Association between statin therapy and long-term clinical outcomes in patients with stable coronary disease undergoing percutaneous coronary intervention.

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.

Multi-heterostructured MXene/NiS2/Co3S4 with S-Vacancies to Promote Polysulfide Conversion in Lithium-Sulfur Batteries.

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.

FoxO3 Regulates Mouse Bone Mesenchymal Stem Cell Fate and Bone-Fat Balance During Skeletal Aging.

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.

A Bionic Thermosensitive Sustainable Delivery System for Reversing the Progression of Osteoarthritis by Remodeling the Joint Homeostasis.

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.

Circ_0087199 depletion attenuates lipopolysaccharides-induced human periodontal ligament cell injury through the miR-527/TLR4 axis.

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.

Multistage Hydrocarbon Generation of Saline Lacustrine Source Rocks in Hydrous Pyrolysis: Insights from Clay Mineral-Organic Matter Interactions.

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.

Understanding the effect of social media marketing activity for promoting intention to participate in martial arts.

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.

Occlusal deviations in adolescents with idiopathic and congenital scoliosis.

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.

Longitudinal investigation of idiopathic osteosclerosis lesions of the jaws in a group of Chinese orthodontically-treated patients using digital panoramic radiography.

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.

Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.

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.

Inhibition of Endoplasmic Reticulum Stress by 4-Phenyl Butyric Acid Presents Therapeutic Effects on Periodontitis: Experimental Studies In Vitro and in Rats.

This study investigated the probable mechanisms of endoplasmic reticulum (ER) stress involved in periodontitis in vitro and in vivo. We isolated periodontal ligament stem cells from periodontitis patients and healthy controls (P-PDLSCs and H-PDLSCs). To further simulate the periodontal microenvironment in patients, lipopolysaccharide (LPS) was used to treat H-PDLSCs. The results showed that periodontitis-related inflammation gave rise to the upregulated expression levels of ER stress representative genes including GRP78, PERK, ATF4, and CHOP. In contrast, the treatment of 4-phenyl butyric acid (4-PBA) remarkably suppressed ER stress and supported cell viability. The increased secretion of proinflammatory factors like TNF-α, IL-1ß, and IL-6 and the activation of NF-κB pathway were also attenuated by 4-PBA treatment. Moreover, 4-PBA treatment restored the impaired osteogenic differentiation ability of PDLSCs, as demonstrated by the upregulated expression levels of Runx2 and OCN as well as the enhanced Alizarin red staining. Local administration of 4-PBA could rescue alveolar bone resorption of LPS-induced periodontitis rats. Thus, our findings suggested ER stress might act as a promising therapeutic target against periodontitis.

A flexible and highly sensitive pressure sensor based on three-dimensional electrospun carbon nanofibers.

High-performance flexible pressure sensors with high sensitivity are important components of the systems for healthcare monitoring, human-machine interaction, and electronic skin. Herein, a flexible and highly sensitive pressure sensor composed of ferrosoferric oxide (Fe3O4)/carbon nanofibers (FeOCN) was fabricated using three-dimensional electrospinning and further heat treatment methods. The obtained pressure sensor demonstrates a wide working range (0-4.9 kPa) and a high sensitivity of 0.545 kPa-1 as well as an ultralow detection limit of 6 Pa. Additionally, the pressure sensor exhibits a rapid response time, good stability, high hydrophobicity, and excellent flexibility. These merits endow the pressure sensor with the ability to precisely detect wrist pulse, phonation, breathing, and finger bending in real-time. Therefore, the FeOCN pressure sensor presents a promising application in real-time healthcare monitoring.

Flexible and wearable strain sensor based on electrospun carbon sponge/polydimethylsiloxane composite for human motion detection.

Flexible and wearable strain sensors have attracted considerable attention due to their potential applications in human motion detection. In this work, the as-fabricated strain sensor was obtained by encapsulation of electrospun carbon sponge (CS) with polydimethylsiloxane (PDMS). The formation mechanism of the self-assembled sponge has been explored. Meanwhile, the piezoresistive properties and the strain sensing mechanism of the CS/PDMS sensor were investigated. The results showed that the as-fabricated CS/PDMS sensor had high piezoresistive sensibility with a maximum gauge factor up to 130.49, superior stability and fast response to various cyclic loading with a tensile strain from 0% up to 40% and a tensile speed range of 2-18 mm min-1. Finally, all the superior performances endow the sensor with abilities to precisely detect pronunciation, human palm motion, wrist joint motion, elbow joint motion, and finger motion in real-time. These results indicate that the strain sensor based on the CS/PDMS could have promising applications in flexible and wearable devices for human motion detection.

Msx2 plays an important role in BMP6-induced osteogenic differentiation of two mesenchymal cell lines: C3H10T1/2 and C2C12.

Bone morphogenetic proteins (BMPs), have been shown to enhance the osteogenic differentiation of mesenchymal cells (MCs) and to promote bone formation. BMP6 is known to play an important role in the process of MCs towards osteogenic differentiation by virtue of their osteoinductive and cell type specific proliferative activity. However, the molecular mechanism relate to BMP6 osteoinductive activity is still unclear and continues to warrant further investigation. Msx2 is a member of the homeobox gene family of transcription factors and promotes calcification. Hence, we wondered if it might also play a role in BMP6-induced osteogenesis. In this study, two mouse mesenchymal cell lines were treated with BMP6, adenovirus-Msx2 (Ad-Msx2) or adenovirus-siMsx2 (Ad-siMsx2). Based on the results of mRNA and protein expression, it was indicated that BMP6 could enhance the expression of Msx2 and activate the phosphorylation of Smad 1/5/8, p38 and ERK1/2. Being transfected by Ad-Msx2, the BMP6-induced activation of phosphorylation was significantly promoted. On the contrary, two cell lines transfected by Ad-siMsx2 presented an inhibited expression of three phosphorylated proteins even after being induced by BMP6. The evaluation of ALP, OPN, OC and calcium deposits revealed the osteogenic results those were corresponding to the results of mRNA and protein. Taken together, these findings can be a novel viewpoint for the understanding of the mechanisms of BMP6-induced osteogenesis and provide therapeutic targets of bone defect.

Curcumin Nicotinate Selectively Induces Cancer Cell Apoptosis and Cycle Arrest through a P53-Mediated Mechanism.

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.

Effect of tumor necrosis factor α on ability of SHED to promote osteoclastogenesis during physiological root resorption.

Physiological root resorption of deciduous teeth is a normal phenomenon, however, the potential mechanisms underlying this process remain unclear. This study aimed to investigate ability of stem cells from human exfoliated deciduous teeth (SHED) on promoting the osteoclastic differentiation of osteoclast precursors and clarify mechanisms underlying this process in vitro. SHED and dental pulp stem cells (DPSCs) were obtained from deciduous teeth and healthy permanent teeth. An indirect co-culture system of SHED or DPSCs were used. The osteoclast precursor peripheral blood mononuclear cells (PBMCs) were established. Ability of SHED and DPSCs in promoting osteoclastogenesis was determined using triiodothyronine receptor auxiliary protein (TRAP) staining, real-time real-time PCR (RT-PCR) and western blotting. The effect of inflammation on the pro-osteoclastogenesis ability of SHED was determined using enzyme linked immunosorbent assay (ELISA), RT-PCR and western blotting. The function of the nuclear factor-κB (NF-κB) pathway in promoting the osteoclastogenesis ability of SHED was determined using RT-PCR and western blotting. SHED exhibited an increased ability to promote osteoclastic differentiation. Expression of tumor necrosis factor-α (TNF-α) was significantly higher in SHED than in DPSCs. Expression of cathepsin K (CTSK), TRAP, and receptor-activator of nuclear-factor-κ B ligand (RANKL), RANKL/osteoprotegerin (OPG) ratio, and expression of cytoplasmic phosphorylated inhibitor of NF-κB α (p-IκBα) and nuclear p65 were markedly up-regulated in SHED post the TNF-α treatment but decreased following NF-κB inhibition. In conclusion, inflammatory cytokine TNF-α appeared to activate NF-κB pathway to up-regulate expression of NF-κB, enhancing ability of SHED in promoting osteoclastogenesis via regulating RANKL/OPG expression.

Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family.

Marie Unna hereditary hypotrichosis (MUHH) and multiple familial trichoepithelioma (MFT) are both autosomal dominant disorders. Recently, certain genes (HR and EPS8L3) have been found to be responsible for MUHH, while CYLD has been demonstrated to be the main pathogenic gene in MFT patients. However, there exist a number of CYLD mutation-negative MFT cases, for which the causative gene has been unknown. Here, we identified a large, five-generation Han Chinese family with several patients presenting with MUHH and MFT. Sanger sequencing of three genes in 13 family members was performed. We found that the c.1A>G mutation in an inhibitory upstream open-reading frame of HR (U2HR) was present in all MUHH patients, while no pathogenic variants were found in the 3'- or 5'-untranslated regions, exons or flanking intronic sequences of EPS8L3 or CYLD in any family members. Subsequently, whole-genome sequencing was performed for five affected and one unaffected family member. We found no CYLD variants but identified an FABP12 variant (rs536105592 G>A) in the patients with both MUHH and MFT. These results suggest that the U2HR mutation was responsible for MUHH and the FABP12 variant may be coincidental in the accompanying MFT in this unique pedigree. This report deepens our understanding of the genetic basis of hair follicle diseases.

Intracellular Mechanism of Rosuvastatin-Induced Decrease in Mature hERG Protein Expression on Membrane.

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.

A Large-Scale Multicenter Study Validates Aldo-Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma.

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.

Organochlorine pesticides in ambient air from the littoral cities of northern China: Spatial distribution, seasonal variation, source apportionment and cancer risk assessment.

Concentrations, composition and seasonal variations of organochlorine pesticides (OCPs) in the atmosphere (particulate phase and gaseous phase) at coastal cities in northern China were determined. OCP transport from emission source areas and lifetime excess cancer risks by inhalation exposure to specific OCPs were also investigated. The annual average concentration of total OCPs in gaseous phase ranged from 1.0ng/m3 to 6.3ng/m3, with the peak observed in summer at most sites. Particulate phase concentrations ranged from 29.9pg/m3 to 103.3pg/m3, with the maximum found in the local heating period at most locations. The detection rates of gaseous samples were considerably higher than those of particulate ones. The dominant components included endosulfan (I and II), (α- and γ-) chlordane, pentachlorobiphenyl (PeCB), hexachlorobenzene (HCB), heptachlor, (α-, ß- and γ-) hexachlorocyclohexane (HCH), dichloro-diphenyl-trichloroethane (DDT) and their metabolic products. The specific ratios indicated different applications of DDT, technical HCH and endosulfan at most sites. Large differences in compositional profiles occurred in January (typical heating period) and July (representative non-heating period), and diurnal changes in component concentrations may have been influenced by local emission pattern. The potential source contribution function (PSCF) manifested seasonal concentrations of airborne OCPs affected by the input of potential sources in different regions. The emission sources with higher contribution probabilities to the sites were primarily distributed in the surrounding areas. The lifetime excess cancer risks for the local residents by inhalation exposure to specific components were not high, though the potential threat of α-HCH and HCB should be concerned. CAPSULE: Gaseous OCPs reached peak values in summer and dominated relative to particulate (PM10) values; meanwhile, surrounding sources affected air OCP concentrations, and cancer risks of OCPs by inhalation exposure were not high.