Acetylshikonin (ASK) is a natural naphthoquinone derivative of traditional Chinese medicine Lithospermum erythrorhyzon. It has been reported that ASK has bactericidal, anti‐inflammatory and ...antitumour effects. However, whether ASK induces apoptosis and autophagy in acute myeloid leukaemia (AML) cells and the underlying mechanism are still unclear. Here, we explored the roles of apoptosis and autophagy in ASK‐induced cell death and the potential molecular mechanisms in human AML HL‐60 cells. The results demonstrated that ASK remarkably inhibited the cell proliferation, viability and induced apoptosis in HL‐60 cells through the mitochondrial pathway, and ASK promoted cell cycle arrest in the S‐phase. In addition, the increased formation of autophagosomes, the turnover from light chain 3B (LC3B) I to LC3B II and decrease of P62 suggested the induction of autophagy by ASK. Furthermore, ASK significantly decreased PI3K, phospho‐Akt and p‐p70S6K expression, while enhanced phospho‐AMP‐activated protein kinase (AMPK) and phospho‐liver kinase B1(LKB1) expression. The suppression of ASK‐induced the conversion from LC3B I to LC3B II caused by the application of inhibitors of AMPK (compound C) demonstrated that ASK‐induced autophagy depends on the LKB1/AMPK pathway. These data suggested that the autophagy induced by ASK were dependent on the activation of LKB1/AMPK signalling and suppression of PI3K/Akt/mTOR pathways. The cleavage of the apoptosis‐related markers caspase‐3 and caspase‐9 and the activity of caspase‐3 induced by ASK were markedly reduced by inhibitor of AMPK (compound C), an autophagy inhibitor 3‐methyladenine (3‐MA) and another autophagy inhibitor chloroquine (CQ). Taken together, our data reveal that ASK‐induced HL‐60 cell apoptosis is dependent on the activation of autophagy via the LKB1/AMPK and PI3K/Akt‐regulated mTOR signalling pathways.
Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the ...occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.
Background The neuroprotective role of propofol (PPF) in cerebral ischemia-reperfusion (I/R) has recently been highlighted. This study aimed to explore whether the neuroprotective mechanisms of PPF ...were linked to its regulation of Ca2+/CaMKKβ (calmodulin-dependent protein kinase kinase β)/AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin)/autophagy pathway. Methods Cultured primary rat cerebral cortical neurons were treated with oxygen-glucose deprivation and re-oxygenation (OGD/R) to mimic cerebral I/R injury in vitro. Results Compared with the control neurons, OGD/R exposure successfully induced neuronal I/R injury. Furthermore, OGD/R exposure notably caused autophagy induction, reflected by augmented LC3-II/LC3-I ratio and Beclin 1 expression, decreased p62 expression, and increased LC3 puncta formation. Moreover, OGD/R exposure induced elevation of intracellular Ca2+ concentration (Ca2+i). However, PPF treatment significantly antagonized OGD/R-triggered cell injury, autophagy induction, and Ca2+i elevation. Further investigation revealed that both autophagy induction by rapamycin and Ca2+i elevation by the Ca2+ ionophore ionomycin significantly reversed the PPF-mediated amelioration of OGD/R-triggered cell injury. Importantly, ionomycin also significantly abrogated the PPF-mediated suppression of autophagy and CaMKKβ/AMPK/mTOR signaling in OGD/R-exposed neurons. Additionally, activation of CaMKKβ/AMPK/mTOR signaling abrogated the PPF-mediated autophagy suppression. Conclusion Our findings demonstrate that PPF antagonized OGD/R-triggered neuronal injury, which might be mediated, at least in part, via inhibition of autophagy through Ca2+/CaMKKβ/AMPK/mTOR pathway.
Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently ...been reported to improve glycaemic control in patients with type 2 diabetes in an insulin-independent manner. The aim of this study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice.
Thirty diabetic KK-Ay mice were administered empagliflozin (10 mg/kg/day) by oral gavage daily for 8 weeks. After 8 weeks, heart structure and function were evaluated by echocardiography. Oxidants and antioxidants were measured and cardiac fibrosis was analysed using immunohistochemistry, Masson's trichrome stain and Western blot.
Results showed that empagliflozin improved diabetic myocardial structure and function, decreased myocardial oxidative stress and ameliorated myocardial fibrosis. Further study indicated that empagliflozin suppressed oxidative stress and fibrosis through inhibition of the transforming growth factor β/Smad pathway and activation of Nrf2/ARE signaling.
Glycaemic control with empagliflozin significantly ameliorated myocardial oxidative stress injury and cardiac fibrosis in diabetic mice. Taken together, these results indicate that the empagliflozin is a promising agent for the prevention and treatment of diabetic cardiomyopathy.
Detecting infrared small targets lacking texture and shape information in cluttered environments is extremely challenging. With the development of deep learning, convolutional neural network ...(CNN)-based methods have achieved promising results in generic object detection. However, existing CNN-based methods with pooling layers may lose the targets in the deep layers and, thus, cannot be directly applied for infrared small target detection. To overcome this problem, we propose an enhanced asymmetric attention (EAA) U-Net. Specifically, we present an efficient and powerful EAA module that uses both same-layer feature information exchange and cross-layer feature fusion to improve feature representation. In the proposed approach, spatial and channel information exchanges occur between the same layers to reinforce the primitive features of small targets, and a bottom-up global attention module focuses on cross-layer feature fusion to enable the dynamic weighted modulation of high-level features under the guidance of low-level features. The results of detailed ablation studies empirically validate the effectiveness of each component in the network architecture. Compared to state-of-the-art methods, the proposed method achieved superior performance, with an intersection-over-union (IoU) of 0.771, normalised IoU (nIoU) of 0.746, and F-area of 0.681 on the publicly available SIRST dataset.
Excessive mitochondrial fission was observed in diabetic kidney disease (DKD). Phosphoglycerate mutase family member 5 (PGAM5) plays an important role in mitochondrial fission by dephosphorylating ...the dynamin-related protein 1 at Ser637 (DRP1S637). Whether PGAM5 participates in the mitochondrial fission in diabetic renal tubular injury is unknown. Clinical trials have observed encouraging effect of Sodium-glucose cotransporter 2 (SGLT2) inhibitors on DKD though the underling mechanisms remain unclear.
We used KK-Ay mice as diabetic model and Empagliflozin (Empa) were administrated by oral gavage. The mitochondrial fission and the expressions of phosphorylated AMP-activated protein kinase (p-AMPK), specificityprotein1 (SP1), PGAM5 and DRP1S637 were tested. We also examined these changes in HK2 cells that cultured in normal glucose (NG), high glucose (HG) and high glucose+Empa (HG + Empa) environment. Then we verified our deduction using AMPK activator (5-aminoimidazole-4-carboximide Riboside, AICAR), inhibitor (Compound C), si-SP1 and si-PGAM5. Lastly, we testified the interaction between SP1 and the PGAM5promotor by CHIP assay.
The mitochondrial fission and the expression of SP1, PGAM5 increased and the expression of p-AMPK, DRP1S637 decreased in diabetic or HG environment. These changes were all reversed in Empa or AICAR treated groups. These reversal effects of Empa could be diminished by Compound C. Either si-SP1 or si-PGAM5 could alleviate the mitochondrial fission without affection on AMPK phosphorylation. Finally, the CHIP assay confirmed the interaction between SP1 and the PGAM5 promotor.
The PGAM5 aggravated the development of diabetic renal tubular injury and the Empa could improve the DKD by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway.
•The present paper demonstrated that the PGAM5 aggravated the mitochondrial fission in the development of diabetic renal tubular injury in KK-Ay mice, and Empa could improve the DKD by recovering the mitochondrial homeostasis via AMPK/SP1/PGAM5 pathway.•The present study depicted a PGAM5 involved mitochondrial fission pathway in DKD.•Our finding not only revealed a new prospective therapeutic target for DKD but also provided the experimental and theoretical basis for the expansion of new indications of Empa.
Time difference of arrival (TDoA) based on a group of sensor nodes with known locations has been widely used to locate targets. Two-step weighted least squares (TSWLS), constrained weighted least ...squares (CWLS), and Newton-Raphson (NR) iteration are commonly used passive location methods, among which the initial position is needed and the complexity is high. This paper proposes a hybrid firefly algorithm (hybrid-FA) method, combining the weighted least squares (WLS) algorithm and FA, which can reduce computation as well as achieve high accuracy. The WLS algorithm is performed first, the result of which is used to restrict the search region for the FA method. Simulations showed that the hybrid-FA method required far fewer iterations than the FA method alone to achieve the same accuracy. Additionally, two experiments were conducted to compare the results of hybrid-FA with other methods. The findings indicated that the root-mean-square error (RMSE) and mean distance error of the hybrid-FA method were lower than that of the NR, TSWLS, and genetic algorithm (GA). On the whole, the hybrid-FA outperformed the NR, TSWLS, and GA for TDoA measurement.
Quality of life (QoL) is one of the most important indicators for evaluating an individual's overall health status. However, evidence exploring the trend in QoL of the Chinese population is still ...lacking. This study aimed to investigate the trend in QoL of the Chinese population measured by the EQ-5D from 2008 to 2020, as well as compare the changing trends in QoL categorized by populations with different socio-demographic characteristics.
Data were obtained from the 2008, 2013, and 2020 waves of the Health Services Surveys conducted in Tianjin, China. Respondents completed the EQ-5D (EQ-5D-3L in 2008 and 2013 and EQ-5D-5L in 2020) through face-to-face interviews or self-administration. Responses of the EQ-5D-3L in 2008 and 2013 were mapped onto the EQ-5D-5L responses, and then converted to utility values using the Chinese value set. The trend in QoL was explored by comparing the percentage of any reported problems on each EQ-5D dimension and the corresponding utility values across the three waves. Subgroup analyses were performed to compare trends in utility values stratified by socio-demographic indicators. The effect of the time variable (year) on utility values was assessed by multiple linear regression analyses using the pooled data.
By analyzing and comparing the three waves of the data (N = 25,939 in the 2008 wave, N = 22,138 in 2013, and N = 19,177 in 2020), an upward trend was observed in the percentages of reporting problems on all five dimensions (p < 0.001), resulting in a decreasing trend in utility values (2008: 0.948, 2013: 0.942, 2020: 0.939, p < 0.001). Utility values declined more over time among the female, the elder, the recipients of medical assistance, the widowed, the unemployed, and respondents with primary or lower education. The effect of the year (Coef. for 2013 = - 0.009, p < 0.001; Coef. for 2020 = - 0.010, p < 0.001) confirmed the downward trend in the utility values.
The overall QoL of the Chinese population decreased over the period from 2008 to 2020. The QoL of the disadvantaged or vulnerable populations in terms of socioeconomic characteristics declined more over time.
This paper presents a novel method for movement disorder detection using a single Kinect sensor. Numerous recent studies have focused on gait analysis involving spatiotemporal parameters, such as the ...step length and gait cycle. However, these methods ignore significant kinematic information, e.g., leg swing characteristics. Therefore, in this paper, we 1) introduce a new concept called gait symmetry to measure the similarity of leg swing motions using the correlation among the angles formed by the hip, knee, and ankle joints; 2) extract the step length and gait cycle using a zero-crossing detection method; and 3) explore the K-means and Bayesian methods to conduct a combined gait analysis using the three extracted gait parameters. In addition, to reduce the effects of walking differences related to age and gender, we conduct a gait analysis of different age and gender groups. In our experiments, we collect a data set consisting of data from 120 participants (50 with disordered walking patterns and 70 with normal walking patterns). The experimental results show that 1) including the proposed gait symmetry parameter greatly improves detection accuracy, 2) joint utilization of the three gait parameters can enable significantly better performance, and 3) considering age and gender information can enable more robust detection.
The detection of small infrared targets lacking texture and shape information in the presence of complex background clutter is a challenge that has attracted considerable research attention in recent ...years. Typical deep learning-based target detection methods are designed with deeper network structures, which may lose targets in the deeper layers and cannot directly be used for small infrared target detection. Therefore, we designed the attention fusion feature pyramid network (AFFPN) specifically for small infrared target detection. Specifically, it consists of feature extraction and feature fusion modules. In the feature extraction stage, the global contextual prior information of small targets is first considered in the deep layer of the network using the atrous spatial pyramid pooling module. Subsequently, the spatial location and semantic information features of small infrared targets in the shallow and deep layers are adaptively enhanced by the designed attention fusion module to improve the feature representation capability of the network for targets. Finally, high-performance detection is achieved through the multilayer feature fusion mechanism. Moreover, we performed a comprehensive ablation study to evaluate the effectiveness of each component. The results demonstrate that the proposed method performs better than state-of-the-art methods on a publicly available dataset. Furthermore, AFFPN was deployed on an NVIDIA Jetson AGX Xavier development board and achieved real-time target detection, further advancing practical research and applications in the field of unmanned aerial vehicle infrared search and tracking.
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