ABSTRACT
Neutrophils need to migrate through tight tissue spaces to eliminate pathogens, but their movement is often hindered by their large and stiff nuclei. Neutrophil migration is impaired in sepsis patients, but it is unclear whether this defect is related to the deformability of their nuclei. Herein, we designed microfluidic devices with micron-scale narrow slits to simulate biological barriers. This setup allowed us to observe and record neutrophil movement and nuclear deformation in real-time. We also developed a method for morphological analysis to quantify nucleus deformation in numerous individual cells. Our studies showed that neutrophils from healthy individuals could adjust their nuclear shape to squeeze through these constrictions, whereas those from sepsis patients demonstrated less flexibility. Neutrophils with rigid nuclei struggled to pass through narrow gaps and were more likely to rupture under pressure. These findings suggest that the migration defects of neutrophils observed in sepsis may be attributed to the inability of neutrophils to deform their nuclei, highlighting the crucial role of microfluidic technologies in offering new insights into migration defects under pathological conditions.
Subject(s)
Cell Movement , Lab-On-A-Chip Devices , Neutrophils , Sepsis , Humans , Neutrophils/cytology , Biosensing Techniques/instrumentation , Equipment Design , Cell NucleusABSTRACT
The inheritance of knowledge and experience was crucial to the development of Traditional Chinese Medicine (TCM). However, the existing methods of inheriting the unique clinical experience of famous veteran TCM doctors still followed the outdated and inefficient Master-Prentice schema. In addition, the inherited medical books and records were usually lack of standardization and systematization. In this article, a new method for inheriting the academic thoughts and clinical experience of famous veteran doctors with the help of artificial intelligence technology was explored. Due to the individualized treatment characteristics namely "same disease with different treatments, different diseases with the same treatment," the intelligent inheritance of TCM faced many technical barriers. To tackle these problems, we proposed a prototype system framework for the intelligent inheritance of famous veteran doctors based on rules and deep learning models and performed a case study on the treatment of pediatric asthma. The architecture could not only make full use of the advantages of deep learning, but also integrate the valuable knowledge and experience analysis of famous veteran doctors from injected rules. Specifically, the study took pediatric asthma medical records as training and test samples and calculated the similarity between the generated prescriptions and the real-world clinical prescriptions from the famous veteran doctors. Experimental results showed that the generated prescription could achieve a similarity of more than 90%. It proved that the proposed framework provided a feasible way for the intelligent inheritance and research of the academic thoughts and clinical experience of famous veteran TCM doctors.
Subject(s)
Asthma , Drugs, Chinese Herbal , Physicians , Child , Humans , Medicine, Chinese Traditional , Artificial Intelligence , Asthma/drug therapy , Drugs, Chinese Herbal/therapeutic useABSTRACT
Aims: Alanine aminotransferase (ALT) is positively related to diabetes risk in observational studies, whereas Mendelian randomization supports a linear causal association. In contrast, the relationship between ALT and diabetic nephropathy, and diabetic retinopathy is counter-intuitive in observational studies. Furthermore, no MR study has examined their causal association. The study aimed to investigate whether genetically determined ALT has a causal effect on diabetic nephropathy and diabetic retinopathy. Methods: Genetic instruments associated with ALT (P < 5×10-8) were obtained from a recent genome-wide association study (GWAS) that included 437,267 individuals of European ancestry. Summary data of diabetic microvascular complications were derived from the FinnGen study (3,283 cases and 181,704 controls for diabetic nephropathy, and 14,584 cases and 176,010 controls for diabetic retinopathy, both were of European ancestry). Effect estimation and pleiotropy testing were performed using inverse variance weighted (IVW), MR-Egger regression, weighted median, and mode-based estimator methods. We additionally performed sensitivity analysis excluding proxy single nucleotide polymorphisms (SNPs) or lowering the GWAS significance threshold (P < 5×10-7) to test the robustness of the results. Results: Based on IVW, a 2-fold increase in genetically determined ALT level was positively associated with diabetic nephropathy (odd ratio, [95% confidence interval], 1.73 [1.26-2.37], P = 0.001) and diabetic retinopathy (1.29 [1.08-1.54], P = 0.005), but a null causal association in three pleiotropy robust methods, namely, MR-Egger, weighted median and mode-based estimator. We obtained similar results in the sensitivity analysis of excluding proxy SNPs or lowering the GWAS significance threshold. Conclusions: With caution, we concluded that ALT plays no linear causal role in developing both diabetic nephropathy and diabetic retinopathy. Further investigations are required to test the hypothesis of a non-linear causal association.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Diabetic Retinopathy , Humans , Alanine Transaminase , Diabetic Nephropathies/genetics , Diabetic Retinopathy/genetics , Genome-Wide Association Study , Mendelian Randomization AnalysisABSTRACT
There is a broad consensus that information and communication technology (ICT) development contributes to economic growth, but its environmental benefits have not been thoroughly studied. This paper explores the impact and mechanisms of ICT development on manufacturing carbon emissions. We first conducted empirical tests based on panel data from 18 manufacturing sectors in 42 countries from 2000 to 2014. The results show that domestic ICT development reduces manufacturing carbon emissions, but the effect is only significant in sectors with high ICT embedded. Second, technological progress, industrial internal structure upgrading, energy consumption intensification, and low carbonization are the main channels for ICT development and embedding to reduce manufacturing carbon emissions. Third, the carbon emissions from manufacturing, which are deeply embedded by ICT, will decrease as the position of ICT forward GVCs improves, and increase as the position of backward GVCs increases. In addition, ICT development has a more significant impact on reducing carbon emissions in high-tech manufacturing. This paper has enriched research on the environmental benefits of ICT development and has been informative and insightful for countries in formulating industrial development policies and implementing the Paris Agreement.
Subject(s)
Carbon , Industrial Development , Carbon Dioxide/analysis , Communication , Information Technology , Economic Development , ChinaABSTRACT
It is critical to determine the real-world performance of vaccines against coronavirus disease 2019 (COVID-19) so that appropriate treatments and policies can be implemented. There was a rapid wave of infections by the Omicron variant in Jilin Province (China) during spring 2022. We examined the effectiveness of inactivated vaccines against Omicron using real-world data from this epidemic. This retrospective case-case study of vaccine effectiveness (VE) examined infected patients who were quarantined and treated from April 16 to June 8, 2022 and responded to an electronic questionnaire. Data were analyzed by univariable and multivariable analyses. A total of 2968 cases with SARS-CoV-2 infections (asymptomatic: 1061, mild disease: 1763, pneumonia: 126, severe disease: 18) were enrolled in the study. Multivariable regression indicated that the risk for pneumonia or severe disease was greater in those who were older or had underlying diseases, but was less in those who received COVID-19 vaccines. Relative to no vaccination, VE against the composite of pneumonia and severe disease was significant for those who received 2 doses (60.1%, 95%CI: 40.0%, 73.5%) or 3 doses (68.1%, 95%CI: 44.6%, 81.7%), and VE was similar in the subgroups of males and females. However, VE against the composite of all three classes of symptomatic diseases was not significant overall, nor after stratification by sex. There was no statistical difference in the VE of vaccines from different manufacturers. The inactivated COVID-19 vaccines protected patients against pneumonia and severe disease from Omicron infection, and booster vaccination enhanced this effect.
Subject(s)
COVID-19 , Pneumonia , Female , Male , Humans , COVID-19 Vaccines , SARS-CoV-2 , COVID-19/prevention & control , Retrospective Studies , China/epidemiologyABSTRACT
BACKGROUND: Acceleration of negative respiratory conversion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19) might reduce viral transmission. Nirmatrelvir/ritonavir is a new antiviral agent recently approved for treatment of COVID-19 that has the potential to facilitate negative conversion. METHODS: A cohort of hospitalized adult patients with mild-to-moderate COVID-19 who had a high risk for progression to severe disease were studied. These patients presented with COVID-19 symptoms between 5 March and 5 April 2022. The time from positive to negative upper respiratory reverse transcription-polymerase chain reaction (RT-PCR) conversion was assessed by Kaplan-Meier plots and Cox proportional hazards regression with the adjustment for patients' baseline demographic and clinical characteristics. RESULTS: There were 258 patients treated with nirmatrelvir/ritonavir and 224 nontreated patients who had mild-to-moderate COVID-19. The median (interquartile range) time for patients who converted from positive to negative RT-PCR was 10 days (7-12 days) in patients treated ≤5 days after symptom onset and 17 days (12-21 days) in nontreated patients. The proportions of patients with a negative conversion at day 15 were 89.7% and 42.0% in treated patients and nontreated patients, corresponding to a hazard ratio of 4.33 (95% confidence interval, 3.31-5.65). Adjustment for baseline differences between the groups had little effect on the association. Subgroup analysis on treated patients suggests that time to negative conversion did not vary with the patients' baseline characteristics. CONCLUSIONS: This cohort study of high-risk patients with mild-to-moderate COVID-19 found an association between nirmatrelvir/ritonavir treatment and accelerated negative RT-PCR respiratory SARS-CoV-2 conversion that might reduce the risk of viral shedding and disease transmission.
Subject(s)
COVID-19 , Adult , Humans , SARS-CoV-2 , Ritonavir/therapeutic use , Reverse Transcriptase Polymerase Chain Reaction , Cohort Studies , Reverse Transcription , COVID-19 Drug Treatment , COVID-19 TestingABSTRACT
Microalgae-based technologies are promising strategies for efficient wastewater treatment and biogas upgrading. In this study, three types of microalga-fungi/bacteria symbiotic systems stimulated with the strigolactone analog (GR24) were used to simultaneously remove nutrients from treated piggery wastewater and CO2 from biogas. The effects of initial concentrations of chemical oxygen demand (COD) and GR24 on nutrient removal and biogas upgrading were investigated. When the initial COD concentration was 1200 mg/L, the Chlorella vulgaris-Ganoderma lucidum-endophytic bacteria co-cultivation systems achieved the best photosynthetic performance and microalgae growth. Moreover, under the appropriate COD concentration (1200 mg/L), the highest nutrient/CO2 removal efficiencies were obtained. In addition, 10-9 M GR24 significantly accelerated nutrient/CO2 removal efficiencies. These findings provide a theoretical basis for scale-up experiments using microalgae-based technologies.
Subject(s)
Chlorella vulgaris , Microalgae , Wastewater , Biofuels/microbiology , Biological Oxygen Demand Analysis , Carbon Dioxide , Biomass , NitrogenABSTRACT
The long noncoding RNA growth arrest-specific transcript 5 (GAS5) has been reported to function as a suppressor in many cancers. However, the role and mechanism of lncRNA GAS5 in pituitary neuroendocrine tumors (PitNETs) remain unclear. Here, we found that lncRNA GAS5 and cylindromatosis (CYLD) expression was downregulated in invasive PitNET tissues and was negatively correlated with miR-27a-5p expression. LncRNA GAS5 overexpression inhibited proliferation of PitNETs cell line MMQ and GH3 cells and induced cell apoptosis, simultaneously, inhibited miR-27a-5p expression and increased CYLD expression. Moreover, miR-27a-5p mimic significantly decreased the luciferase activities of lncRNA GAS5 and CYLD luciferase reporter vector and downregulated CYLD expression, while miR-27a-5p inhibitor increased the expression of CYLD in MMQ and GH3 cells. Furthermore, RNA-immunoprecipitation assay revealed the direct binding between lncRNA GAS5 and miR-27a-5p. Additionally, miR-27a-5p mimic or silenced CYLD attenuated the effect of lncRNA GAS5 on MMQ and GH3 cell proliferation. In vivo lncRNA GAS5 overexpression inhibited GH3 cell tumor growth, while miR-27a-5p mimic or silenced CYLD attenuated the effect of lncRNA GAS5 on GH3 cell tumor growth. These results suggest that lncRNA GAS5 acts as an endogenous sponge by binding miR-27a-5p to increase the expression of its target gene CYLD, thereby inhibits PitNETs cell proliferation and tumor growth.
Subject(s)
MicroRNAs , Neuroendocrine Tumors , RNA, Long Noncoding , Animals , Apoptosis/genetics , Cell Proliferation/genetics , Humans , Luciferases , MicroRNAs/genetics , MicroRNAs/metabolism , Neuroendocrine Tumors/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Small Nucleolar , RatsABSTRACT
Zinc (Zn) and magnesium (Mg) are essential trace elements in humans. Their deficiency may be associated with inflammation and oxidative stress (OS) in patients with diabetic nephropathy (DN), but the mechanisms involved have not been fully characterized. We aimed to investigate the relationships between circulating concentrations of Zn and Mg and pro-inflammatory factors with DN-associated renal functional damage in patients with type 2 diabetes mellitus (T2DM). To this end, we studied 20 healthy people, 24 patients with T2DM, and 59 patients with T2DM and T2DN. Serum and urine Zn and Mg concentrations were measured using the 2-(5-nitro-2-pyridylazo)-5-(N-propyl-N-sulfopropylamine) phenol (nitro-PAPS) chromogenic method and the xylidyl blue method, respectively, and the circulating concentrations of pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor-α (TNF-α)] were measured using flow cytometry. The serum concentrations of Zn and Mg were significantly lower in patients with T2DM and DN than in healthy controls. Serum Zn, urine Zn, and urine Mg concentrations decreased, while those of IL-6 and IL-8 increased with the progression of DN-associated renal functional damage. Furthermore, the serum and urine Zn concentrations negatively correlated with the serum IL-6 and IL-8 concentrations. Notably, the serum Zn concentration was found to independently protect against DN in patients with T2DM. Hypozincemia may be associated with the T2DN-associated renal functional damage because it exacerbates inflammation.
ABSTRACT
Activin A levels are elevated during multiple severe infections and associated with an increased risk of death. However, the role of activin A in bacterial infection is still unclear. Here, we found that activin A levels were increased during S. aureus skin infection in mice. Administration of activin A increased the bacterial burden and promoted the spread of bacteria in vivo. Moreover, activin A inhibited neutrophil chemotaxis to N-formylmethionine-leucyl-phenylalanine via the type IIA activin receptor (ActRIIA) in vitro and impaired ActRIIA+ neutrophil recruitment to infection foci in vivo. Additionally, we identified a novel subpopulation of neutrophils, ActRIIA+ neutrophils, which exhibit superior phagocytic capacity compared to ActRIIA- neutrophils and possess an N2-like immunoregulatory activity via secreting IL-10 and TGF-ß. Taken together, these findings indicate that activin A inhibits the recruitment of ActRIIA+ neutrophils to infected foci, leading to the impairment of bacterial clearance, and thus may hamper early infection control.
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) occurs in patients with type 2 diabetes mellitus (T2DM). Trelagliptin is an important member of the Gliptins family, which has been recently licensed for the treatment of T2DM. However, the pharmacological function of trelagliptin in NAFLD has not been previously reported. In this study, we aimed to investigate the roles of trelagliptin in the development of NAFLD in a mouse model. To induce NAFLD disease, C57BL/6 mice were fed a high-fat diet for 10 weeks. Our results indicate that trelagliptin reduced plasma lipid levels in NAFLD mice by reducing triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Treatment with trelagliptin exhibited an improvement in insulin resistance. More important, trelagliptin improved liver function by reducing alanine transaminase, aspartate transaminase, lactate dehydrogenase, and total bile acid. In addition, trelagliptin ameliorated oxidative stress in the liver of NAFLD mice by reducing malondialdehyde and increasing the levels of reduced glutathione and superoxide dismutase activity. Also, the enzyme-linked immunosorbent assay results indicate that trelagliptin-treated mice displayed anti-inflammatory properties by reducing the levels of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor-α. Hematoxylin and eosin and Oil red O staining show that trelagliptin treatment ameliorates liver tissue damage and hepatic lipid deposition. Mechanistically, we found that the administration of trelagliptin reduced the activity of hepatic nuclear factor-κB but increased the activity of AMP-activated protein kinase. These findings suggest that trelagliptin might become a promising therapeutic agent for the treatment of NAFLD.
Subject(s)
Diet, High-Fat/adverse effects , Non-alcoholic Fatty Liver Disease/prevention & control , Uracil/analogs & derivatives , Animals , Liver/metabolism , Liver/pathology , Male , Mice , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Oxidative Stress/drug effects , Uracil/pharmacologyABSTRACT
INTRODUCTION: Deregulation of adipogenesis plays an important role in obesity and other metabolism disorders. PPAR, C/EBP and SREBP1c are key transcriptional factors involved in adipogenesis and lipogenesis. Juglanin is a natural compound belonging to flavonoids, and it has been reported that juglanin has a potent inhibitory effect on inflammation and certain type of cancers. However, the effects of juglanin in adipogenesis have not been reported before. MATERIALS AND METHODS: 3T3-L1 preadipocytes were incubated with differentiation induction medium in the presence or absence of 0.5, 2.5, or 5 µM juglanin for an 8-day differentiation period. The lipid droplets accumulated in the cytoplasm were monitored by Oil Red O staining on days 0, 2, 5, and 8. The regulatory effects of juglanin on adipogenesis-related genes and proteins were investigated by real-time polymerase chain reaction and Western blot analysis. RESULTS: Juglanin significantly decreased lipid accumulation in differentiated adipocytes. Our findings show that juglanin reduced the expression of C/EBPα, C/EBPß, and SREBP-1c without affecting PPARα or PPARγ expression. Additionally, juglanin increased the activation of the SIRT1/AMPK signaling pathway through the phosphorylation of AMPKα. Finally, we performed an AMPK inhibitor experiment, which revealed that the inhibitory effects of juglanin on adipogenesis are mediated through AMPK. DISCUSSION: Juglanin can prevent adipogenesis by suppressing lipid accumulation and the differentiation of preadipocytes. The mechanism of juglanin regulating adipogenesis requires further investigation. Future clinical study in vivo could shed more light on its implication in modulating obesity and metabolic disorders.
Subject(s)
Adipogenesis/drug effects , Glycosides/pharmacology , Kaempferols/pharmacology , 3T3-L1 Cells , Adipocytes/drug effects , Adipogenesis/genetics , Animals , Cell Differentiation/drug effects , Cells, Cultured , Glycosides/chemistry , Kaempferols/chemistry , Mice , Molecular StructureABSTRACT
BACKGROUND AND PURPOSE: obesity is defined as excessive accumulation of adipose tissues and is becoming one of the main global severe public health issues. The present study aims to investigate the anti-adipogenesis of laquinimod and the underlying mechanism. METHODS: a differentiation cocktail was used to differentiate 3T3-L1 cells, and mice were fed with high fat food to establish the obesity animal model. Oil red O staining, glycerol production assay, and the release of triglyceride were used to evaluate the differentiation degree of 3T3-L1 cells. The expression level of sterol regulatory element binding transcription factor 1 (Srebp1), fatty acid binding protein-4 (FABP4), glucose transporter 4 (GLUT4), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT enhancer-binding proteins (C/EBPα), and phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase α (p-AMPKα) was determined by quantitative real time PCRqRT-PCR and western blot analysis. The pathological state of adipose tissues was evaluated by hematoxylin-eosin staining. RESULTS: the amount and UV absorption of oil red O, glycerol production, release of triglyceride, and the expression of SREBP1, FABP4, and Glut4 in differentiated 3T3-L1 cells were decreased by the administration of laquinimod. PPAR-γ and C/EBPα were down-regulated, and p-AMPKα was up-regulated by laquinimod. The down-regulated PPAR-γ and C/EBPα, as well as the inhibited lipid accumulation functioned by laquinimod, were reversed by the coincubation with the AMPK inhibitor compound C. Decreased body weight, visceral adipocyte tissue weight, and size of adipocytes were observed in in vivo obesity mice after administration with laquinimod. CONCLUSION: laquinimod might prevent adipogenesis by down-regulating PPAR-γ and C/EBPα through activating AMPK.
ABSTRACT
BACKGROUND: This study aimed to investigate the involvement of lncRNA CTBP1-AS2 in the progression of diabetic nephropathy (DN) by affecting high glucose (HG)-induced human glomerular mesangial cells (HGMCs). METHODS: HGMCs were selected for the establishment of cell injury induced by HG. The expression of CTBP1-AS2, miR-155-5p and FOXO1 was detected by real-time PCR and western blotting. The target association between miR-155-5p and CTBP1-AS2 or FOXO1 was confirmed by dual-luciferase reporter assays. Cell proliferation and oxidative stress were revealed by CCK-8 colorimetry, and the measurement of reactive oxygen species (ROS) and the activities of antioxidant enzymes. Extracellular matrix (ECM) protein accumulation and the production of inflammatory cytokines were investigated by western blotting and ELISA. RESULTS: The expression of CTBP1-AS2 was downregulated, and miR-155-5p was highly expressed in peripheral blood of DN patients and HG-treated HGMCs. Further investigation revealed that CTBP1-AS2 overexpression inhibited proliferation, oxidative stress, ECM accumulation and inflammatory response in HG-induced HGMCs. Mechanical analysis revealed that CTBP1-AS2 regulated FOXO1 expression via sponging miR-155-5p. Rescue experiments demonstrated that miR-155-5p overexpression or FOXO1 inhibition reversed the effects of CTBP1-AS2 in HG-stimulated HGMCs. CONCLUSION: Taken together, this study revealed CTBP1-AS2 attenuated HG-induced HGMC proliferation, oxidative stress, ECM accumulation, and inflammation through miR-155-5p/FOXO1 signaling.
Subject(s)
Diabetic Nephropathies/genetics , Glomerulonephritis/genetics , MicroRNAs/genetics , RNA, Long Noncoding/blood , Case-Control Studies , Cell Proliferation , Cells, Cultured , Diabetic Nephropathies/blood , Extracellular Matrix/genetics , Extracellular Matrix/pathology , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/metabolism , Gene Regulatory Networks , Glomerulonephritis/pathology , Glucose/pharmacology , Humans , Mesangial Cells/drug effects , Mesangial Cells/pathology , Mesangial Cells/physiology , MicroRNAs/metabolism , Oxidative Stress/drug effects , Oxidative Stress/physiology , RNA, Long Noncoding/genetics , Reactive Oxygen Species/metabolismABSTRACT
Here, a new cell line, Ha168, was established from Helicoverpa armigera eggs and has been stably subcultured for over 30 passages in TNM-FH medium supplemented with 10% fetal bovine serum. The cell line consists of round and spindle-shaped cells and several giant cells. The round cells, with a cell diameter of 14.30 ± 2.804 µm, account for 77% of the cells. DNA amplification fingerprinting, random amplified polymorphic DNA analysis, and analysis of the mitochondrial cytochrome c oxidase subunit I gene confirmed that the Ha168 cells were derived from H. armigera. Karyotype analysis revealed the average chromosome number of Ha168 cells to be 71. Growth curves at passage 25 were determined and demonstrated that the cell population doubling time is 56.8 h. No mycoplasma contamination was detected in the cell line. Ha168 cells can be infected by recombinant baculovirus AcMNPV-EGFP, and exogenous protein expression level in this cell line is 70% of that in the Sf9 cell line.
Subject(s)
Cell Culture Techniques/methods , Embryo, Nonmammalian/cytology , Moths/cytology , Moths/embryology , Animals , Baculoviridae/physiology , Cell Line , Cell Proliferation , Electron Transport Complex IV/genetics , Green Fluorescent Proteins/metabolism , Karyotyping , Mycoplasma/isolation & purification , Random Amplified Polymorphic DNA Technique , Recombinant Proteins/metabolismABSTRACT
Bile acids (BAs) play essential physiological roles not only by facilitating the absorption and transport of nutrients but also by acting as a complex molecular signaling system. Reduced levels of BAs have been observed in obesity and other metabolic disorders. In the present study, we explored the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin on BA synthesis, both in vitro and in vivo. In our in vivo experiments, we found that teneligliptin increased the liver, ileal, and serum BA concentrations in mice undergoing teneligliptin treatment for 10 weeks. We further found that in mice fed a high-fat diet, teneligliptin prevented an increase in markers of obesity (body weight, total cholesterol, total triglyceride, adipocyte size) while increasing the total serum and ileal levels of BA. Mechanistically, teneligliptin increased BA synthesis through the alternative synthesis pathway, as the levels of both 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) along with downstream oxysterol 7α-hydroxylase (CYP7B1) but not sterol 12α-hydroxylase (CYP8B1) were increased. Importantly, teneligliptin suppressed the expression of the BA synthesis inhibitory factor Fgf15, which was mediated through phosphatidylinositol 3-kinase (PI3K)/AKT/Krüppel-like factor 15 (KLF15) signaling. Inhibition of KLF15 abolished this effect. Together, our results provide evidence of the potential benefit of teneligliptin in the treatment of metabolic disorders via increased BA production.
Subject(s)
Bile Acids and Salts/biosynthesis , Fibroblast Growth Factors/antagonists & inhibitors , Kruppel-Like Transcription Factors/antagonists & inhibitors , Pyrazoles/pharmacology , Thiazolidines/pharmacology , Administration, Oral , Animals , Bile Acids and Salts/analysis , Cells, Cultured , Fibroblast Growth Factors/metabolism , Kruppel-Like Transcription Factors/metabolism , Lipid Metabolism/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Pyrazoles/administration & dosage , Thiazolidines/administration & dosageABSTRACT
BACKGROUND AND PURPOSE: Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism. EXPERIMENTAL APPROACH: Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study. KEY RESULTS: C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism. CONCLUSION AND IMPLICATIONS: These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment.
Subject(s)
Mitophagy , Non-alcoholic Fatty Liver Disease , Animals , Anthocyanins , Glucosides/pharmacology , Humans , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Protein KinasesABSTRACT
Aims: Nuclear factor E2-related factor 2 (Nrf2) is a regulator of cellular oxidative stress and is also involved in lipid metabolism in adipocytes. However, it remains unknown as to whether Nrf2 is the link between oxidative stress and the induction of lipid accumulation in adipocytes. Results: Here, we show that oxidative stress is markedly increased in white adipose tissue from mice with high-fat diet-induced or genetically (ob/ob)-induced obesity and from human subjects with obesity. Notably, in response to oxidative stress, Nrf2 expression and activity were induced, further promoting lipid accumulation in adipocytes and exacerbating the development of obesity. In contrast, Nrf2 ablation alleviated oxidative stress-induced lipid accumulation. Mechanistically, oxidative stress promoted Nrf2 recruitment to the sterol regulatory element binding protein 1 promoter, inducing target gene transcription and subsequent lipogenesis. In addition, Nrf2 mediated oxidative stress-inhibited lipolysis in adipocytes via the protein kinase A pathway. Innovation and Conclusion: Our data provide a novel insight that Nrf2, as a critical signaling node, links oxidative stress to the induction of fat accumulation in adipocytes.
Subject(s)
Adipocytes/metabolism , Lipolysis/physiology , NF-E2-Related Factor 2/metabolism , Oxidative Stress/physiology , 3T3-L1 Cells , Adult , Animals , Cell Line , Diet, High-Fat/adverse effects , Female , Humans , Lipid Metabolism/physiology , Lipogenesis/physiology , Male , Mice , Mice, Knockout , Middle Aged , Obesity/metabolismABSTRACT
Magnesium (in its ionized and biologically active form, Mg2+) is an essential trace element that participates in numerous physiologic processes. Abnormal Mg2+ homeostasis can lead to many metabolic disorders, including diabetes mellitus (DM) and its complications. Mg2+ participates in energy generation and is required for DNA and RNA synthesis, reproduction, and protein synthesis. Additionally, Mg2+ acts as a calcium antagonist and protects vascular endothelial cells from oxidative stress. Imbalances in Mg2+ status, more frequently hypomagnesemia, inhibit glucose transporter type 4 translocation, increase insulin resistance, affect lipid metabolism, induce oxidative stress, and impair the antioxidant system of endothelial cells, In these ways, hypomagnesemia contributes to the initiation and progression of DM and its macrovascular and microvascular complications. In this review, we summarize recent advances in knowledge of the mechanisms whereby Mg2+ regulates insulin secretion and sensitivity. In addition, we discuss the future prospects for research regarding the mechanisms whereby Mg2+ status impacts DM and its complications.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Magnesium/metabolism , Calcium/metabolism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Insulin/metabolism , Magnesium/pharmacology , Oxidative Stress/drug effectsABSTRACT
Competing endogenous RNAs (ceRNAs) are considered as transcripts that can regulate each other at post-transcription level by competing for shared miRNAs. Considering the key roles of lncRNAs acting as ceRNAs in progression of solid tumors, to develop prognostic signatures in thyroid cancer (THCA), patients with corresponding clinical data were selected and two ceRNA networks were constructed using online databases. Two prognostic signatures (Lnc5m4 and Lnc2mi1m2) were found to be more efficient in predicting long-term survival of THCA patients. However, the high-risk score of Lnc2mi1m2 was not an independent factor.The risk score of Lnc5m4 was able to effectively stratify patients in stage III-IV into low- and high-risk groups, and also could predict poor prognosis of patients in stage III-IV. In conclusion, these findings indicate that Lnc5m4 is a novel prognostic signature for predicting long-term overall survival of THCA patients, which could provide a new approach to lncRNA research in THCA progression.