-effects model. Dose-response analysis was implemented by using a restricted cubic spline regression model. Ten independent prospective cohort studies with 387,076 participants and 9,564 events were included. Higher intakes of flavanones were inversely associated with stroke risk (RR = 0.85; 95%CI: 0.78, 0.93). Dose-response analysis showed that 50 mg/day increment of flavanones was associated with 11% reduction in stroke risk (RR = 0.89; 95%CI: 0.84, 0.94). Flavan-3-ols was marginally inversely associated with stroke risk (RR = 0.92; 95%CI: 0.82, 1.02). Dose-response analysis showed that 200 mg/day increment of flavan-3-ols was associated with 14% reduction in stroke risk (RR = 0.86; 95%CI: 0.75, 0.98). The non-significant association was observed with respect to other flavonoid subclasses. This study demonstrated higher intakes of flavanones and flavan-3-ols were associated with a lower risk of stroke. Dietary intakes of lemon and citrus rich in flavanones and flavan-3-ols might have beneficial functions for the protection against stroke. The findings of these associations of the present study need to be confirmed in other regions and ethnic origins.


Subject(s)
Diet , Stroke , Flavonoids , Humans , Prospective Studies , Risk Factors , Stroke/epidemiology , Stroke/prevention & control
5.
Yi Chuan ; 44(12): 1117-1127, 2022 Dec 20.
Article in English | MEDLINE | ID: mdl-36927557

ABSTRACT

Anthocyanins are a class of important flavonoid compounds widely present in plants, and play important roles in plant growth, metabolism and stress responses. In the process of growth and development, anthocyanin renders the flowers and fruits of plants displaying rich colors, attracts insect pollination and animal feeding, thereby facilitating seed spreading and dissemination. In metabolic stress, anthocyanin can resist low temperature, drought, fungal infection, ultraviolet damage, insect pests and other stress-resistant processes. The anthocyanin biosynthesis is co-regulated by related structural genes as well as transcription factor genes. Recent studies have showed that the anthocyanin biosynthesis-related genes in plants are epigenetically regulated, thus affecting the synthesis of anthocyanin glycosides. Epigenetics is one of the hot topics in the field of biological sciences. In this review, we summarize the advances of epigenetic modifications in anthocyanin biosynthesis and the application of genome editing in epigenetics, thereby providing new ideas for flower color breeding improvement by epigenetic regulation.


Subject(s)
Anthocyanins , Epigenesis, Genetic , Anthocyanins/genetics , Anthocyanins/metabolism , Plant Breeding , Plants/metabolism
6.
BMC Cancer ; 21(1): 651, 2021 Jun 01.
Article in English | MEDLINE | ID: mdl-34074258

ABSTRACT

OBJECTIVE: Plasma Epstein-Barr virus (EBV) DNA is considered a biomarker for nasopharyngeal carcinoma (NPC). However, its long-term role in NPC development is unclear. MATERIALS AND METHODS: A total of 1363 participants seropositive for EBV VCA-IgA and EBNA1-IgA in a community-based NPC screening program in southern China were tested for plasma EBV DNA levels by real-time qPCR between 2008 and 2015. New NPC cases were confirmed by active follow-up approach and linkage to local cancer registry through the end of 2016. Cox proportional hazards regression analysis was performed to calculate the hazard ratios (HRs) for NPC risk with plasma EBV DNA. RESULTS: Thirty patients were newly diagnosed during a median 7.5 years follow-up. NPC incidence increased with the plasma EBV DNA load ranging from 281.46 to 10,074.47 per 100,000 person-years in participants with undetectable and ≥ 1000 copies/ml levels; the corresponding cumulative incidence rates were 1.73 and 50%. Furthermore, plasma EBV DNA loads conferred an independent risk for NPC development after adjustment for other risk factors, with HRs of 7.63 for > 3-999 copies/ml and 39.79 for ≥1000 copies/ml. However, the HRs decreased gradually after excluding NPC cases detected in the first 2 to 3 years and became statistically nonsignificant by excluding cases detected during the first 4 years. CONCLUSION: Elevated plasma EBV DNA can predict NPC risk over 3 years. Monitoring plasma EBV DNA can be used as a complementary approach to EBV serological antibody-based screening for NPC.


Subject(s)
Biomarkers, Tumor/blood , DNA, Viral/blood , Epstein-Barr Virus Infections/epidemiology , Nasopharyngeal Carcinoma/epidemiology , Nasopharyngeal Neoplasms/epidemiology , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antigens, Viral/immunology , Capsid Proteins/immunology , Epstein-Barr Virus Infections/blood , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/virology , Female , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/immunology , Herpesvirus 4, Human/isolation & purification , Humans , Male , Middle Aged , Nasopharyngeal Carcinoma/blood , Nasopharyngeal Carcinoma/diagnosis , Nasopharyngeal Carcinoma/virology , Nasopharyngeal Neoplasms/blood , Nasopharyngeal Neoplasms/diagnosis , Nasopharyngeal Neoplasms/virology , Prospective Studies , Real-Time Polymerase Chain Reaction , Risk Factors , Serologic Tests/statistics & numerical data
7.
Acta Pharmacol Sin ; 41(8): 1111-1118, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32203081

ABSTRACT

Some studies have shown that gut microbiota along with its metabolites is closely associated with diabetic mellitus (DM). In this study we explored the relationship between gut microbiota and kidney injuries of early diabetic nephropathy (DN) and its underlying mechanisms. Male SD rats were intraperitoneally injected with streptozotocin to induce DM. DM rats were orally administered compound broad-spectrum antibiotics for 8 weeks. After the rats were sacrificed, their blood, urine, feces, and renal tissues were harvested for analyses. We found that compared with the control rats, DM rats had abnormal intestinal microflora, increased plasma acetate levels, increased proteinuria, thickened glomerular basement membrane, and podocyte foot process effacement in the kidneys. Furthermore, the protein levels of angiotensin II, angiotensin-converting enzyme, and angiotensin II type 1 receptor in the kidneys of DM rats were significantly increased. Administration of broad-spectrum antibiotics in DM rats not only completely killed most intestinal microflora, but also significantly lowered the plasma acetate levels, inhibited intrarenal RAS activation, and attenuated kidney damage. Finally, we showed that plasma acetate levels were positively correlated with intrarenal angiotensin II protein expression (r = 0.969, P < 0.001). In conclusion, excessive acetate produced by disturbed gut microbiota might be involved in the kidney injuries of early DN through activating intrarenal RAS.


Subject(s)
Acetates/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/physiopathology , Dysbiosis/physiopathology , Gastrointestinal Microbiome/physiology , Renin-Angiotensin System/physiology , Acetates/blood , Animals , Anti-Bacterial Agents/pharmacology , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/pathology , Gastrointestinal Microbiome/drug effects , Kidney/pathology , Male , Rats, Sprague-Dawley
8.
BMC Cardiovasc Disord ; 19(1): 89, 2019 04 08.
Article in English | MEDLINE | ID: mdl-30961533

ABSTRACT

BACKGROUND: Coronary bifurcation remains one of the most challenging lesion subsets in interventinal cardiology. Provisional stenting (PS) is the dominate technique for bifurcation lesions, but the key problem is the deterioration of side branch. Balloon-stent kissing technique (BSKT) as a new systematic approach which is based on modified jailed balloon technique is applied to improve the procedure success. In our center, we proposed a modified balloon-stent kissing technique(M-BSKT), which routine usage of proximal optimizing technique (POT) after rewiring was added as an optimization step to BSKT. Thus, whether M-BSKT for addressing simple true coronary bifurcation lesions can provide more benefits in intra-operation effect and long term outcomes is still unknown. METHODS: A cohort of 120 consecutive patients underwent Percutaneous Coronary Intervention (PCI) with simple true coronary bifurcation lesions satisfied the criteria were included in this retrospective, single-center registry. To assemble a cohort with similar baseline characteristics, a 1:1 propensity-matched score was used. The primary outcomes were the rate of device and procedural success, the situation of side branch (SB) after main vessel (MV) inflation and the complications during intra-operative. The secondary outcomes were the clinical prognosis at 12 months such as rehospitalization for unstable angina and MACEs. RESULTS: Before propensity matching, there were no significant differences in primary and secondary outcomes between two groups. After propensity-matched was used, 68 patients with similar propensity scores were included. At immediate procedural, M-BSKT was associated with a lower risk of SB deterioration and the application of final kissing balloon inflation (FKBI)[P = 0.036]. For ACS patients, besides the significant differences of immediate SB deterioration [P = 0.014] and FKBI application [P = 0.033], the incidence of TIMI flow< 3 in the PS was statistically significant higher than M-BSKT [P= 0.042]. The prognosis at 12 months such as rehospitalization for unstable angina and MACEs were similar for two groups [P = 0.613]. CONCLUSION: These observations prove that the M-BSKT enables side branch to be better protected in simple true bifurcation lesions, by a narrow margin. It may improve the angiographic outcomes about side branch deterioration and final kissing balloon performing compared with PS, especially in ACS patients. However, long-term clinical outcomes did not differ between patients treated for M-BSKT and PS at 12 months.


Subject(s)
Angioplasty, Balloon, Coronary/methods , Coronary Artery Disease/therapy , Adolescent , Adult , Aged , Angina, Unstable/etiology , Angioplasty, Balloon, Coronary/adverse effects , Angioplasty, Balloon, Coronary/instrumentation , Coronary Artery Disease/complications , Coronary Artery Disease/diagnostic imaging , Disease Progression , Female , Humans , Male , Middle Aged , Patient Readmission , Registries , Retrospective Studies , Risk Factors , Stents , Time Factors , Treatment Outcome , Young Adult
9.
BMC Nephrol ; 20(1): 303, 2019 08 05.
Article in English | MEDLINE | ID: mdl-31382919

ABSTRACT

BACKGROUND: New non-invasive biomarkers are demanded to identify renal damage in various autoimmune-associated kidney diseases. Glomerular podocyte damage mediated by systemic lupus erythematosus (SLE) plays an important role in the pathogenesis and progression of lupus nephritis (LN). This study evaluated whether the podocyte-derived microparticles (MPs) were novel biomarkers of clinical and histological features in SLE patients with LN. METHODS: A cross-sectional study, including 34 SLE patients and 16 healthy controls, was designed. Urinary annexin V+ podocalyxin+ MPs of all participants were quantified by flow cytometry. The correlation of podocyte-derived MPs with clinical and histological parameters of SLE patients was analysed. RESULTS: The number of annexin V+ podocalyxin+ MPs from urine samples were markly increased in patients with SLE. Furthermore, the level of urinary podocyte-derived MPs was positively correlated with the SLE Disease Activity Index (SLEDAI) score, anti-dsDNA antibody titre, erythrocyte sedimentation rate, and proteinuria. Conversely, it was negatively correlated with the level of complement C3 and serum albumin. The number of urinary podocyte-derived MPs was significantly increased in SLE patients with high activity indices. Receiver operating characteristic (ROC) curves were calculated to assess the power for podocyte-derived MP levels in differentiating between SLE patients with and without LN. Podocyte-derived MP levels were able to differentiate between SLE patients with mild disease activity, as well as those with moderate and above disease activity. SLE patients showed increased podocyte-derived MP excretion into the urine. CONCLUSIONS: These findings suggest that the change in urinary podocyte-derived MP levels could be useful for evaluating and monitoring SLE disease activity.


Subject(s)
Cell-Derived Microparticles , Lupus Erythematosus, Systemic/urine , Podocytes , Annexin A5 , Case-Control Studies , Cell-Derived Microparticles/pathology , Chi-Square Distribution , Cross-Sectional Studies , Female , Flow Cytometry , Humans , Lupus Erythematosus, Systemic/pathology , Lupus Nephritis/pathology , Lupus Nephritis/urine , Male , Middle Aged , Podocytes/chemistry , Podocytes/pathology , Podocytes/ultrastructure , ROC Curve , Sialoglycoproteins , Statistics, Nonparametric
10.
Cell Physiol Biochem ; 47(3): 1051-1059, 2018.
Article in English | MEDLINE | ID: mdl-29843130

ABSTRACT

BACKGROUND/AIMS: The epithelial sodium channel (ENaC) in cortical collecting duct (CCD) principal cells plays a critical role in regulating systemic blood pressure. We have previously shown that cholesterol (Cho) in the apical cell membrane regulates ENaC; however, the underlying mechanism remains unclear. METHODS: Patch-clamp technique and confocal microscopy were used to evaluate ENaC activity and density. RESULTS: Here we show that extraction of membrane Cho with methyl-ß-cyclodextrin (MßCD) significantly reduced amiloride-sensitive current and ENaC single-channel activity. The effects were reproduced by inhibition of Cho synthesis in the cells with lovastatin. We have previously shown that phosphatidylinositol-4,5-bisphosphate (PIP2), an ENaC activator, is predominantly located in the microvilli, a specialized apical membrane domain. Here, our confocal microscopy data show that α-ENaC was co-localized with PIP2 in the microvilli and that Cho was also co-localized with PIP2 in the microvilli. Either extraction of Cho with MßCD or inhibition of Cho synthesis with lovastatin consistently reduced the levels of Cho, PIP2, and ENaC in the microvilli. CONCLUSIONS: Since PIP2 can directly stimulate ENaC and also affect ENaC trafficking, these data suggest that depletion of Cho reduces ENaC apical density and activity at least in part by decreasing PIP2 in the microvilli.


Subject(s)
Cholesterol/metabolism , Epithelial Sodium Channels/metabolism , Kidney Tubules, Collecting/metabolism , Microvilli/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Animals , Xenopus Proteins , Xenopus laevis , beta-Cyclodextrins/pharmacology
11.
Pharmacogenet Genomics ; 26(11): 497-504, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27602548

ABSTRACT

OBJECTIVE: The aim of this study was to refine the chromosomal region 12q24.1 associated with coronary artery disease in Han Chinese populations. METHODS AND RESULTS: Twenty tagging single nucleotide polymorphisms covering 1.2 Mb of chromosomal 12q24.1 were selected and genotyped in three geographically isolated case-control populations consisting of 7076 coronary artery disease (CAD) patients and non-CAD participants. In addition to replication of the previous block (block 1), we identified a novel block (block 2) associated with CAD. In a combined analysis, the odds ratio (95% confidence interval, permuted P value) were 0.79 (0.72-0.86, 8.358×10) and 1.24 (1.13-1.36, 2.576×10) for haplotypes ATGGG and GCACA in block 1 and 1.22 (1.14-1.30, 6.484×10) and 0.82 (0.77-0.88, 6.484×10) for haplotypes GA and AG in block 2, respectively. Protective alleles of two index single nucleotide polymorphisms decreased the expression of NAA25 (P=0.034), but did not alter the expression of other genes within block 2. CONCLUSION: We identified a novel block associated with CAD at chromosomal 12q24.


Subject(s)
Asian People/ethnology , Chromosomes, Human, Pair 12/genetics , Coronary Artery Disease/genetics , Polymorphism, Single Nucleotide , Asian People/genetics , Case-Control Studies , China/ethnology , Female , Genetic Predisposition to Disease , Human Umbilical Vein Endothelial Cells , Humans , Male , Middle Aged , Odds Ratio
12.
Biochim Biophys Acta ; 1833(6): 1434-42, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23499875

ABSTRACT

Podocyte number is significantly reduced in diabetic patients and animal models, but the mechanism remains unclear. In the present study, we found that high glucose induced apoptosis in control podocytes which express transient receptor potential canonical 6 (TRPC6) channels, but not in TRPC6 knockdown podocytes in which TRPC6 was knocked down by TRPC6 silencing short hairpin RNA (shRNA). This effect was reproduced by treatment of podocytes with the reactive oxygen species (ROS), hydrogen peroxide (H2O2). Single-channel data from cell-attached, patch-clamp experiments showed that both high glucose and H2O2 activated the TRPC6 channel in control podocytes, but not in TRPC6 knockdown podocytes. Confocal microscopy showed that high glucose elevated ROS in podocytes and that H2O2 reduced the membrane potential of podocytes and elevated intracellular Ca(2+) via activation of TRPC6. Since intracellular Ca(2+) overload induces apoptosis, H2O2-induced apoptosis may result from TRPC6-mediated elevation of intracellular Ca(2+). These data together suggest that high glucose induces apoptosis in podocytes by stimulating TRPC6 via elevation of ROS.


Subject(s)
Apoptosis/drug effects , Calcium/metabolism , Glucose/pharmacology , Podocytes/pathology , Reactive Oxygen Species/metabolism , Sweetening Agents/pharmacology , TRPC Cation Channels/metabolism , Blotting, Western , Cells, Cultured , Humans , Hydrogen Peroxide/pharmacology , Membrane Potentials/drug effects , Oxidants/pharmacology , Patch-Clamp Techniques , Podocytes/drug effects , Podocytes/metabolism , TRPC6 Cation Channel
13.
Mol Biol Rep ; 41(8): 4997-5003, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24748432

ABSTRACT

Myocardial infarction (MI) is a serious heart disease. The cardiac cells of patients with MI will die due to lack of blood for a long time. In this study, we aimed to find new targets for MI diagnosis and therapy. We downloaded GSE22229 including 12 blood samples from healthy persons and GSE29111 from Gene Expression Omnibus including 36 blood samples from MI patients. Then we identified differentially expressed genes (DEGs) in patients with MI compared to normal controls with p value < 0.05 and |logFC| > 1. Furthermore, interaction network and sub-network of these of these DEGs were constructed by NetBox. Linker genes were screened in the Global Network database. The degree of linker genes were calculated by igraph package in R language. Gene ontology and kyoto encyclopedia of genes and genomes pathway analysis were performed for DEGs and network modules. A total of 246 DEGs were identified in MI, which were enriched in the immune response. In the interaction network, LCK, CD247, CD3D, FYN, HLA-DRA, IL2, CD8A CD3E, CD4, CD3G had high degree, among which CD3E, CD4, CD3G were DEGs while others were linker genes screened from Global Network database. Genes in the sub-network were also enriched in the immune response pathway. The genes with high degree may be biomarkers for MI diagnosis and therapy.


Subject(s)
Biomarkers/metabolism , Gene Expression Regulation/genetics , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Cluster Analysis , Computational Biology , Gene Expression Profiling , Gene Expression Regulation/immunology , Gene Ontology , Humans , Microarray Analysis , Myocardial Infarction/immunology , Protein Interaction Mapping
14.
Am J Physiol Renal Physiol ; 305(3): F304-13, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23720343

ABSTRACT

We used mouse cortical collecting duct principal cells (mpkCCDc14 cell line) as a model to determine whether statins reduce the harmful effects of cyclosporine A (CsA) on the distal nephron. The data showed that treatment of cells with CsA increased transepithelial resistance and that the effect of CsA was abolished by lovastatin. Scanning ion conductance microscopy showed that CsA significantly increased the height of cellular protrusions near tight junctions. In contrast, lovastatin eliminated the protrusions and even caused a modest depression between cells. Western blot analysis and confocal microscopy showed that lovastatin also abolished CsA-induced elevation of both zonula occludens-1 and cholesterol in tight junctions. In contrast, a high concentration of CsA induced apoptosis, which was also attenuated by lovastatin, elevated intracellular ROS via activation of NADPH oxidase, and increased the expression of p47phox. Sustained treatment of cells with lovastatin also induced significant apoptosis, which was attenuated by CsA, but did not elevate intracellular ROS. These results indicate that both CsA and lovastatin are harmful to principal cells of the distal tubule, but via ROS-dependent and ROS-independent apoptotic pathways, respectively, and that they counteract probably via mobilization of cellular cholesterol levels.


Subject(s)
Apoptosis/drug effects , Cyclosporine/antagonists & inhibitors , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Immunosuppressive Agents/antagonists & inhibitors , Kidney Tubules, Collecting/cytology , Kidney Tubules, Collecting/drug effects , Lovastatin/pharmacology , Tight Junctions/drug effects , Analysis of Variance , Animals , Blotting, Western , Cells, Cultured , Cholesterol/biosynthesis , Coloring Agents , Cyclosporine/pharmacology , Epithelial Cells/drug effects , Epithelial Cells/ultrastructure , Immunosuppressive Agents/pharmacology , Kidney Tubules, Collecting/ultrastructure , Mice , Microscopy, Confocal , Microscopy, Electron, Scanning , NADPH Oxidases/metabolism , Permeability , Reactive Oxygen Species/metabolism , Tight Junctions/metabolism , Tight Junctions/ultrastructure , Zonula Occludens-1 Protein/biosynthesis
15.
JCI Insight ; 8(20)2023 Oct 23.
Article in English | MEDLINE | ID: mdl-37870960

ABSTRACT

Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes' autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.


Subject(s)
Acetate-CoA Ligase , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Animals , Humans , Mice , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/metabolism , Disease Models, Animal , Kidney/metabolism , Ligases , Mammals , Mechanistic Target of Rapamycin Complex 1 , Acetate-CoA Ligase/metabolism
16.
Theranostics ; 13(12): 3988-4003, 2023.
Article in English | MEDLINE | ID: mdl-37554279

ABSTRACT

Rationale: Chronic tubulointerstitial inflammation is a common pathological process in diabetic kidney disease (DKD). However, its underlying mechanism is largely unknown. This study aims at investigating the role of gut microbiota-derived outer membrane vesicles (OMVs) in tubulointerstitial inflammation in DKD. Methods: Gut microbiota in diabetes mellitus rats was manipulated by microbiota depletion and fecal microbiota transplantation to explore its role in tubulointerstitial inflammation. To check the direct effects of OMVs, fecal bacterial extracellular vesicles (fBEVs) were administrated to mice orally and HK-2 cells in vitro. For mechanistic investigations, HK-2 cells were treated with small interfering RNA against caspase-4 and fBEVs pre-neutralized by polymyxin B. Results: By performing gut microbiota manipulation, it was confirmed that gut microbiota mediated tubulointerstitial inflammation in DKD. In diabetic rats, gut microbiota-derived OMVs were increased and were clearly detected in distant renal tubulointerstitium. Diabetic fBEVs directly administered by gavage translocated into tubular epithelial cells and induced tubulointerstitial inflammation and kidney injury. In vitro, OMVs were internalized through various endocytic pathways and triggered cellular inflammatory response. Mechanistically, it was revealed that OMVs-derived lipopolysaccharide induced tubular inflammation, which was mediated by the activation of the caspase-11 pathway. Conclusions: Increased OMVs due to dysbiosis translocated through leaky gut barrier into distant tubulointerstitium and induced cellular inflammation and renal tubulointerstitial injury in DKD. These findings enrich the mechanism understanding of how gut microbiota and its releasing OMVs influence the development and progression of kidney disease.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , Gastrointestinal Microbiome , Rats , Mice , Animals , Diabetic Nephropathies/pathology , Inflammation , Caspases
17.
Int Urol Nephrol ; 55(2): 355-366, 2023 Feb.
Article in English | MEDLINE | ID: mdl-35931920

ABSTRACT

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury is a critical cellular event involved in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. This study aimed to investigate whether PMPs are deposited in podocytes and to assess their potential effects on podocyte injury in DN. METHODS: The deposition of PMPs in podocytes was assessed by immunofluorescent staining and electron microscopy. The changes in renal pathology and ultra-microstructure were assessed by periodic acid-Schiff staining and electron microscopy, respectively. The expression of inflammatory cytokines and extracellular matrix proteins was measured by immuno-histochemical staining and western blot. RESULTS: PMPs were widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with DN progression. Interestingly, aspirin treatment significantly inhibited the accumulation of PMPs in the glomeruli of diabetic rats, alleviated mesangial matrix expansion and fusion of foot processes, and decreased the protein expression of inflammatory cytokines and extracellular matrix secretion. An in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMP stimulation induced the phenotypic transition of podocytes through decreased podocin protein expression and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines. CONCLUSION: Our findings demonstrated for the first time that the deposition of PMPs in podocytes contributed to the development of DN.


Subject(s)
Cell-Derived Microparticles , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Podocytes , Rats , Animals , Diabetic Nephropathies/complications , Podocytes/metabolism , Diabetes Mellitus, Experimental/metabolism , Cell-Derived Microparticles/metabolism , Cell-Derived Microparticles/pathology , Cytokines/metabolism
18.
J Comput Assist Tomogr ; 36(6): 646-53, 2012.
Article in English | MEDLINE | ID: mdl-23192200

ABSTRACT

OBJECTIVE: The objective of this study was to compare the accuracy of 320-row computed tomography angiography (CTA) with conventional coronary angiography. METHODS: Two hundred seventy-four patients with coronary artery disease who received both invasive coronary angiography and 320-row CTA were included. Stenosis of 50% or greater was considered obstructive. RESULTS: In patient-based analysis, accuracy of CTA was 89.4%, with sensitivity of 94.6% and specificity of 54.3%. In segment-based analysis, the overall (4110 segments) accuracy of CTA was 90.7%, with sensitivity of 66.5% and specificity of 95.8%. For the segments with plaques (1191 segments), accuracy of CTA was 80.1%, with sensitivity of 83.5% and specificity of 77.0%. For segments with no plaque (2919 segments), accuracy of CTA was 95.0%, with sensitivity of 0.7% and specificity of 100.0%. For the segments with stents (110 segments), the accuracy of CTA was 86.4%. CONCLUSIONS: A 320-row CTA has potential to detect coronary lesions with soft and intermediate plaques.


Subject(s)
Coronary Angiography/methods , Coronary Artery Disease/diagnostic imaging , Plaque, Atherosclerotic/diagnostic imaging , Tomography, X-Ray Computed/methods , Adult , Aged , Aged, 80 and over , Coronary Artery Disease/complications , Coronary Stenosis/complications , Coronary Stenosis/diagnostic imaging , Female , Humans , Male , Middle Aged , Observer Variation , Plaque, Atherosclerotic/complications , Reproducibility of Results , Sensitivity and Specificity , Stents
19.
Int Heart J ; 53(1): 1-4, 2012.
Article in English | MEDLINE | ID: mdl-22398668

ABSTRACT

To date, most studies conducted on cilostazol have examined its effects as an agent of maintenance-dose therapy, but its loading effects on platelet inhibition have never been reported. This study aimed to determine the loading effects of 200 mg cilostazol in addition to aspirin and clopidogrel on platelet inhibition in patients undergoing percutaneous coronary intervention.Sixty consecutive patients undergoing coronary intervention were enrolled and assigned to receive 300 mg of aspirin and clopidogrel with or without 200 mg of cilostazol. All loading doses were given at least 3 hours before percutaneous coronary intervention and followed by dual or triple maintenance-dose therapy. Platelet function tests were performed just before and at 24 hours and 30 days after percutaneous coronary intervention by light transmittance aggregometry and VerifyNow® P2Y12 assay.There were no significant differences in baseline or angiographic characteristics between the 2 groups. The results of platelet function tests revealed that the adjunctive loading dose of 200 mg of cilostazol induced more potent platelet inhibition compared to a dual regimen at each time point. Cilostazol reduced the incidence of high post-treatment platelet reactivity (HPPR).Adjunctive 200 mg cilostazol can improve platelet responsiveness to clopidogrel in the pre- and postprocedural phases, reducing the prevalence of HPPR.


Subject(s)
Endovascular Procedures , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation/drug effects , Tetrazoles/administration & dosage , Adult , Aged , Aspirin/administration & dosage , Cilostazol , Clopidogrel , Female , Humans , Male , Middle Aged , Platelet Function Tests , Ticlopidine/administration & dosage , Ticlopidine/analogs & derivatives
20.
Int J Biol Sci ; 18(1): 96-111, 2022.
Article in English | MEDLINE | ID: mdl-34975320

ABSTRACT

Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms. Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting. Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results. Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/metabolism , Early Growth Response Protein 1/metabolism , Lipid Metabolism , MAP Kinase Signaling System , Podocytes/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Disease Models, Animal , Mice , Receptors, LDL/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL