ABSTRACT
Drug-mediated or medical condition-mediated disruption of hERG function accounts for the main cause of acquired long-QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG-HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG ) was measured by patch-clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell-based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after-depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long-term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.
Subject(s)
Action Potentials , Arrhythmias, Cardiac/pathology , ERG1 Potassium Channel/antagonists & inhibitors , Indole Alkaloids/adverse effects , Long QT Syndrome/pathology , Quinazolines/adverse effects , Vasodilator Agents/adverse effects , Ventricular Dysfunction/pathology , Animals , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/metabolism , Cells, Cultured , Electrophysiological Phenomena , Guinea Pigs , HEK293 Cells , Humans , Long QT Syndrome/chemically induced , Long QT Syndrome/metabolism , Male , Ventricular Dysfunction/chemically induced , Ventricular Dysfunction/metabolismABSTRACT
Aldo-keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time-resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha-fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early-stage HCC and AFP-negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion: AKR1B10 is a potent serum marker for detection of HCC and early-stage HCC, with better diagnostic performance than AFP.
Subject(s)
Aldo-Keto Reductase Family 1 member B10/blood , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/blood , Liver Neoplasms/pathology , Adult , Biomarkers, Tumor , Biopsy, Needle , Carcinoma, Hepatocellular/diagnosis , Case-Control Studies , China , Female , Hospitals, University , Humans , Immunohistochemistry , Liver Neoplasms/diagnosis , Male , Middle Aged , ROC Curve , Reference Values , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
The hERG potassium channel (IKr) encoded by human ether-a-go-go-related gene plays an important role in cardiac repolarization. Decreased IKr may lead to long QT syndrome, which subsequently causes torsade de pointes and sudden cardiac death. Previous studies have shown that statins inhibit IKr and are more potent in inhibiting hERG currents when combined with other drugs. Since chemical structure of rosuvastatin is similar to that of several IKr blockers (ibutilide and E-4031), the present study aimed to reveal the mechanism that underlies rosuvastatin-induced hERG current reduction and to evaluate the possibility of cardiac toxicity. The results showed that rosuvastatin reduced hERG currents by accelerating the inactivation and prolonged action potential duration (APD) in hiPSC-CMs. Meanwhile, it was observed that rosuvastatin reduced the expression of the mature hERG. Transcription factor Sp1 was involved in hERG protein downregulation induced by rosuvastatin, and the result was verified by Sp1 siRNA and Sp1 agonist epicatechin. These results indicated that rosuvastatin could potentially inhibit transcription and reduce hERG mRNA expression. The interaction between hERG and heat shock protein was evaluated to study the mechanism of trafficking inhibition through co-immunoprecipitation. We found that rosuvastatin reduces the interaction of heat shock protein 70 (Hsp70) with the hERG protein, thereby affecting the folding of the hERG channel. Additionally, rosuvastatin significantly activates ATF6, which plays a key role in the activation of the unfolded protein response (UPR) pathway. Increased expression of the molecular chaperone calnexin and calreticulin, which are activated by ATF6 to help channel folding, further confirmed UPR activation. Meanwhile, the degradation of the hERG channel was mediated by lysosomes and proteasomes. In conclusion, Rosuvastatin reduced the expression of hERG plasma membrane by two pathways, the first is to disrupt the transport of immature hERG channels to the membrane, and the second is to increase the degradation of mature hERG channels. In addition, Rosuvastatin potently blocked hERG current, delayed cardiac repolarization, and thereby prolonged APDs and QTc intervals. Therefore, caution should be taken when rosuvastatin is used in the treatment of hyperlipidemia, especially when combined with drugs that can prolong the QT interval.
Subject(s)
Anticholesteremic Agents/pharmacology , Cell Membrane/metabolism , Ether-A-Go-Go Potassium Channels/metabolism , Induced Pluripotent Stem Cells/metabolism , Myocytes, Cardiac/metabolism , Proteolysis/drug effects , Rosuvastatin Calcium/pharmacology , Action Potentials , Cell Membrane/drug effects , Ether-A-Go-Go Potassium Channels/drug effects , HEK293 Cells , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/drug effects , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Protein Transport , Unfolded Protein ResponseABSTRACT
Curcumin is an anticancer agent, but adverse effects and low bioavailability are its main drawbacks, which drives efforts in chemical modifications of curcumin. This study evaluated antiproliferative activity and cancer cell selectivity of a curcumin derivative, curcumin nicotinate (CN), in which two niacin molecules were introduced. Our data showed that CN effectively inhibited proliferation and clonogenic growth of colon (HCT116), breast (MCF-7) and nasopharyngeal (CNE2, 5-8F and 6-10B) cancer cells with IC50 at 27.7 µM, 73.4 µM, 64.7 µM, 46.3 µM, and 31.2 µM, respectively. In cancer cells, CN induced apoptosis and cell cycle arrest at G2/M phase through a p53-mediated mechanism, where p53 was activated, p21 and pro-apoptotic proteins Bid and Bak were upregulated, and PARP was cleaved. In non-transformed human mammary epithelial cells MCF10A, CN at 50 µM had no cytotoxicity and p53 was not activated, but curcumin at 12.5 µM activated p53 and p21 and inhibited MCF10A cell growth. These data suggest that CN inhibits cell growth and proliferation through p53-mediated apoptosis and cell cycle arrest with cancer cell selectivity.
Subject(s)
Apoptosis/drug effects , Cell Cycle/drug effects , Curcumin/analogs & derivatives , Niacin/analogs & derivatives , Tumor Suppressor Protein p53/metabolism , Cell Proliferation/drug effects , Curcumin/pharmacology , Drug Screening Assays, Antitumor , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , MCF-7 Cells , Niacin/pharmacologyABSTRACT
BACKGROUND: Inflammation is a common feature of both peripheral arterial disease (PAD) and periodontitis. Some studies have evaluated the association between PAD and periodontitis. However, there is still no specialized meta-analysis that has quantitatively assessed the strength of the association. Thus, we conducted this meta-analysis to critically assess the strength of the association between PAD and periodontitis. METHODS: PubMed, Embase, and the Cochrane Library were searched for observational studies of the association between periodontitis and PAD in February 2018. Risk ratios (RRs) and their 95% confidence intervals (CIs) from included studies were pooled to evaluate the strength of the association between periodontitis and PAD. Weighted mean differences (WMDs) and their 95% CIs were pooled to compare the difference in periodontal-related parameters between PAD and non-PAD patients. RESULTS: Seven studies including a total of 4307 participants were included in the meta-analysis. The pooled analysis showed that there was a significant difference in the risk of periodontitis between PAD patients and non-PAD participants (RR = 1.70, 95% CI = 1.25-2.29, P = 0.01). There was also a significant difference in number of missing teeth between PAD patients and non-PAD participants (WMD = 3.75, 95% CI = 1.31-6.19, P = 0.003). No significant difference was found in clinical attachment loss between PAD patients and non-PAD participants (WMD = - 0.05, 95% CI = - 0.03-0.19, P = 0.686). CONCLUSION: In conclusion, the results of this meta-analysis revealed a significant relationship between periodontitis and PAD. Moreover, our study indicated that PAD patients had more missing teeth than control subjects did. Further high-quality and well-designed studies with specific inclusion and exclusion criteria are required to strengthen the conclusions of this study.
Subject(s)
Periodontitis/epidemiology , Peripheral Arterial Disease/epidemiology , Tooth Loss/epidemiology , Adult , Aged , Biomarkers/blood , Female , Humans , Inflammation Mediators/blood , Male , Middle Aged , Periodontitis/blood , Periodontitis/diagnosis , Peripheral Arterial Disease/blood , Peripheral Arterial Disease/diagnosis , Risk Factors , Tooth Loss/blood , Tooth Loss/diagnosisABSTRACT
Becker's naevus is androgen-dependent. The aim of this study was to investigate whether oestrogen and progesterone receptors are involved in this disorder. Immunohistochemistry showed that epidermal expression of androgen receptors, oestrogen receptors (α, ß) and progesterone receptors was higher in skin lesions of Becker's naevus than in perilesional and control skin. Androgen receptor overexpression was observed in pilosebaceous glands, while oestrogen and progesterone receptor overexpression was seen in hair follicles, but not in sebaceous glands in skin lesions compared with perilesional skin. Reverse tran-scription PCR and Western blot revealed that levels of androgen, oestrogen and progesterone receptors were generally upregulated in skin lesions compared with perilesional and control skin, and their expression was usually higher in perilesional than in control skin. These results suggest that simultaneous overexpression of androgen, oestrogen and progesterone receptors might be implicated in the pathogenesis of Becker's naevus.
Subject(s)
Estrogen Receptor alpha/analysis , Estrogen Receptor beta/analysis , Nevus/chemistry , Receptors, Androgen/analysis , Receptors, Progesterone/analysis , Skin Neoplasms/chemistry , Adolescent , Adult , Blotting, Western , Child , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/genetics , Female , Humans , Immunohistochemistry , Male , Nevus/genetics , Nevus/pathology , Receptors, Androgen/genetics , Receptors, Progesterone/genetics , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Up-Regulation , Young AdultABSTRACT
Electrophilic carbonyl compounds are highly cytotoxic and genotoxic. Aldo-keto reductase 1B10 (AKR1B10) is an enzyme catalyzing reduction of carbonyl compounds to less toxic alcoholic forms. This study presents novel evidence that AKR1B10 protects colon cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 is specifically expressed in epithelial cells of the human colon, but this study found that AKR1B10 expression was lost or markedly diminished in colorectal cancer, precancerous tissues, and a notable portion of normal adjacent tissues (NAT). SiRNA-mediated silencing of AKR1B10 in colon cancer cells HCT-8 enhanced cytotoxicity of acrolein and HNE, whereas ectopic expression of AKR1B10 in colon cancer cells RKO prevented the host cells against carbonyl cytotoxicity. Furthermore, siRNA-mediated AKR1B10 silencing led to DNA breaks and activation of γ-H2AX protein, a marker of DNA double strand breaks, particularly in the exposure of HNE (10 µM). In the AKR1B10 silenced HCT-8 cells, hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutant frequency increased by 26.8 times at basal level and by 33.5 times in the presence of 10 µM HNE when compared to vector control cells. In these cells, the cyclic acrolein-deoxyguanosine adducts levels were increased by over 10 times. These findings were confirmed by pharmacological inhibition of AKR1B10 activity by Epalrestat. Taken together, these data suggest that AKR1B10 is a critical protein that protects host cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 deficiency in the colon may be an important pathogenic factor in disease progression and carcinogenesis. © 2016 Wiley Periodicals, Inc.
Subject(s)
Acrolein/toxicity , Aldehyde Reductase/metabolism , Aldehydes/toxicity , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/metabolism , DNA Damage/drug effects , Mutagens/toxicity , Acrolein/metabolism , Aldehyde Reductase/analysis , Aldehyde Reductase/genetics , Aldehydes/metabolism , Aldo-Keto Reductases , Cell Line, Tumor , Colon/metabolism , Colon/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Gene Silencing , Humans , Mutagens/metabolism , Rectum/metabolism , Rectum/pathologyABSTRACT
Hundreds of NF-κB inhibitors have been developed for cancer therapy, but their clinical efficacy is unsatisfactory. Here we show that the phosphorylation activation at Ser536 of RelA/p65 protein, a main subunit in the NF-κB family, may play a tumor-suppressive role. In normal colon mucosa, RelA/p65 phosphorylation at Ser536 was increasingly increased with the maturation and apoptotic shedding of epithelial cells, but the phosphorylation at Ser536 was decreased in colon cancer. In colon (HCT116 p53 wt and p53 -/-), breast (MCF7), and prostate (LNCaP and DU145) cancer cells, a phosphomimetic mutation of RelA/p65 at Ser536 (named p65/S536D) triggered dramatic apoptosis through affecting expression of a wide range of cell death/survival genes, such as Bim, Puma, Noxa, Bcl-2 and survivin. In HCT116 cells, p65/S536D mutant upregulated Fas, insulted mitochondrial membrane potential, and triggered cleavage and activation of caspase-3, 7, 8 and 9. A FasL neutralizing antibody (NOK1) prevented cell death induced by the p65/S536D. A pan inhibitor of caspases, Z-VAD-FMK (20 µM), blocked caspase-mediated mitochondrial membrane depolarization. This p65/S536D also triggered senescence in HCT116 cells through a p16-dependent pathway, but not in MFC7 due to lack of p16. Intratumoral delivery of the p65/S536D effectively suppressed tumor growth in nude mice. Together our data suggest that the phosphorylation of RelA/p65 at Ser536 may confer it a tumor-suppressive role by inducing apoptosis and senescence, highlighting the importance of discriminating the function and active status of individual active sites in RelA/p65 when NF-κB inhibitors are considered for targeted therapy of cancer.
Subject(s)
Apoptosis , Colonic Neoplasms/pathology , Transcription Factor RelA/physiology , Tumor Suppressor Proteins/physiology , Animals , Cell Line, Tumor , Cellular Senescence , Humans , Mice , Mutation , Phosphorylation , SerineABSTRACT
Yogurt is a food produced by bacterial fermentation of milk. All kinds of nutrition components are changing dramatically in the process of fermentation. Therefore, it is important to establish a fast and efficient measurement technology of yogurt nutrition, which is also an important goal for food safety supervision in terms of monitoring the yogurt production process in real time. Fourier transform infrared spectroscopy (FTIR) has been widely used in the field of food safety, for it has high efficiency, high throughput, no chemical pollution, thus it can be used in the inspection of food adulteration. Our study has established a quantitative model to predict the nutrition components in yogurt, such as energy value, protein, fat, carbohydrates and sodium content. Based on the least squares (PLS) method, the model used CaF(2) film FTIR technology. The results show that the new model can be used in quality control of yogurt production process: The R(2) values of the model were 0.938 9, 0.926 6, 0.918 6, 0.941 8 and 0.977 1, comparing energetic value, protein, fat, carbohydrate and sodium contents with the original spectrum of calibration samples by cross validation. And the predictive R(2) are 0.920 5, 0.905 3, 0.908 5, 0.939 3 and 0.936 4 respectively. Thus, the model has good prediction accuracy and reliability, which provides a feasible method for the rapid measurement of yogurt quality. As a preliminary exploration of the quality control technology of dairy products, this method has a good prospect of application.
Subject(s)
Spectroscopy, Fourier Transform Infrared , Yogurt , Animals , Calibration , Carbohydrates , Fermentation , Food Contamination , Least-Squares Analysis , Milk , Proteins , Quality Control , Reproducibility of ResultsABSTRACT
BACKGROUND: Circular RNAs participate in the development of periodontitis. The present work aims to reveal the role and mechanism of circ_0087199 in human periodontal ligament cell (PDLC) injury during periodontitis. METHODS: PDLCs were treated with lipopolysaccharides (LPS) to establish a periodontitis cell model. Quantitative real-time polymerase chain reaction was used to detect the expression of circ_0087199, miR-527, toll-like receptor 4 (TLR4). Western blot analysis assay was performed to assess protein expression. Cell viability, proliferation, apoptosis and inflammation were investigated by cell counting kit-8, EdU assay, flow cytometry and enzyme-linked immunosorbent assay, respectively. Oxidative stress was evaluated by malondialdehyde assay kit and superoxide dismutase activity assay kit. The interaction between miR-527 and circ_0087199 or TLR4 was confirmed by a dual-luciferase reporter assay. RESULTS: Circ_0087199 and TLR4 expression levels were significantly increased, while miR-527 was decreased in the periodontal ligament tissues of periodontitis patients and LPS-stimulated PDLCs when compared with controls. LPS treatment inhibited cell viability and proliferation but induced cell apoptosis, inflammation and oxidative stress, whereas these effects were attenuated after circ_0087199 knockdown. Circ_0087199 bound to miR-527 and regulated LPS-caused PDLC damage by targeting miR-527. Additionally, the overexpression of TLR4, a target gene of miR-527, rescued miR-527 mimic-mediated effects on LPS-treated PDLCs. Further, the regulation of circ_0087199 toward TLR4 involved miR-527. CONCLUSION: Circ_0087199 knockdown attenuated LPS-induced apoptosis, inflammation and oxidative stress of PDLCs by regulating the miR-527/TLR4 pathway.
Subject(s)
MicroRNAs , Periodontitis , RNA, Circular , Toll-Like Receptor 4 , Humans , Inflammation , Lipopolysaccharides/toxicity , MicroRNAs/genetics , Periodontal Ligament/cytology , Periodontitis/genetics , Toll-Like Receptor 4/genetics , RNA, Circular/genetics , Oxidative StressABSTRACT
The severe shuttle effect of polysulfides (LiPSs) and the slow liquid-solid phase conversion are the main obstacles hindering the practical application of lithium-sulfur (Li-S) batteries. Separator modification with a high-activity catalyst can boost LiPSs conversion and suppress their shuttle effect. In this work, multi-heterostructured MXene/NiS2/Co3S4 with rich S-vacancies was constructed facilely with a hydrothermal and high-temperature annealing strategy for separator modification. The MXene sheet not only provides a physical barrier but also ensures a high conductivity and adsorption capacity of the catalyst; the dual active centers of NiS2 and Co3S4 catalyze LiPSs conversion. In addition, the vacancies and heterostructures can modulate the electronic structure of the catalyst, improve its intrinsic activity, and reduce the polysulfides reaction barrier, thus facilitating ion/electron transport and inhibiting the shuttle effect. Benefiting from these advantages, the Li-S battery with MXene/NiS2/Co3S4 modified separator exhibits exciting discharge capacities (1495.4 mAh g-1 at 0.1C and 549.0 mAh g-1 at 6C) and an excellent ultra-long cycle life (average capacity decay rate of 0.026% for 2000 cycles at 2C); at a high sulfur loading of 10.0 mg cm-2, the battery operates for nearly 80 cycles at 0.2C, giving a capacity retention rate of 75.76%. This work provides a high-activity catalyst for Li-S batteries.
ABSTRACT
This longitudinal cohort study examined the long-term effect of statin therapy on clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). A total of 1760 patients with stable coronary artery disease (CAD) were divided by receipt of statin therapy or not after index PCI. Baseline clinical characteristics, risk factors, angiographic findings, and medications after interventional procedure were assessed to compare long-term clinical outcomes between groups. Predictors for all-cause death and major adverse cardiovascular events (MACE), including myocardial infarction (MI), cardiovascular death, and repeated PCI procedures, were also analyzed. The statin therapy group had higher average serum cholesterol and more elevated low-density lipoprotein cholesterol (LDL-C) than the non-statin therapy group (189.0 ± 47.9 vs 169.3 ± 37.00 mg/dl, 117.2 ± 42.6 vs 98.7 ± 31.8 mg/dl, respectively, both P < 0.001). The non-statin group had higher rates of all-cause death and cardiovascular death compared to statin group (both P < 0.001). After adjustment for age, diabetes, and chronic kidney disease, Cox proportion hazard analysis revealed statin use significantly reduced all-cause death and repeated PCI procedure (hazard ratio: 0.53 and 0.69, respectively). Statin use seemed not reduce the hazard of cardiovascular death or MI in patients with stable CAD after PCI; however, statin therapy still was associated with reduced rates of all-cause death and repeat PCI procedure.
Subject(s)
Coronary Artery Disease , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Percutaneous Coronary Intervention , Humans , Percutaneous Coronary Intervention/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Female , Middle Aged , Aged , Coronary Artery Disease/surgery , Coronary Artery Disease/mortality , Treatment Outcome , Longitudinal Studies , Risk Factors , Myocardial Infarction , Cholesterol, LDL/bloodABSTRACT
Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint homeostasis by simultaneously remodeling the anti-inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease-modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral-biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)-based nanoparticles (NPs) are integrated into poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self-assembled ChS and ε-poly-l-lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin-1ß (IL-1ß)-mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS-based hydrogel system offers a potential strategy to regulate the chondrocyte-macrophage crosstalk, thus re-establishing the anti-inflammatory and immunomodulatory microenvironment for OA therapy.
Subject(s)
Chondrocytes , Chondroitin Sulfates , Homeostasis , Nanoparticles , Osteoarthritis , Osteoarthritis/pathology , Osteoarthritis/drug therapy , Osteoarthritis/metabolism , Animals , Chondrocytes/metabolism , Chondrocytes/drug effects , Homeostasis/drug effects , Nanoparticles/chemistry , Chondroitin Sulfates/chemistry , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/pharmacology , Mice , Hydrogels/chemistry , Bionics , RAW 264.7 Cells , Male , Drug Delivery Systems/methods , Humans , Rats , Rats, Sprague-Dawley , Cartilage, Articular/pathology , Cartilage, Articular/drug effects , Cartilage, Articular/metabolismABSTRACT
Age-related osteoporosis is characterized by an imbalance between osteogenic and adipogenic differentiation in bone mesenchymal stem cells (BMSCs). Forkhead box O 3 (FoxO3) transcription factor is involved in lifespan and cell differentiation. In this study, we explore whether FoxO3 regulates age-related bone loss and marrow fat accumulation. The expression levels of FoxO3 in BMSCs during aging were detected in vivo and in vitro. To explore the role of FoxO3 in osteogenic and adipogenic differentiation, primary BMSCs were isolated from young and aged mice. FoxO3 expression was modulated by adenoviral vector transfection. The role of FoxO3 in bone-fat balance was evaluated by alizarin red S staining, oil red O staining, quantitative reverse transcription-polymerase chain reaction, Western blot, and histological analysis. Age-related bone loss and fat deposit are associated with downregulation of FoxO3. Overexpression of FoxO3 alleviated age-related bone loss and marrow fat accumulation in aged mice. Mechanistically, FoxO3 reduced adipogenesis and enhanced osteogenesis of BMSCs via downregulation of PPAR-γ and Notch signaling, respectively. In conclusion, FoxO3 is an essential factor controlling the fate of BMSCs and is a potential target for the prevention of age-related osteoporosis.
Subject(s)
Adipogenesis , Aging , Forkhead Box Protein O3 , Mesenchymal Stem Cells , Osteogenesis , Animals , Forkhead Box Protein O3/metabolism , Forkhead Box Protein O3/genetics , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Aging/genetics , Aging/metabolism , Osteogenesis/genetics , Mice , Adipogenesis/genetics , Cell Differentiation/genetics , Mice, Inbred C57BL , Osteoporosis/metabolism , Osteoporosis/pathology , Osteoporosis/genetics , Bone and Bones/metabolism , Signal Transduction , PPAR gamma/metabolism , PPAR gamma/genetics , Male , Cells, Cultured , Receptors, Notch/metabolism , Receptors, Notch/geneticsABSTRACT
OBJECTIVE: To investigate the mechanism(s) that prostaglandin E1 (PGE1) promotes human umbilical vein endothelial cell (HUVEC)proliferation and migration. METHODS: Western blot, enzyme linked immunosorbent assay, cell proliferation and cell migration tests, and tube formation were used for analyzing the roles and mechanisms of PGE1 on HUVEC; Western blot was used for analyzing the effects of PGE1 on the expression of vascular endothelial growth factor (VEGF) in rat aortic vascular smooth muscle cells (VSMC). RESULTS: PGE1 significantly increased VEGF expression of HUVEC in time and a dose dependent manner with concomitantly increased HUVEC proliferation; treatment of HUVEC with Bevacizumab apparently suppressed PGE1-stimulated VEGF expression, which led to decreased tube formation, reduced cell proliferation and migration by 41% and 38%, respectively, compared with PGE1 treatment alone; PGE1 time-dependently induced both phosphorylation of ERK and p38 in HUVEC, whereas ERK inhibitor, PD98059, or p38 inhibitor, SB203580, blocked PGE1-induced VEGF expression of HUVEC, resulting in dramatically suppression of HUVEC proliferation and migration compared with PGE1 treatment alone (60% and 55% by PD98059, 62% and 51% by SB203580, respectively); in addition, cAMP-dependent protein kinase A inhibitor, H89 or Rp-cAMP blocked PGE1-induced VEGF expression in VSMC. CONCLUSION: PGE1 promotion of proliferation, migration and tube formation of HUVEC via VEGF further provides a novel theoretical support in efficacy of PGE1 treatment of critical limb ischemia and other related diseases.
Subject(s)
Alprostadil/pharmacology , Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/cytology , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/drug effects , Animals , Aorta/cytology , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Endothelial Cells/metabolism , Humans , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Rats , Vascular Endothelial Growth Factor A/metabolismABSTRACT
The organic matter (OM) in shale is closely associated with clay minerals, and its maturation is usually accompanied by the diagenesis of these minerals, especially smectite illitization. However, the effect of mineral transformation and its accompanying change of mineral-OM interactions in shale on hydrocarbon generation is still unclear. To investigate this question, smectite-rich immature shale was selected to carry out hydrous pyrolysis. Organic geochemistry and mineralogy of pyrolysates at different temperatures show that the maturation of OM is accompanied by the transformation of bulk and clay minerals. Based on the change in hydrocarbon yield, Rock-Eval parameters, and mineral composition, hydrocarbon generation in this study is divided into three stages: 25-300, 300-400, and 400-500 °C, which are the result of the synergistic evolution of clay minerals and OM. Multistage hydrocarbon generation can be attributed to the mineral transformation-induced desorption of mineral-bound soluble OM (SOM), decarboxylation and hydrocracking of kerogen promoted by solid acids, and cross-linking and cracking reactions of free SOM and residual kerogen under high temperatures. Although different from the classical hydrocarbon generation model of kerogen, this multistage hydrocarbon generation is consistent with the characteristics of the saline lacustrine source rocks in nature. The mineral transformation-induced desorption of SOM is a new pathway for petroleum formation, which can well explain the formation of low-mature oils in nature. In addition, the release of mineral-bound and kerogen-bound biomarkers results in two reversals of isomerization ratios. Considering mineral transformation and mineral-OM interactions can help us better understand and refine the hydrocarbon generation theory of OM.
ABSTRACT
OBJECTIVE: To study the effect of Kaixin San on the rate-limiting enzyme in biosynthesis of melatonin (MT) and pineal body in rat depression model. METHOD: The unpredictable chronic mild stress was used to establish the rat depression model for 21 days. The rats were divided into the normal control group, the model group, Kaixin San low, medium and high dose groups (KXS 65, 130, 260 mg x kg x d(-1)) and the trazodone group. All groups were administered at 30 min after modeling each day. Rats were sacrificed and the pineal glands were isolated immediately after acquisition tail venous blood at 2:00a. m on the 22nd day. The plasma was analyzed for melatonin content by using a rat metabolic panel Milliplex kit. The pineal glands were analyzed for AANAT and HIOMT mRNA levels by Real-time quantitative PCR and for AANAT and HIOMT activity by a radiometric assay simultaneously. RESULT: The plasma MT concentration, expression of AANT and HIOMT mRNA, activity of AANAT in rat pineal glands of the model group were significantly lower than the control group (P < 0.05), but the activity of HIOMT showed not change. Compared with the model group, all of Kaixin San groups showed increase in MT concentration in plasma (P <0. 05) , with the medium dose group revealing the highest level. Besides, the medium dose group displayed significant increase in AANAT, HIOMT mRNA level and AANAT activity (P < 0.05), but no increase in HIOMT activity. CONCLUSION: Kaixin San can regulate AANAT activity of pineal bodyand regulate MT biosynthesis in rat depression model.
Subject(s)
Depression/metabolism , Drugs, Chinese Herbal/pharmacology , Melatonin/biosynthesis , Acetylserotonin O-Methyltransferase/genetics , Animals , Arylalkylamine N-Acetyltransferase/genetics , Depression/blood , Depression/genetics , Disease Models, Animal , Gene Expression Regulation, Enzymologic/drug effects , Male , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, WistarABSTRACT
The development of folk martial arts in China has encountered many obstacles and difficulties in promoting the sport. Although there are many martial arts-related groups on WeChat, the largest social media in China, the interaction is not enthusiastic enough and the participation is too low. The main purpose of this study is to understand the impact of social media marketing activities and user experience on the intention of people to participate in martial arts through a quantitative research method. After the literature study, a research model was developed based on Theory of Planned Behavior (TPB), in which the constructs include social media marketing activities, user experience, attitudes toward martial arts, subjective norms, martial arts attachment, and participation intention. The results of the study illustrated that social media marketing activities and user experience had a positive and significant effect on martial arts attitudes, subjective norms, and martial arts attachment via Structural Equation Modeling (SEM). Martial arts attitudes, subjective norms, and martial arts attachment had a positive and significant effect on the intention to participate. Finally, based on the results of this study, we propose suggestions for social media marketing activities, user experience, martial arts attachment, attitudes toward martial arts, subjective norms, and martial arts participation intentions for martial arts social media operators, martial arts promotion organizations, and subsequent studies.
ABSTRACT
BACKGROUND/PURPOSE: Idiopathic osteosclerosis (IO) is an intraosseous lesion of asymptomatic, non-expansive, radiopaque. The study aimed to investigate the prevalence and morphometric parameters of IO in orthodontic patients and variations in longitudinal observations and to assess the relationship between IO and orthodontic treatment. MATERIALS AND METHODS: Five hundred and seventy-one orthodontically-treated patients were reviewed. A cross-sectional study was performed with the evaluated parameters, including the age and sex of patients, as well as the number, shape, location and morphometric data of IO observed in panoramic radiography. Long-term behaviour of IO and orthodontic tooth movement were also observed. Also, a control group was set up for comparisons. RESULTS: Sixty-eight (11.3%) patients had 78 lesions all in the mandible with premolar/molar preference and no sex predilection. Lesions were located more commonly at apical and separate sites related to teeth. A large majority of lesions enlarged in the 10-19 years old group, while most lesions had no change in the 30-39 years old group. Hindrances of tooth movement and external root resorption around IO were not found in affected patients. CONCLUSION: IO is labile lesion that may develop in early stages of life, with little change occurring once the affected individual is mature and being relatively stable in the middle stage of life. Our study supports the hypothesis that IO may be developmental anatomic variations of normal bone. However, no obvious association between IO and orthodontic treatment was found in patients, which may be due to the limitations of two-dimensional shooting of panoramic radiography and the sample size.
ABSTRACT
Objective: This cross-sectional study aimed to investigate the characteristics of malocclusions in scoliotic patients through clinical examinations. Methods: Fifty-eight patients with idiopathic scoliosis (IS) and 48 patients with congenital scoliosis (CS) participated in the study. A randomly selected group of 152 orthopedically healthy children served as the control group. Standardized orthodontic and orthopedic examination protocols were used to record the occlusal patterns and type of scoliosis. Assessments were made by three experienced orthodontists and a spinal surgery team. The differences in the frequency distribution of occlusal patterns were evaluated by the chi-squared test. Results: In comparison with patients showing IS, patients with CS showed a higher incidence of Cobb angle ≥ 45° (p = 0.020) and included a higher proportion of patients receiving surgical treatments (p < 0.001). The distribution of the Angle Class II subgroup was significantly higher in the IS (p < 0.001) and CS (p = 0.031) groups than in the control group. In comparison with the healthy controls, the CS and IS groups showed significantly higher (p < 0.05) frequencies of asymmetric molar and asymmetric canine relationships, upper and lower middle line deviations, anterior deep overbite, unilateral posterior crossbite, and canted occlusal plane, with the frequencies being especially higher in CS patients and to a lesser extent in IS patients. Conclusions: Patients with scoliosis showed a high frequency of malocclusions, which were most obvious in patients with CS.