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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an emerging regulator in metabolic control. Hypothalamic pro-opimelanocortin (POMC) neurons play critical roles in maintaning whole-body energy homeostasis. Whether MANF in POMC neurons is required for the proper regulation of energy balance remains unknown. Here, we showed that mice lacking MANF in POMC neurons were more prone to develop diet-induced obesity. In addition, the ablation of MANF induced endoplasmic reticulum (ER) stress and leptin resistance in the hypothalamus, reduced POMC expression and post-translational processing, and ultimately decreased sympathetic nerve activity and thermogenesis in brown adipose tissue (BAT). Conversely, MANF overexpression in hypothalamic POMC neurons attenuated ER stress, increased POMC expression and processing, and then stimulated sympathetic innervation and activity in BAT, resulting in increased BAT thermogenesis, thus protecting mice against dietary obesity. Overall, our findings provide evidence that MANF is required for POMC neurons to combat obesity.

Introduction: Stroke due to sickle cell disease is often attributed to large vessel involvement in the disorder. The role of cerebral microvascular disease in sickle cell disease has received little attention. In this study, we examined development of cerebral microvascular lesions in a mouse model of sickle cell disease. We focused on cerebral microhemorrhages, the neuropathologic substrate of cerebral microbleeds. Methods: We studied microvascular disease in a well-characterized mouse model of humanized transgenic sickle (HbSS-BERK) and control (HbAA-BERK) mice expressing >99% human sickle hemoglobin (Hb) and normal human HbA, respectively. HbSS-BERK express human α and βS globins on a mixed genetic background. HbAA-BERK mice express normal human α and βA globin thus producing only normal human hemoglobin A, on the same mixed genetic background as HbSS-BERK. Seven- to nine-month-old mice (N=18 HbSS, N=12 HbAA) were examined. We collected mouse brains and performed standard histology using Prussian blue staining to detect CMH formation at 20x magnification. The average number, total area, and size of Prussian blue-positive deposits were quantified. In separate studies, Toluidine Blue staining was used to identify mast cells. Results: HbSS mice showed approximately 70% more cerebral microhemorrhages than controls (mean±SE of 1.17± 0.22 vs 0.69±0.13 number/cm 2, p=0.04). Lesion size did not differ between HbSS and control mice. Activated mast cells were identified in HbSS mouse brain but not in control mice. Conclusions: In this mouse model of sickle cell disease, HbSS mice demonstrated significantly increased development of cerebral microhemorrhages. These findings emphasize the potential importance of cerebral microvascular disease in sickle cell disease. Cerebral mast cell activation in sickle cell disease may be a novel target for investigation.

Hui Huang,1,2 Qinhui Liu,1 Ting Zhang,2 Jinhang Zhang,1,2 Jian Zhou,1,2 Xiandan Jing,2 Qin Tang,1 Cuiyuan Huang,1,2 Zijing Zhang,1 Yingnan Zhao,1,2 Guorong Zhang,1,2 Jiamin Yan,1,2 Yan Xia,1,2 Ying Xu,1,2 Jiahui Li,1,2 Yanping Li,1 Jinhan He1,2 1Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Yanping LiLaboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaTel +86-28-85164128Email liyanping_512@163.comJinhan HeDepartment of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaTel +86-28-85426416Email jinhanhe@scu.edu.cnBackground: Renal fibrosis is the common pathway in chronic kidney diseases progression to end-stage renal disease, but to date, no clinical drug for its treatment is approved. It has been demonstrated that the inhibitor of proto-oncogene Ras, farnesylthiosalicylic acid (FTS), shows therapeutic potential for renal fibrosis, but its application was hindered by the water-insolubility and low bioavailability. Hence, in this study, we improved these properties of FTS by encapsulating it into bovine serum albumin nanoparticles (AN-FTS) and tested its therapeutic effect in renal fibrosis.Methods: AN-FTS was developed using a classic emulsification-solvent ultrasonication. The pharmacokinetics of DiD-loaded albumin nanoparticle were investigated in SD rats. The biodistribution and therapeutic efficacy of AN-FTS was assessed in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO).Results: AN-FTS showed a uniform spherical shape with the size of 100.6 ± 1.12 nm and PDI < 0.25. In vitro, AN-FTS displayed stronger inhibitory effects on the activation of renal fibroblasts cells NRK-49F than free FTS. In vivo, AN-FTS showed significantly higher peak concentration and area under the concentration-time curve. After intravenous administration to UUO-induced renal fibrosis mice, AN-FTS accumulated preferentially in the fibrotic kidney, and alleviated renal fibrosis and inflammation significantly more than the free drug. Mechanistically, the improved anti-fibrosis effect of AN-FTS was associated with greater inhibition in renal epithelial-to-mesenchymal transformation process via Ras/Raf1/p38 signaling pathway.Conclusion: The study reveals that AN-FTS is capable of delivering FTS to fibrotic kidney and showed superior therapeutic efficacy for renal fibrosis.Keywords: albumin nanoparticle, epithelial–mesenchymal transition, farnesylthiosalicylic acid, Ras, renal fibrosis

Objective Previous studies have established that deficiency in Nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain containing 6 (Nlrp6) changes the configuration of the gut microbiota, which leads to hepatic steatosis. Here, we aimed to determine the hepatic function of Nlrp6 in lipid metabolism and inflammation and its role in the development of non-alcoholic steatohepatitis (NASH). Methods Nlrp6Loxp/Loxp and hepatocyte-specific Nlrp6-knockout mice were fed a high-fat diet (HFD) or methionine-choline deficient (MCD) diet to induce fatty liver or steatohepatitis, respectively. Primary hepatocytes were isolated to further explore the underlying mechanisms in vitro. In addition, we used adenovirus to overexpress Nlrp6 in ob/ob mice to demonstrate its role in NASH. Results Hepatic Nlrp6 expression was downregulated in NASH patients and in obese mice. Hepatocyte-specific Nlrp6 deficiency promoted HFD- or MCD diet-induced lipid accumulation and inflammation, whereas Nlrp6 overexpression in ob/ob mice had beneficial effects. In vitro studies demonstrated that knockdown of Nlrp6 aggravated hepatic steatosis and inflammation in hepatocytes, but its overexpression markedly attenuated these abnormalities. Moreover, both in vitro and in vivo study demonstrated that Nlrp6 inhibited Cd36‐mediated lipid uptake. Nlrp6 deficiency-enhanced fatty acid uptake was blocked by a Cd36 inhibitor in hepatocytes. Nlrp6 ablation increased the expression of proinflammatory cytokines, likely as a result of increased NF-κB phosphorylation and activation. Mechanistically, Nlrp6 promoted the degradation of transforming growth factor-β-activated kinase 1 (TAK1)-binding protein 2/3 (TAB2/3) via a lysosomal-dependent pathway, which suppressed NF-κB activation. Conclusions Nlrp6 may play a key role in the pathological process of NASH by inhibiting Cd36 and NF-κB pathways. It may be a potential therapeutic target for NASH.

Alcoholic fatty liver disease (AFLD) is induced by alcohol consumption and may progress to more severe liver diseases such as alcoholic steatohepatitis, fibrosis and cirrhosis, and even hepatocellular carcinoma. Mesencephalic astrocyte-derived neurotrophic factor (MANF) participates in maintaining lipid homeostasis. However, the role of MANF in the pathogenesis of AFLD remains unclear. We established an AFLD mouse model following the US National Institute on Alcohol Abuse and Alcoholism procedure. Both mRNA and protein levels of MANF were significantly increased in the chronic binge alcohol feeding model. Liver-specific knockout of MANF aggravated hepatic lipid accumulation. Similarly, liver-specific overexpression of MANF alleviated AFLD in mouse livers. MANF affected hepatic lipid metabolism by modulating autophagy. The levels of LC3-II and Atg5-Atg12 were decreased in mouse livers with MANF liver-specific knockout and increased with MANF liver-specific overexpression. Furthermore, MANF changed the phosphorylation of Stat3 and its nuclear localization. MANF may have a protective role in the development of AFLD.

The establishment of sensing platform for trace analysis of Fe3+ in biological systems is meaningful for health monitoring. Herein, a Fe3+ sensitive fluorescent nanoprobe was constructed based on highly fluorescent N-doped carbon quantum dots (NCQDs) derived from bamboo stems through a hydrothermal method employing ethylenediamine as the nitrogen dopant. The prepared NCQDs had a uniformly distributed size and their mean size was around 2.43 nm. Abundant functional groups (C=N, N-H, C=O, and carboxyl) anchored on NCQDs demonstrated successful doping of N in CQDs. The obtained NCQDs possessed a high fluorescence quantum yield of 20.02% and outstanding fluorescence stability over a wide pH range and at high ionic strengths. Moreover, Fe3+ ions presented a specific fluorescent quenching effect to the as-prepared NCQDs. The calibration curve for fluorescence quenching degree corresponding to Fe3+ concentration showed a linear response in a range of 0.01–10 µM, and detection limit was 0.486 µM, which indicated that the NCQDs had high sensitivity to Fe3+ ions. Ascribed to these unique properties, the NCQDs were selected as luminescent probes for trace amount of Fe3+ ions in human serum. These results demonstrated their promising use in clinical diagnostics and other biologically relevant studies.

BACKGROUND The aim of this study was to explore the relationship between C-reactive protein (CRP) and respiratory diseases in patients with diabetic retinopathy. MATERIAL AND METHODS We identified 855 patients with diabetic retinopathy who met the inclusion criteria from the "Diabetes Complications Data Set" in the National Population Health Data Center. We divided patients into 3 groups according to CRP tertiles: Q1 (0.3 mg/dL), Q2 (0.3-0.35 mg/dL), and Q3 (0.35 mg/dL). A multivariate logistic regression model was used to evaluate the relationship between CRP and respiratory diseases. The area under the receiver operating characteristic (ROC) curve was used to investigate the independent predictive effect of CRP on respiratory diseases. RESULTS Of the 855 patients with diabetic retinopathy, 137 (16%) had respiratory diseases. Prevalence of respiratory diseases gradually increased with an increase in CRP level (P for trend=0.001). With CRP as a continuous variable in the logistic regression model adjusted for confounding factors (model 3), the odds ratio (OR) per 1 standard deviation increment of CRP was 1.25 (95% CI 1.07-1.45, P=0.004). When the lowest CRP tertile group was used as the reference group, the OR of the highest CRP tertile group was 1.99 (95% CI 1.22-1.3.26, P=0.006). Adding CRP to the risk factor model increased the area under the ROC curve (0.68 vs 0.65, P=0.017). Subgroup analysis showed that the relationship between CRP and respiratory diseases had no potential heterogeneity among subgroups. CONCLUSIONS CRP can be used as an effective biomarker in predicting risk of respiratory diseases in patients with diabetic retinopathy.

Excessive lipid accumulation, inflammation, and fibrosis in the liver are the major characteristics of non-alcoholic steatohepatitis (NASH). Mesencephalic astrocyte-derived neurotrophic factor (MANF) plays an important role in metabolic homeostasis, raising the possibility that it is involved in NASH. Here, we reduced and increased MANF levels in mice in order to explore its influence on hepatic triglyceride homeostasis, inflammation, and fibrosis during NASH progression. The MANF expression was decreased in Western diet-induced NASH mice. In vivo, liver-specific MANF knockout exacerbated hepatic lipid accumulation, inflammation, and fibrosis of mice induced by Western diet, while liver-specific MANF overexpression mitigated these NASH pathogenic features. In vitro, knocking down MANF in primary hepatocyte cultures aggravated hepatic steatosis and inflammation, which MANF overexpression markedly attenuated. Studies in vitro and in vivo suggested that MANF regulated hepatic lipid synthesis by modulating SREBP1 expression. Inhibiting SREBP1 in primary hepatocytes blocked lipid accumulation after MANF knockdown. MANF overexpression reversed LXRs agonist GW3965 induced SREBP1 and LIPIN1 expression. MANF decreased the expression of pro-inflammatory cytokines by inhibiting NF-κB phosphorylation. These results suggest that MANF can protect against NASH by regulating SREBP1 expression and NF-κB signaling.

Paracetamol (APAP), an over-the-counter drug, is normally safe within the therapeutic dose range but can cause irreversible liver damage after an overdose. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress protein and plays a crucial role in metabolic disease. However, the role of MANF in APAP-induced acute hepatotoxicity is still unknown. We used hepatocyte-specific MANF-knockout mice and hepatocyte-specific MANF transgenic mice to investigate the role of hepatocyte-derived MANF in APAP-induced acute liver injury. MANF deficiency was associated with a decreased expression of detoxification enzymes, aggravated glutathione depletion and apoptosis in hepatocytes. Mechanistically, MANF knockout significantly increased PERK-eIF2α-ATF4-CHOP signaling pathway. Blockade of PERK abolished MANF deficiency-over-induced hepatotoxicity after APAP administration. Conversely, hepatocyte-specific MANF overexpression attenuated APAP-induced hepatotoxicity by downregulating the PERK-eIF2α-ATF4-CHOP signaling pathway. Thus, hepatocyte-derived MANF may play a protective role in APAP-induced hepatotoxicity.

Diapause is a common phenomenon during which organisms suspend development to overcome difficult environmental conditions. The silkworm is a classical model for the study of egg diapause. Our previous study showed that gene expression is similar in silkworm eggs treated with hyperoxia or HCl. In the present study, to further explore the mechanism of diapause prevention, nondiapause eggs and hyperoxia-/HCl-activated diapause eggs were treated with hypoxia. Embryo morphology, hatching time, and reactive oxygen species (ROS) levels were analyzed across different developmental stages. The results showed that hypoxia may inhibit the embryonic development of silkworm eggs. The morphology of nondiapause eggs under hypoxia differed from that of nondiapause eggs under normoxia during embryonic development, which, in turn, was similar to that of diapause eggs. Meanwhile, the hatching time of nondiapause eggs under hypoxia was delayed significantly. Moreover, the ROS levels of nondiapause eggs changed under hypoxia, showing a pattern similar to that of diapause eggs. Interestingly, when activated diapause eggs were treated with hypoxia, some eggs hatched in the following spring. These results suggest that early embryogenesis is largely dependent on oxygen levels and that hypoxia may induce a diapause-like state in activated diapause eggs. Additionally, ROS levels may play a key role in diapause. Thus, this study provides valuable information on the mechanisms of diapause and diapause prevention in silkworms.

Insect serum proteins, also termed storage proteins (SPs), are hexamer proteins that form amino acid reservoirs important for the development of pupae and embryos in most insects. In this study, we investigated the SP genes expression and regulation pathways in silkworms (Bombyx mori). We observed that B. mori SPs (BmSPs) in the fat body of larvae were strongly decreased by starvation, suggesting they respond to nutrition deprivation. Further, we examined the relationship between BmSP expression and the insulin-like signaling pathway (ILS) to study the regulation of BmSPs expression. The results showed that insulin up-regulated the expression of BmSPs, but an inhibitor of the ILS pathway protein PI3K downregulated the expression of BmSPs in B. mori larvae. Similar results were observed in cultured fat body in vitro and BmE cells. We then over-expressed FoxO, an ILS transcriptional factor, in BmE cells and B. mori larvae to further verify the regulatory role of ILS on expression of BmSPs and found BmFoxO negatively regulates the expression of BmSPs in both BmE cells and larvae. Moreover, BmFoxO was dephosphorylated and translocated from the cytoplasm to the nucleus under starvation treatment. Finally, an element on -2627-2644 bp upstream of the transcription start site of BmSP1 was identified as the binding site of BmFoxO by electrophoretic mobility shift assay and verified by chromatin immunoprecipitation. In summary, our results indicate that nutrient uptake triggers the expression of BmSPs via the ILS/FoxO signaling pathway. This study provides a reference for further study on the expression and regulation of insect SP genes.

The establishment of sensing platform for trace analysis of Fe

Sirtuin 6 (Sirt6), a member of the Sirtuin family, has important roles in maintaining glucose and lipid metabolism. Our previous studies demonstrated that the deletion of Sirt6 in pro-opiomelanocortin (POMC)-expressing cells by the loxP-Cre system resulted in severe obesity and hepatic steatosis. However, whether overexpression of Sirt6 in hypothalamic POMC neurons could ameliorate diet-induced obesity is still unknown. Thus, we generated mice specifically overexpressing Sirt6 in hypothalamic POMC neurons (PSOE) by stereotaxic injection of Cre-dependent adeno-associated viruses into the arcuate nucleus of Pomc-Cre mice. PSOE mice showed increased adiposity and decreased energy expenditure. Furthermore, thermogenesis of BAT and lipolysis of WAT were both impaired, caused by reduced sympathetic nerve innervation and activity in adipose tissues. Mechanistically, Sirt6 overexpression decreasing STAT3 acetylation, thus lowering POMC expression in the hypothalamus underlined the observed phenotypes in PSOE mice. These results demonstrate that Sirt6 overexpression specifically in the hypothalamic POMC neurons exacerbates diet-induced obesity and metabolic disorders via the hypothalamus-adipose axis.

According to the definition of the Doppler effect, walking and running can generate the frequency shift when the human target is moving forth or back with respect to the radar sensor. Compared with walking and running, the periodic body movement (i.e. breathing and heartbeat) and non-periodic body movement cause the microDoppler effect. The vital sign-induced micro-Doppler effect, which is also called vital Doppler [1], has been widely used for radar-based non-contact vital sign detection. Various types of radar sensors have been developed for non-contact vital sign detection including single-carrier continuous-wave (CW) Doppler radar, frequency-modulated CW radar, stepped frequency CW radar and ultra-wideband radar [2-6]. The homodyne CW Doppler radar is widely used due to its simple structure and low cost [2]. However, it encounters several problems such as quadrature channel imbalance and DC offset [2]. Fortunately, the digital receiver with direct intermediate-frequency (IF)-to-digital conversion (IF sampling) is a suitable alternative [7-13]. In this chapter, the principle of the digital-IF Doppler radar is introduced. Then, the radio frequency (RF) layer, IF layer and optimised baseband signal processing are discussed. Recently, developed from the conventional application of vital sign detection, the digital-IF Doppler radar is widely applied for healthcare sensing. The digital-IF Doppler radar can not only work as a single sensor but also serve as a sensor in the multi-sensor network. After the introduction of radar sensor, two applications, i.e. non-contact beat-to-beat blood pressure (BP) estimation and multi-sensor-based sleep-stage classification, are briefly introduced.

The midbrain is a subcortical area involved in central functions such as integrating sensory modalities, movement initiation and bottom-up and top-down attention. In chicken, the midbrain roof is termed optic tectum (TeO) and consists of 15 layers with distinct in- and output regions. Visual input targets the superficial layers, while auditory input terminates in deeper layers. It has been shown that ablation of sensory epithelia leads to changes in the cellular patterning and structural organization of the sensory pathways. For the tectum, ablation of the eye anlagen was shown to affect retinorecipient neurons. While the gross morphology remained intact after enucleation, the shape of dendritic endings was changed presumably due to missing presynaptic input during synaptic pruning. We investigated the effect of deafferentation in a multisensory cell type, the Shepherd's crook neuron (SCN) in the TeO. SCNs have distinct dendritic branches in retinorecipient layers (superficial layers 1 to 5 and 7) and in layers where auditory input terminates. To assess whether removal of a single sensory input only affects the dendrites recipient for that input, we removed the eye anlagen and retrogradely labeled SCNs later in embryogenesis to visualize the morphology in lesioned and non-lesioned embryos. We found no changes in the gross morphology or in the basal dendrites, but an altered growth of the fine structures at the apical dendrite of SCNs in the retinorecipient layers. Our data indicate that the neuronal morphology of SCNs is mostly predefined before retinal innervation affect the fine structure.

Intrauterine hypoxia (IUH) is a common intrauterine dysplasia that can cause programming of the offspring cardiovascular system. In this study, we hypothesized that placental treatment with spermidine (SPD) can prevent heart injury in neonatal offspring exposed to IUH. Pregnant rats were exposed to 21% O

Thermal transfer enhanced multifunctional energy conversion form-stabilized composite phase change materials (PCMs) present attractive research prospects for the energy management materials. However, complicated preparation, unsatisfied heat storage capacity and limited thermal transfer enhancement restrict their application. In this work, high-performance thermal transfer enhanced composited PCMs are facilely prepared via integration of polypyrrole/Fe3O4- functionalized hollow kapok fiber (KF) aerogel supports with paraffin wax (PW). The prepared composite PCMs achieve high thermal storage density (melting enthalpy of 161.4 J/g for the PW load mass fractions of 88%), greatly enhancement of thermal conductivity (1.06 W/m K, 307% higher than pristine PW) and outstanding cycling thermal stability. The hollow kapok fiber aerogel supports prevent the leakage and improve loading amount, and also endow the renewable and pollution-free features for the composite PCMs, which provides great potential for the commercial application on a large scale. Simultaneously, the continuous polypyrrole (PPy) dual coating and Fe3O4 nanoparticles endow the composite PCMs not only with excellent thermal conductivity, but also with solar /magnetic- thermal energy conversion characteristics which enriches the energy storage source of the materials.

Green synthesis and the adjustable microwave attenuation capability are crucial for the microwave absorption materials. In this paper, we report a green metal-sericin complexation method to synthesize the core-shell structured multicomponent alloy/carbon nanocomposites. The experimental characterizations demonstrate that by controlling the chemical compositions the alloy nanoparticles can be uniformly embedded in the carbon shell, forming a unique heterostructure that is able to enhance the dielectric loss of the nanocomposites. In specific, the optimized 1.49 mm-thick FeCoNiZn alloy@carbon nanocomposite exhibits the minimum reflection loss (RLmin) of −54.46 dB at 16.65 GHz and the 1.62 mm-thick one shows the maximum effective bandwidth (RL ≤−10 dB) of 4.19 GHz. Notably, the robust heterostructure of the synthesized nanocomposite leads to the synergistic effect of the impedance matching and the multi-loss mechanisms that involve the conduction loss, dielectric loss, and the magnetic loss, resulting in the enhanced microwave absorption performance. In short, this experimental work presents a novel and green fabrication method for constructing the magnetic metal/carbon absorbers. Based on their remarkable and adjustable microwave absorption performance, we envision the great potential applications of the FeCoNiZn alloy/carbon nanocomposite.

Background Our objective was to evaluate the prevalence and different diagnostic methods of breastmilk (BM)‐acquired cytomegalovirus (CMV) infection in a pathologically jaundiced cohort. Methods A total of 400 infants confirmed with pathological jaundice at The People's Hospital of Qingyang City were screened for BM‐acquired CMV infection between February 2018 and February 2019. A total of 300 infants were finally enrolled in our study. CMV infection was confirmed by detecting both CMV‐DNA in various samples using FQ‐PCR and CMV‐IgM with chemiluminescence. Clinical and other laboratory data were collected from these infants during their hospitalization or regular visits. Results Ninety‐eight (32.67%) subjects were confirmed to be BM CMV‐DNA–positive, and 18 (18.37%) were diagnosed with a BM‐acquired CMV infection. All 18 (100%) infants with a BM‐acquired CMV infection were CMV‐DNA–positive in urine, while 5 (27.78%) cases and 11 (61.11%) cases were confirmed in plasma and peripheral blood mononuclear cells (PBMCs), respectively. Only 6 (33.33%) infants were CMV‐IgM–positive. Birthweight, direct bilirubin, aspartate aminotransferase, and the viral load in BM of the BM‐acquired CMV group were higher than those in the non‐infected group (P

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are widely used because of their excellent anti-inflammatory and analgesic effects. However, NSAIDs could cause certain cardiac side effects, such as myocardial infarction, heart failure, atrial fibrillation, arrhythmia and sudden cardiac death. Therefore, meloxicam, nimesulide, piroxicam, and diclofenac were selected and the whole cell patch clamp technique was used to investigate the electrophysiological regulatory effects of them on the sodium channel hNav1.5 and potassium channel hKv11.1, which were closely associated to the biotoxicity of cardiac, and to explore the potential cardiac risk mechanism. The results showed that the four NSAIDs could inhibit the peak currents of hNav1.5 and hKv11.1. Furthermore, the four NSAIDs could affect both the activation and inactivation processes of hNav1.5 with I-V curves left-shifted to hyperpolarized direction in activation phase. These data indicate that the inhibition effects of Nav1.5 and Kv11.1 by meloxicam, nimesulide, piroxicam, and diclofenac might contribute to their potential cardiac risk. These findings provide a basis for the discovery of other potential cardiac risk targets for NSAIDs.