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The importance of ferroptosis in the occurrence and progression of atherosclerosis is gradually being recognized. The stimulatory G protein α subunit (Gsα) plays a crucial role in the physiology of endothelial cells (ECs). Our previous study showed that endothelial Gsα could regulate angiogenesis and preserve endothelial permeability. In this study, we investigated whether endothelial Gsα contributed to atherosclerosis through ferroptosis and oxidative stress. We generated endothelial Gsα-specific knockout mice in apolipoprotein E-deficient (ApoE -/- ) background (ApoE -/- Gsα ECKO ), and found that the mice exhibited aggravated atherosclerotic lesions and signs of ferroptosis compared with their wild-type littermates (ApoE -/- Gsα fl/fl ). In human aortic endothelial cells (HAECs), overexpression of Gsα reduced lipid peroxidation and ferroptosis, whereas Gsα knockdown exacerbated oxidative stress and ferroptosis. Further, Gsα overexpression in HAECs increased the expression of antioxidant genes nuclear factor erythroid 2-related 2 (NRF2) and its downstream genes. Gsα regulated the expression of NRF2 through CCCTC-binding factor (CTCF). In conclusion, this study has revealed that Gsα acts as a defense factor against endothelial ferroptosis and is a potential target for the treatment of atherosclerosis and associated ischemic heart disease. A model depicting the increase in the endothelial Gsα protein level in response to atherosclerotic stimuli. Gsα regulates NRF2 expression through cAMP/Epac/CTCF-mediated transcription and inhibits ferroptosis. Endothelial Gsα deficiency alleviates antioxidative stress and exacerbates atherosclerosis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy and the only curable therapy is allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, allo-HSCT is not appropriate for all CMML patients, and relapse is the leading cause of treatment failure. This project conducted a nationwide multicenter real-world study to develop a novel prediction scoring system for early relapse. A total of 238 CMML patients from twenty-seven medical centers treated with allo-HSCT, and 307 adult patients with CMML who underwent allo-HSCT in a publicly available research dataset from the Center for International Blood and Marrow Transplantation Registry (CIBMTR) database were included. Independent prognostic factors for the early relapse of CMML posttransplantation were identified according to competing risk regression methods. Four prognostic factors were identified: bone marrow blasts >10% (hazard ratio [HR], 4.262; P = 0.014), age >60 years (HR, 6.221; P = 0.007), hemoglobin level <100 g/L (HR, 3.695; P = 0.004), and non TET2 gene mutation (HR, 3.425; P = 0.017). A risk-grading scoring system was developed based on the regression coefficients and patients were stratified into low-risk (0-1 point), intermediate-risk (1.5-2 points) and high-risk ( > 2 points) groups. The validated internal c-statistic was 0.767 (95% confidence interval [CI], 0.674-0.860), and the external c-statistic was 0.769 (95% CI, 0.703-0.836). In the derivation cohort, the cumulative incidence rates of early relapse in the low-risk, intermediate-risk, and high-risk groups were 1.35% (95% CI: 1-4%), 10.40% (95% CI: 4-16%), and 29.54% (95% CI: 16-39%) (P < 0.001), respectively. This scoring system can be utilized to early identification of patients at a high risk of relapse and contributing to the implementation of urgent medical support., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Knee osteoarthritis (KOA) usually leads to quadriceps femoris atrophy, which in turn can further aggravate the progression of KOA. Curcumin (CUR) has anti-inflammatory and antioxidant effects and has been shown to be a protective agent for skeletal muscle. CUR has been shown to have a protective effect on skeletal muscle. However, there are no studies related to whether CUR improves KOA-induced quadriceps femoris muscle atrophy. We established a model of KOA in rats. Rats in the experimental group were fed CUR for 5 weeks. Changes in autophagy levels, reactive oxygen species (ROS) levels, and changes in the expression of the Sirutin3 (SIRT3)-superoxide dismutase 2 (SOD2) pathway were detected in the quadriceps femoris muscle of rats. KOA led to quadriceps femoris muscle atrophy, in which autophagy was induced and ROS levels were increased. CUR increased SIRT3 expression, decreased SOD2 acetylation and ROS levels, inhibited the over-activation of autophagy, thereby alleviating quadriceps femoris muscle atrophy and improving KOA. CUR has a protective effect against quadriceps femoris muscle atrophy, and KOA is alleviated after improvement of quadriceps femoris muscle atrophy, with the possible mechanism being the reduction of ROS-induced autophagy via the SIRT3-SOD2 pathway., (© 2024. The Author(s).)

To explore the effects of foot reflexology massage on anxiety, pain, duration of labor, labor satisfaction, blood pressure, pulse rate and respiratory rate in pregnant women. We systematically searched eight databases for randomized controlled studies on the effects of foot reflexology massage on pregnant women. The inclusion criteria were as follow: participants were pregnant woman; the intervention is foot reflexology or foot massage; the control intervention is placebo, usual care, or no intervention; outcome indicators included pain, anxiety, birth satisfaction, duration of labor, blood pressure, pulse, and respiration; and study type was randomized controlled study. Studies that did not meet the above requirements were excluded. We assessed the quality of the included studies using the Physiotherapy Evidence Database scale, the risk of bias using the Risk of Bias 2.0 tool, and the level of evidence for the outcomes using the Grading of Recommendations Assessment Development and Evaluation. We used Review Manager 5.3 for data analysis and generated funnel plots to assess publication bias. In addition, sensitivity analysis was used to test the stability of the results. A total of 13 randomized controlled studies with 1189 participants were included in this study. Compared to the control group, foot reflexology massage reduced anxiety and pain in pregnant women, shortened the three stages of labor, and increased birth satisfaction. In addition, it also reduced the pulse rate and respiratory rate of pregnant women, but not for blood pressure. Foot reflexology massage can significantly reduce anxiety and pain, shorten the duration of labor, increase birth satisfaction, and stabilize vital signs in pregnant women. It is a safe and non-invasive form of complementary therapy.PROSPERO registered number: CRD42022359641. URL: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=359641 ., (© 2024. The Author(s).)

To investigate the effects of rapeseed oil on body composition, blood glucose and lipid metabolism in people with overweight and obesity compared to other cooking oils. We searched eight databases for randomized controlled studies (including randomized crossover trials). The risk of bias for the included studies was assessed using the Cochrane Risk of Bias 2.0 tool. The Grading of Recommendations Assessment Development and Evaluation (GRADE) criteria were used to evaluate the quality of the outcomes. The methodological quality of the included studies was assessed using the Physiotherapy Evidence Database (PEDro) scale. Sensitivity analysis was used to check the stability of the pooled results. Statistical analysis was carried out using Review Manager 5.3 software. As a result, fifteen randomized controlled studies (including six parallel studies and nine crossover studies) were included in this study. Compared to other edible oils, rapeseed oil significantly reduced low density lipoprotein cholesterol (LDL-C) (MD = -0.14 mmol/L, 95% CI: -0.21, -0.08, I 2  = 0%, P < 0.0001), apolipoprotein B (ApoB) (MD = -0.03 g/L, 95% CI: -0.05, -0.01, I 2  = 0%, P = 0.0003), ApoB/ApoA1 (MD = -0.02, 95% CI: -0.04, -0.00, I 2  = 0%, P = 0.02) and insulin (MD = -12.45 pmol/L, 95% CI: -19.61, -5.29, I 2  = 37%, P = 0.0007) levels, and increased fasting glucose (MD = 0.16 mmol/L, 95% CI: 0.05, 0.27, I 2  = 27%, P = 0.003) levels. However, the differences in body weight and body composition between rapeseed oil and control oils were not significant. In a word, rapeseed oil is effective in reducing LDL-C, ApoB and ApoB/ApoA1 levels in people with overweight and obesity, which is helpful in preventing and reducing the risk of atherosclerosis. PROSPERO registration number: CRD42022333436., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

CD4 + T cells, particularly IL-17-secreting helper CD4 + T cells, play a central role in the inflammatory processes underlying autoimmune disorders. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is pivotal in CD8 + T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension. However, its specific immunological role in CD4 + T cell activities and related inflammatory diseases remains elusive. Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4 + T cells, impairs their ability to secrete cytokines. Notably, this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17, fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4 + T cells. Furthermore, the absence of eEF2K in CD4 + T cells is linked to increased metabolic activity and mitochondrial bioenergetics. We have shown that eEF2K regulates mitochondrial function and CD4 + T cell activity through the upregulation of the transcription factor, signal transducer and activator of transcription 3 (STAT3). Crucially, the deficiency of eEF2K exacerbates the severity of inflammation-related diseases, including rheumatoid arthritis, multiple sclerosis, and ulcerative colitis. Strikingly, the use of C188-9, a small molecule targeting STAT3, mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout (KO) CD4 + T cells. These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4 + T cells and its indispensable involvement in inflammation-related diseases. Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders., (© 2023. West China Hospital, Sichuan University.)

Pharmacological manipulation of mGluR5 has showed that mGluR5 is implicated in the pathophysiology of anxiety and mGluR5 has been proposed as a potential drug target for anxiety disorders. Nevertheless, the mechanism underlying the mGluR5 involvement in stress-induced anxiety-like behavior remains largely unknown. Here, we found that chronic restraint stress induced anxiety-like behavior and decreased the expression of mGluR5 in hippocampal CA1. Specific knockdown of mGluR5 in hippocampal CA1 pyramidal neurons produced anxiety-like behavior. Furthermore, both chronic restraint stress and mGluR5 knockdown impaired inhibitory synaptic inputs in hippocampal CA1 pyramidal neurons. Notably, positive allosteric modulator of mGluR5 rescued stress-induced anxiety-like behavior and restored the inhibitory synaptic inputs. These findings point to an essential role for mGluR5 in hippocampal CA1 pyramidal neurons in mediating stress-induced anxiety-like behavior., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

The association between nonalcoholic fatty liver disease (NAFLD) and sarcopenia is known. We aimed to determine the association between skeletal muscle mass changes and NAFLD status. This retrospective single-center study analyzed patients who underwent health screening twice between November 2009 and December 2017, with a temporal gap of 6 ± 0.5 years. The degree of sarcopenia was assessed using appendicular skeletal muscle mass (ASM) adjusted for weight and body mass index (BMI). Changes in hepatic steatosis and fibrosis status were evaluated using noninvasive serum markers. Patients with a decrease in ASM/BMI (n = 353) had increased hepatic steatosis index (HSI) and fatty liver index (FLI) scores during 6 years (p < 0.05). The baseline sarcopenia group had a greater elevation in NAFLD fibrosis score (NFS) over 6 years than those without baseline sarcopenia. ASM changes over 6 years showed a negative correlation with variations in HSI (β = - 0.96 in ASM/Weight and -28.93 in ASM/BMI) and FLI (β = - 5.44 in ASM/Weight and - 167.12 in ASM/BMI). Subgroup analyses showed similar results according to sex and age. Sarcopenia may worsen steatosis and vice versa. Skeletal muscle status can be used to predict the course of NAFLD and establish individualized treatment strategies., (© 2023. The Author(s).)

In binocular animals that exhibit stereoscopic visual responses, the axons of retinal ganglion cells (RGCs) connect to brain areas bilaterally by forming a commissure called the optic chiasm (OC). Ventral anterior homeobox 1 (Vax1) contributes to the formation of the OC, acting endogenously in optic pathway cells and exogenously in growing RGC axons. Here, we generated Vax1 AA/AA mice expressing the Vax1 AA mutant, which is incapable of intercellular transfer. We found that RGC axons cannot take up Vax1 AA protein from the Vax1 AA/AA mouse optic stalk (OS) and grow slowly to arrive at the hypothalamus at a late stage. The RGC axons of Vax1 AA/AA mice connect exclusively to ipsilateral brain areas after failing to access the midline, resulting in reduced visual acuity and abnormal oculomotor responses. Overall, our study provides physiological evidence for the necessity of intercellular transfer of Vax1 and the importance of the bilateral RGC axon projection in proper visuomotor responses., (© 2023. The Author(s).)

A localized nanoparticle insertion scheme is developed to decouple electron injection from laser evolution in laser wakefield acceleration. Here we report the experimental realization of a controllable electron injection by the nanoparticle insertion method into a plasma medium, where the injection position is localized within the short range of 100 μm. Nanoparticles were generated by the laser ablation process of a copper blade target using a 3-ns 532-nm laser pulse with fluence above 100 J/cm 2 . The produced electron bunches with a beam charge above 300 pC and divergence of around 12 mrad show the injection probability over 90% after optimizing the ablation laser energy and the temporal delay between the ablation and the main laser pulses. Since this nanoparticle insertion method can avoid the disturbing effects of electron injection process on laser evolution, the stable high-charge injection method can provide a suitable electron injector for multi-GeV electron sources from low-density plasmas., (© 2022. The Author(s).)

We aimed to characterize the vascular phenotypes of an experimental autoimmune retinal uveitis (EAU) model induced by interphotoreceptor retinoid-binding protein (IRBP) using multimodal imaging techniques. We systemically administered IRBP or vehicle to adult C57BL/6 mice. Fundus photography, optical coherence tomography (OCT), in vivo live confocal imaging using different tracers, OCT angiography (OCTA), and electroretinography (ERG) were performed after IRBP immunization. Hematoxylin and eosin and immunofluorescence staining were performed to characterize the immune response and vascular permeability. Mice with EAU exhibited perivascular inflammation, vitritis, and superficial retinal inflammation on fundus photography and OCT. H&E revealed immune cell infiltration in the perivascular area of the retina and choroid accompanied by a significant degree of perivasculitis that subsequently damaged photoreceptors 3 weeks postimmunization. Immunofluorescence staining showed subsequent transcytosis induction after local microglial activation followed by neutrophil recruitment in the perivascular area. Transcytosis in the superficial and deep vascular areas was improved by immune cell suppression. Intravital in vivo confocal imaging showed signs of neutrophil infiltration and obstructive vasculitis with perivascular leakage 3 weeks postimmunization. OCTA revealed a significant decrease in vascular flow in the deep capillary layer of the retina. Functional analysis showed that scotopic responses were intact at 2 weeks; however, normal photopic and scotopic responses were hardly detected in mice with EAU mice at 3 weeks postimmunization. Our data suggest that inflammatory cell activation and subsequent transcytosis induction in endothelial cells might be a major pathogenic factor for vascular leakage in uveitis, providing new insights into the pathophysiology of retinal vasculitis in noninfectious uveitis., (© 2022. The Author(s).)

Interleukin-17A (IL-17), a potent proinflammatory cytokine, has been shown to participate in cardiac electrical disorders. Diabetes mellitus is an independent risk factor for ventricular arrhythmia. In this study, we investigated the role of IL-17 in ventricular arrhythmia of diabetic mice. Diabetes was induced in both wild-type and IL-17 knockout mice by intraperitoneal injection of streptozotocin (STZ). High-frequency electrical stimuli were delivered into the right ventricle to induce ventricular arrhythmias. We showed that the occurrence rate of ventricular tachycardia was significantly increased in diabetic mice, which was attenuated by IL-17 knockout. We conducted optical mapping on perfused mouse hearts and found that cardiac conduction velocity (CV) was significantly decreased, and action potential duration (APD) was prolonged in diabetic mice, which were mitigated by IL-17 knockout. We performed whole-cell patch clamp recordings from isolated ventricular myocytes, and found that the densities of I to , I Na and I Ca,L were reduced, the APDs at 50% and 90% repolarization were increased, and early afterdepolarization (EAD) was markedly increased in diabetic mice. These alterations were alleviated by the knockout of IL-17. Moreover, knockout of IL-17 alleviated the downregulation of Nav1.5 (the pore forming subunit of I Na ), Cav1.2 (the main component subunit of I Ca,L ) and KChIP2 (potassium voltage-gated channel interacting protein 2, the regulatory subunit of I to ) in the hearts of diabetic mice. The expression of NF-κB was significantly upregulated in the hearts of diabetic mice, which was suppressed by IL-17 knockout. In neonatal mouse ventricular myocytes, knockdown of NF-κB significantly increased the expression of Nav1.5, Cav1.2 and KChIP2. These results imply that IL-17 may represent a potential target for the development of agents against diabetes-related ventricular arrhythmias., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Protein kinase-inhibitor interactions are key to the phosphorylation of proteins involved in cell proliferation, differentiation, and apoptosis, which shows the importance of binding mechanism research and kinase inhibitor design. In this study, a novel machine learning module (i.e., the WL Box) was designed and assembled to the Prediction of Interaction Sites of Protein Kinase Inhibitors (PISPKI) model, which is a graph convolutional neural network (GCN) to predict the interaction sites of protein kinase inhibitors. The WL Box is a novel module based on the well-known Weisfeiler-Lehman algorithm, which assembles multiple switch weights to effectively compute graph features. The PISPKI model was evaluated by testing with shuffled datasets and ablation analysis using 11 kinase classes. The accuracy of the PISPKI model with the shuffled datasets varied from 83 to 86%, demonstrating superior performance compared to two baseline models. The effectiveness of the model was confirmed by testing with shuffled datasets. Furthermore, the performance of each component of the model was analyzed via the ablation study, which demonstrated that the WL Box module was critical. The code is available at https://github.com/feiqiwang/PISPKI ., (© 2022. The Author(s).)

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Interleukin-17 (IL-17), also called IL-17A, is an important regulator of cardiac diseases, but its role in calcium-related cardiac dysfunction remains to be explored. Thus, we investigated the influence of IL-17 on calcium handling process and its contribution to the development of heart failure. Mice were subjected to transaortic constriction (TAC) to induce heart failure. In these mice, the levels of IL-17 in the plasma and cardiac tissue were significantly increased compared with the sham group. In 77 heart failure patients, the plasma level of IL-17 was significantly higher than 49 non-failing subjects, and was negatively correlated with cardiac ejection fraction and fractional shortening. In IL-17 knockout mice, the shortening of isolated ventricular myocytes was increased compared with that in wild-type mice, which was accompanied by significantly increased amplitude of calcium transient and the upregulation of SERCA2a and Cav1.2. In cultured neonatal cardiac myocytes, treatment of with IL-17 (0.1, 1 ng/mL) concentration-dependently suppressed the amplitude of calcium transient and reduced the expression of SERCA2a and Cav1.2. Furthermore, IL-17 treatment increased the expression of the NF-κB subunits p50 and p65, whereas knockdown of p50 reversed the inhibitory effects of IL-17 on SERCA2a and Cav1.2 expression. In mice with TAC-induced mouse heart, IL-17 knockout restored the expression of SERCA2a and Cav1.2, increased the amplitude of calcium transient and cell shortening, and in turn improved cardiac function. In addition, IL-17 knockout attenuated cardiac hypertrophy with inhibition of calcium-related signaling pathway. In conclusion, upregulation of IL-17 impairs cardiac function through NF-κB-mediated disturbance of calcium handling and cardiac remodeling. Inhibition of IL-17 represents a potential therapeutic strategy for the treatment of heart failure., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Many studies have proven the power of gene expression profile in cancer identification, however, the explosive growth of genomics data increasing needs of tools for cancer diagnosis and prognosis in high accuracy and short times. Here, we collected 6136 human samples from 11 cancer types, and integrated their gene expression profiles and protein-protein interaction (PPI) network to generate 2D images with spectral clustering method. To predict normal samples and 11 cancer tumor types, the images of these 6136 human cancer network were separated into training and validation dataset to develop convolutional neural network (CNN). Our model showed 97.4% and 95.4% accuracies in identification of normal versus tumors and 11 cancer types, respectively. We also provided the results that tumors located in neighboring tissues or in the same cell types, would induce machine make error classification due to the similar gene expression profiles. Furthermore, we observed some patients may exhibit better prognosis if their tumors often misjudged into normal samples. As far as we know, we are the first to generate thousands of cancer networks to predict and classify multiple cancer types with CNN architecture. We believe that our model not only can be applied to cancer diagnosis and prognosis, but also promote the discovery of multiple cancer biomarkers., (© 2021. The Author(s).)

Relational formulation of quantum mechanics is based on the idea that relational properties among quantum systems, instead of the independent properties of a quantum system, are the most fundamental elements to construct quantum mechanics. In a recent paper (Yang in Sci Rep 8:13305, 2018), basic relational quantum mechanics framework is formulated to derive quantum probability, Born's Rule, Schrödinger Equations, and measurement theory. This paper further extends the reformulation effort in three aspects. First, it gives a clearer explanation of the key concepts behind the framework to calculate measurement probability. Second, we provide a concrete implementation of the relational probability amplitude by extending the path integral formulation. The implementation not only clarifies the physical meaning of the relational probability amplitude, but also allows us to elegantly explain the double slit experiment, to describe the interaction history between the measured system and a series of measuring systems, and to calculate entanglement entropy based on path integral and influence functional. In return, the implementation brings back new insight to path integral itself by completing the explanation on why measurement probability can be calculated as modulus square of probability amplitude. Lastly, we clarify the connection between our reformulation and the quantum reference frame theory. A complete relational formulation of quantum mechanics needs to combine the present works with the quantum reference frame theory.

Retinal degenerative disorders, including age-related macular degeneration and retinitis pigmentosa (RP), are characterized by the irreversible loss of photoreceptor cells and retinal pigment epithelial (RPE) cells; however, the long-term effect of implanting both human induced pluripotent stem cell (hiPSC)-derived RPE and photoreceptor for retinal regeneration has not yet been investigated. In this study, we evaluated the long-term effects of hiPSC-derived RPE and photoreceptor cell transplantation in Pde6b knockout rats to study RP; cells were injected into the subretinal space of the right eyes of rats before the appearance of signs of retinal degeneration at 2-3 weeks of age. Ten months after transplantation, we evaluated the cells using fundus photography, optical coherence tomography, and histological evaluation, and no abnormal cell proliferation was observed. A relatively large number of transplanted cells persisted during the first 4 months; subsequently, the number of these cells decreased gradually. Notably, immunohistochemical analysis revealed that the hiPSC-derived retinal cells showed characteristics of both RPE cells and photoreceptors of human origin after transplantation. Functional analysis of vision by scotopic electroretinogram revealed significant preservation of vision after transplantation. Our study suggests that the transplantation of hiPSC-derived retinal cells, including RPE cells and photoreceptors, has a potential therapeutic effect against irreversible retinal degenerative diseases.

Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells. We demonstrated that the promotive effect of RSK2 on autophagy resulted from directly binding of AMPKα2 in nucleus and phosphorylating it at Thr172 residue. IRE1α, an ER membrane-associated protein mediating unfolded protein response (UPR), is required for transducing the signal for activation of ERK1/2-RSK2 under ER stress. Suppression of autophagy by knockdown of RSK2 enhanced the sensitivity of breast cancer cells to ER stress both in vitro and in vivo. Furthermore, we demonstrated that inhibition of RSK2-mediated autophagy rendered breast cancer cells more sensitive to paclitaxel, a chemotherapeutic agent that induces ER stress-mediated cell death. This study identifies RSK2 as a novel controller of autophagy in tumor cells and suggests that targeting RSK2 can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.

There is a close relationship between serotonergic (5-HT) activity and anxiety. ErbB4, a receptor tyrosine kinase, is expressed in 5-HT neurons. However, whether ErbB4 regulates 5-HT neuronal function and anxiety-related behaviors is unclear. Here, using transgenic and viral approaches, we show that mice with ErbB4 deficiency in 5-HT neurons exhibit heightened anxiety-like behavior and impaired fear extinction, possibly due to an increased excitability of 5-HT neurons in the dorsal raphe nucleus (DRN). Notably, the chemogenetic inhibition of 5-HT neurons in the DRN of ErbB4 mutant mice rescues anxiety-like behaviors. Altogether, our results unravel a previously unknown role of ErbB4 signaling in the regulation of DRN 5-HT neuronal function and anxiety-like behaviors, providing novel insights into the treatment of anxiety disorders.

The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC 50 value of 2.7, 4.2, and 5.3 μM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.

Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barré syndrome (GBS) in adults and microcephaly in newborns. There exists an urgent unmet clinical need for anti-ZIKV drugs for the treatment of infected individuals. In the current work, we aimed at the promising virus drug target, ZIKV NS3 protease and constructed a Pharmacophore Anchor (PA) model for the active site. The PA model reveals a total of 12 anchors (E, H, V) mapped across the active site subpockets. We further identified five of these anchors to be critical core anchors (CEH1, CH3, CH7, CV1, CV3) conserved across flaviviral proteases. The ZIKV protease PA model was then applied in anchor-enhanced virtual screening yielding 14 potential antiviral candidates, which were tested by in vitro assays. We discovered FDA drugs Asunaprevir and Simeprevir to have potent anti-ZIKV activities with EC 50 values 4.7 µM and 0.4 µM, inhibiting the viral protease with IC 50 values 6.0 µM and 2.6 µM respectively. Additionally, the PA model anchors aided in the exploration of inhibitor binding mechanisms. In conclusion, our PA model serves as a promising guide map for ZIKV protease targeted drug discovery and the identified 'previr' FDA drugs are promising for anti-ZIKV treatments.

Autophagy, a form of cellular self-digestion by lysosome, is associated with various disease processes including cancers, and modulating autophagy has shown promise in the treatment of various malignancies. A number of natural products display strong antitumor activity, yet their mechanisms of action remain unclear. To gain a better understanding of how traditional Chinese medicine agents exert antitumor effects, we screened 480 natural compounds for their effects on autophagy using a high content screening assay detecting GFP-LC3 puncta in HeLa cells. Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), was identified as a potent activator of autophagy. The activation of autophagy by TBMS1 was evidenced by increased LC3-II amount and GFP-LC3 dots, observation of autophagosomes under electron microscopy, and enhanced autophagic flux. To explore the mechanisms underlying TBMS1-activated autophagy, we performed cheminformatic analyses and surface plasmon resonance (SPR) binding assay that showed a higher likelihood of the binding between Akt protein and TBMS1. In three human breast cancer cell lines, we demonstrated that Akt-mTOR-eEF-2K pathway was involved in TBMS1-induced activation of autophagy, while Akt-mediated downregulations of Mcl-1, Bcl-xl, and Bcl-2 led to the activation of apoptosis of the breast cancer cells. Inhibition of autophagy enhanced the cytotoxic effect of TBMS1 via promoting apoptosis. Our results demonstrate the role and mechanism of TBMS1 in activating autophagy, suggesting that inhibition of cytoprotective autophagy may act as a therapeutic strategy to reinforce the activity of TBMS1 against cancers.

To compare the efficacy and toxicity of a novel regimen called FBA, consisting of fludarabine, busulfan, and cytarabine, with the standard BuCy2 regimen for younger adult patients with acute myeloid leukemia, we conducted a prospective randomized phase II study. Patients in complete remission were randomly assigned to receive either the FBA (n = 56) or the BuCy2 regimen (n = 55). The difference in 100-day transplant-related mortality (TRM) was not statistically significant between the two arms (1.79% for FBA versus 5.45% for BuCy2, P = 0.260), as were the cumulative incidences of relapse, TRM, overall survival (OS) and event-free survival (EFS) at 3 years. However, the 100-day cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease (aGVHD) were lower in the FBA group [(8.93% versus 21.86%, P = 0.032) (1.79% versus 9.09%, P = 0.025)]. The 3-year GVHD and relapse-free survival (GRFS) was 31.20% for the FBA group and 14.96% for the BuCy2 group (P = 0.004). The incidences of diarrhea and severe oral mucositis within the first 30 days post-transplantation were lower in the FBA group [(28.57% versus 65.45%; P < 0.001) (51.79% versus 70.91%; P = 0.039)]. In conclusion, allogenic transplantation with the FBA regimen achieved similar TRM, relapse rate, OS and EFS, as that with the BuCy2 regimen but with less frequent and less severe complications in early stage after transplantation and a trend toward higher GRFS.

Non-relativistic quantum mechanics is reformulated here based on the idea that relational properties among quantum systems, instead of the independent properties of a quantum system, are the most fundamental elements to construct quantum mechanics. This idea, combining with the emphasis that measurement of a quantum system is a bidirectional interaction process, leads to a new framework to calculate the probability of an outcome when measuring a quantum system. In this framework, the most basic variable is the relational probability amplitude. Probability is calculated as summation of weights from the alternative measurement configurations. The properties of quantum systems, such as superposition and entanglement, are manifested through the rules of counting the alternatives. Wave function and reduced density matrix are derived from the relational probability amplitude matrix. They are found to be secondary mathematical tools that equivalently describe a quantum system without explicitly calling out the reference system. Schrödinger Equation is obtained when there is no entanglement in the relational probability amplitude matrix. Feynman Path Integral is used to calculate the relational probability amplitude, and is further generalized to formulate the reduced density matrix. In essence, quantum mechanics is reformulated as a theory that describes physical systems in terms of relational properties.

In this article, the authors recently noticed that the tubulin blots in Figs. 2a and 6a were inadvertently misplaced during the preparation of these figures due to their similarity. The amended versions of the figures are now shown below. The conclusions of this paper are not affected. The authors sincerely apologize for these errors.

Influenza is an annual seasonal epidemic that has continually drawn public attentions, due to the potential death toll and drug resistance. Neuraminidase, which is essential for the spread of influenza virus, has been regarded as a valid target for the treatment of influenza infection. Although neuraminidase drugs have been developed, they are susceptible to drug-resistant mutations in the sialic-binding site. In this study, we established computational models (site-moiety maps) of H1N1 and H5N1 to determine properties of the 150-cavity, which is adjacent to the drug-binding site. The models reveal that hydrogen-bonding interactions with residues R118, D151, and R156 and van der Waals interactions with residues Q136, D151, and T439 are important for identifying 150-cavitiy inhibitors. Based on the models, we discovered three new inhibitors with IC 50 values <10 μM that occupies both the 150-cavity and sialic sites. The experimental results identified inhibitors with similar activities against both wild-type and dual H274Y/I222R mutant neuraminidases and showed little cytotoxic effects. Furthermore, we identified three new inhibitors situated at the sialic-binding site with inhibitory effects for normal neuraminidase, but lowered effects for mutant strains. The results suggest that the new inhibitors can be used as a starting point to combat drug-resistant strains.

Free-standing films of metal octaethylporphyrins (MOEPs) were prepared for the first time by a physical vapor deposition on surface of an ionic liquid (IL). Different from those on solid surfaces, the as-obtained films were very compact and with plannar structure. The monitoring of time-dependent process indicated that the high surface energy of IL and the strong π…π interaction between MOEP molecules played key roles in forming such films. Furthermore, the as-obtained film showed good transferability, which made it possible to be easily transferred to any substrates for further device application. More importantly, the prototype photodetectors based on free-standing films of MOEP showed ultra flexibility, mechanical stability, and durability.

Nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB/POZ gene family, has emerging roles in cancer. In this study, we identified the NAC1-HDAC4-HIF-1α axis as an important pathway in regulating glycolysis and hypoxic adaptation in tumor cells. We show that nuclear NAC1 binds to histone deacetylase type 4 (HDAC4), hindering phosphorylation of HDAC4 at Ser 246 and preventing its nuclear export that leads to cytoplasmic degradation of the deacetylase. Accumulation of HDAC4 in the nuclei results in an attenuation of HIF-1α acetylation, enhancing the stabilization and transcriptional activity of HIF-1α and strengthening adaptive response of cells to hypoxia. We also show the role of NAC1 in promoting glycolysis in a mouse xenograft model, and demonstrate that knockdown of NAC1 expression can reinforce the antitumor efficacy of bevacizumab, an inhibitor of angiogenesis. Clinical implication of the NAC1-HDAC4-HIF-1α pathway is suggested by the results showing that expression levels of these proteins are significantly correlative in human tumor specimens and associated with the disease progression. This study not only reveals an important function of NAC1 in regulating glycolysis, but also identifies the NAC1-HDAC4-HIF-1α axis as a novel molecular pathway that promotes survival of hypoxic tumor cells.

PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity. Cellular and biochemical analyses as well as structural modelling revealed that two mutations disrupt intramolecular interaction of PTEN and open its conformation, enhancing polyubiquitination of PTEN and decreasing protein stability. Moreover, promoting mono-ubiquitination increases protein stability and nuclear localization of mutant PTEN. Thus, our findings provide a molecular mechanism for cancer-associated PTEN defects and may lead to a brain cancer treatment that targets PTEN mono-ubiquitination.

Histone deacetylases (HDAC) contain eighteen isoforms that can be divided into four classes. Of these isoform enzymes, class IIa (containing HDAC4, 5, 7 and 9) target unique substrates, some of which are client proteins associated with epigenetic control. Class IIa HDACs are reportedly associated with some neuronal disorders, making HDACs therapeutic targets for treating neurodegenerative diseases. Additionally, some reported HDAC inhibitors contain hydroxamate moiety that chelates with zinc ion to become the cofactor of HDAC enzymes. However, the hydroxamate functional group is shown to cause undesirable effects and has poor pharmacokinetic profile. This study used in silico virtual screening methodology to identify several nonhydroxamate compounds, obtained from National Cancer Institute database, which potentially inhibited HDAC4. Comparisons of the enzyme inhibitory activity against a panel of HDAC isoforms revealed these compounds had strong inhibitory activity against class IIa HDACs, but weak inhibitory activity against class I HDACs. Further analysis revealed that a single residue affects the cavity size between class I and class IIa HDACs, thus contributing to the selectivity of HDAC inhibitors discovered in this study. The discovery of these inhibitors presents the possibility of developing new therapeutic treatments that can circumvent the problems seen in traditional hydroxamate-based drugs.

Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment actively changes. However, how these dynamic alterations affect the macrophage phenotype is unknown. Here, we observed that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generated M2 macrophages by regulating their shape during recovery. Notably, rounded macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodeled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrated that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization.

Cancer cells predominantly metabolize glucose by glycolysis to produce energy in order to meet their metabolic requirement, a phenomenon known as Warburg effect. Although Warburg effect is considered a peculiarity critical for survival and proliferation of cancer cells, the regulatory mechanisms behind this phenomenon remain incompletely understood. We report here that eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, has a critical role in promoting glycolysis in cancer cells. We showed that deficiency in eEF-2K significantly reduced the uptake of glucose and decreased the productions of lactate and adenosine triphosphate in tumor cells and in the Ras-transformed mouse embryonic fibroblasts. We further demonstrated that the promotive effect of eEF-2K on glycolysis resulted from the kinase-mediated restriction of synthesis of the protein phosphatase 2A-A (PP2A-A), a key factor that facilitates the ubiquitin-proteasomal degradation of c-Myc protein, as knockdown of eEF-2K expression led to a significant increase in PP2A-A protein synthesis and remarkable downregulation of c-Myc and pyruvate kinase M2 isoform, the key glycolytic enzyme transcriptionally activated by c-Myc. In addition, depletion of eEF-2K reduced the ability of the transformed cells to proliferate and enhanced the sensitivity of tumor cells to chemotherapy both in vitro and in vivo. These results, which uncover a role of the eEF-2K-mediated control of PP2A-A in tumor cell glycolysis, provide new insights into the regulation of the Warburg effect.

Vegetative but not reproductive stage of Saposhnikovia divaricate (Turxz.) schischk possesses pharmacological activities. However, our recent study showed that reproductive S. divaricate supplemented with polysaccharide showed evidently elevated pharmacological activities and increased cimifugin content in rat serum. The aims of present study were to assess the influence of polysaccharides on the chromones pharmacological activities in Radix Saposhnikoviae (RS), the dried root of vegetative stage of S. divaricate, and to explore the underlying mechanisms. Only cimifugin was detected in the plasma of chromone treated animals and RS polysaccharide significantly increased the plasma content of cimifugin. It was shown that neither cimifugin absorption nor glycoside components transformation in simulated digestive fluid was affected by RS polysaccharide. However, a significant promotion of transformation of cimifugin to more stable prime-O-glucosylcimifugin (PGCN) by RS polysaccharide, and a protective effect of polysaccharide on chromone components were observed in small intestine solutions. Meanwhile, RS polysaccharide produced a significant elevation of cimifugin and PGCN concentration in vivo. Based on these findings, we concluded that RS polysaccharide could greatly increase the content of cimifugin, which might be related to its degradation-proof effect on cimifugin, via transforming cimifugin to comparatively more stable PGCN and spatial structure protection.

Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity.

We aimed to investigate whether there is a correlation between elevated serum uric acid (SUA) concentration and endothelial inflammatory response in women with preeclampsia (PE). On the basis of clinical and laboratory findings, patients were assigned to three groups: normal blood pressure (Control (Con)), gestational hypertension (GH) and PE (n=50 in each group). SUA concentration was measured by spectrophotometry, and serum tumour necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) levels were measured by enzyme-linked immunosorbent assay. Western blotting and immunohistochemical staining were also used to detect the changes in TNF-α and ICAM-1 expression in subcutaneous fat tissue. PE patients showed significantly higher systolic and diastolic blood pressures compared with Con and GH pregnant women (P=0.02 and P=0.02, respectively). The changes of body mass index (ΔBMI) before and after pregnancy and 24-h urine protein were significantly different among the three groups (P<0.001). Maternal SUA, TNF-α and soluble ICAM-1 (sICAM-1) levels were significantly increased in the patients with PE (P<0.05) compared with the other two groups. Scatterplot analysis revealed that elevated SUA concentration positively correlated with TNF-α and sICAM-1 in pregnant women. Moreover, vessels in subcutaneous fat tissues of preeclamptic patients showed intense TNF-α and ICAM-1 staining compared with Con and GH patients. The results support that, to a certain extent, elevated SUA concentration is significantly associated with inflammation of maternal systemic vasculature as indicated by increased TNF-α and ICAM-1 expression in women with PE.

Somatostatin (SST)-positive interneurons in the anterior cingulate cortex (ACC) play important roles in neuronal diseases, memory and cognitive functions. However, their development in the ACC remains unclear. Using postnatal day 3 (P3) to P45 GIN mice, we found that most of the intrinsic membrane properties of SST interneurons in the ACC were developmentally mature after the second postnatal week and that the development of these neurons differed from that of parvalbumin (PV) interneurons in the prefrontal cortex. In addition, electrical coupling between SST interneurons appeared primarily between P12-14. The coupling probability plateaued at approximately P21-30, with a non-age-dependent development of coupling strength. The development of excitatory chemical afferents to SST interneurons occurred earlier than the development of inhibitory chemical afferents. Furthermore, eye closure attenuated the development of electrical coupling probability at P21-30 but had no effect on coupling strength. Eye closure also delayed the development of inhibitory chemical afferent frequency but had no effect on the excitatory chemical afferent amplitude, frequency or rise time. Our data suggest that SST interneurons in the ACC exhibit inherent developmental characteristics distinct from other interneuron subtypes, such as PV interneurons, and that some of these characteristics are subject to environmental regulation.

Magnesium is a light metal, with a density two-thirds that of aluminium, is abundant on Earth and is biocompatible; it thus has the potential to improve energy efficiency and system performance in aerospace, automobile, defence, mobile electronics and biomedical applications. However, conventional synthesis and processing methods (alloying and thermomechanical processing) have reached certain limits in further improving the properties of magnesium and other metals. Ceramic particles have been introduced into metal matrices to improve the strength of the metals, but unfortunately, ceramic microparticles severely degrade the plasticity and machinability of metals, and nanoparticles, although they have the potential to improve strength while maintaining or even improving the plasticity of metals, are difficult to disperse uniformly in metal matrices. Here we show that a dense uniform dispersion of silicon carbide nanoparticles (14 per cent by volume) in magnesium can be achieved through a nanoparticle self-stabilization mechanism in molten metal. An enhancement of strength, stiffness, plasticity and high-temperature stability is simultaneously achieved, delivering a higher specific yield strength and higher specific modulus than almost all structural metals.

Tumor suppressor PTEN mainly functions at two subcellular locations, the plasma membrane and the nucleus. At the plasma membrane, PTEN dephosphorylates the tumorigenic second messenger PIP3, which drives cell proliferation and migration. In the nucleus, PTEN controls DNA repair and genome stability independently of PIP3. Whereas the concept that a conformational change regulates protein function through post-translational modifications has been well established in biology, it is unknown whether a conformational change simultaneously controls dual subcellular localizations of proteins. Here, we discovered that opening the conformation of PTEN is the crucial upstream event that determines its key dual localizations of this crucial tumor suppressor. We identify a critical conformational switch that regulates PTEN's localization. Most PTEN molecules are held in the cytosol in a closed conformation by intramolecular interactions between the C-terminal tail and core region. Dephosphorylation of the tail opens the conformation and exposes the membrane-binding regulatory interface in the core region, recruiting PTEN to the membrane. Moreover, a lysine at residue 13 is also exposed and when ubiquitinated, transports PTEN to the nucleus. Thus, opening the conformation of PTEN is a key mechanism that enhances its dual localization and enzymatic activity, providing a potential therapeutic strategy in cancer treatments.

Phosphatase and tensin homolog (PTEN), which negatively regulates tumorigenic phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling, is a commonly mutated tumor suppressor. The majority of cancer-associated PTEN mutations block its essential PIP3 phosphatase activity. However, there is a group of clinically identified PTEN mutations that maintain enzymatic activity, and it is unknown how these mutations contribute to tumor pathogenesis. Here, we show that these enzymatically competent PTEN mutants fail to translocate to the plasma membrane where PTEN converts PIP3 to PI(4,5)P2. Artificial membrane tethering of the PTEN mutants effectively restores tumor suppressor activity and represses excess PIP3 signaling in cells. Thus, our findings reveal a novel mechanism of tumorigenic PTEN deficiency.

Tyrosine kinases regulate various biological processes and are drug targets for cancers. At present, the design of selective and anti-resistant inhibitors of kinases is an emergent task. Here, we inferred specific site-moiety maps containing two specific anchors to uncover a new binding pocket in the C-terminal hinge region by docking 4,680 kinase inhibitors into 51 protein kinases, and this finding provides an opportunity for the development of kinase inhibitors with high selectivity and anti-drug resistance. We present an anchor-based classification for tyrosine kinases and discover two type-C inhibitors, namely rosmarinic acid (RA) and EGCG, which occupy two and one specific anchors, respectively, by screening 118,759 natural compounds. Our profiling reveals that RA and EGCG selectively inhibit 3% (EGFR and SYK) and 14% of 64 kinases, respectively. According to the guide of our anchor model, we synthesized three RA derivatives with better potency. These type-C inhibitors are able to maintain activities for drug-resistant EGFR and decrease the invasion ability of breast cancer cells. Our results show that the type-C inhibitors occupying a new pocket are promising for cancer treatments due to their kinase selectivity and anti-drug resistance.

A module is a group of closely related proteins that act in concert to perform specific biological functions through protein-protein interactions (PPIs) that occur in time and space. However, the underlying module organization and variance remain unclear. In this study, we collected module templates to infer respective module families, including 58,041 homologous modules in 1,678 species, and PPI families using searches of complete genomic database. We then derived PPI evolution scores and interface evolution scores to describe the module elements, including core and ring components. Functions of core components were highly correlated with those of essential genes. In comparison with ring components, core proteins/PPIs were conserved across multiple species. Subsequently, protein/module variance of PPI networks confirmed that core components form dynamic network hubs and play key roles in various biological functions. Based on the analyses of gene essentiality, module variance, and gene co-expression, we summarize the observations of module organization and variance as follows: 1) a module consists of core and ring components; 2) core components perform major biological functions and collaborate with ring components to execute certain functions in some cases; 3) core components are more conserved and essential during organizational changes in different biological states or conditions.

Aim: Excess dietary fat intake can induce lipotoxicity in non-adipose tissues. The aim of this study was to observe the effects of dietary high-fat lard intake on thyroid in rats., Methods: Male Sprague-Dawley rats were fed a high-fat lard diet for 24 weeks, and then the rats were fed a normal control diet (acute dietary modification) or the high-fat lard diet for another 6 weeks. The serum lipid profile, total thyroxine (TT4), free thyroxine (FT4) and thyrotropin (TSH) levels were determined at the 12, 18, 24 and 30 weeks. High-frequency ultrasound scanning of the thyroid glands was performed at the 24 or 30 weeks. After the rats were sacrificed, the thyroid glands were collected for histological and immunohistochemical analyses., Results: The high-fat lard diet significantly increased triglyceride levels in both the serum and thyroid, and decreased serum TT4 and FT4 levels in parallel with elevated serum TSH levels. Ultrasonic imaging revealed enlarged thyroid glands with lowered echotexture and relatively heterogeneous features in the high-fat lard fed rats. The thyroid glands from the high-fat lard fed rats exhibited enlarged follicle cavities and flattened follicular epithelial cells under light microscopy, and dilated endoplasmic reticulum cisternae, twisted nuclei, fewer microvilli and secretory vesicles under transmission electron microscopy. Furthermore, the thyroid glands from the high-fat lard fed rats showed markedly low levels of thyroid hormone synthesis-related proteins TTF-1 and NIS. Acute dietary modification by withdrawal of the high-fat lard diet for 6 weeks failed to ameliorate the high-fat lard diet-induced thyroid changes., Conclusion: Dietary high-fat lard intake induces significant thyroid dysfunction and abnormal morphology in rats, which can not be corrected by short-term dietary modification.

The purpose of this study was to define the roles of miR-181a in determining sensitivity of cervical cancer to radiation therapy, to explore the underlying mechanism and to evaluate the potential of miR-181a as a biomarker for predicting radio-sensitivity. Tumor specimens from 18 patients with a histological diagnosis of squamous cervical carcinoma (stage IIIB) were used in the micro-RNA profiling and comparison. These patients never received any chemotherapy before radiation therapy. Human cervical cancer cell lines, SiHa and Me180, were used in vitro (cell culture) and in vivo (animal) studies. Transfection of tumor cells with the mimic or inhibitor of miR-181a, and reporter gene assay, were performed to investigate the role of miR-181a in determining radio-sensitivity and the target gene. Higher expression of miR-181a was observed in human cervical cancer specimens and cell lines that were insensitive to radiation therapy, as compared with sensitive cancer specimens and the cell lines. We also found that miR-181a negatively regulated the expression of PRKCD, a pro-apoptotic protein kinase, via targeting its 3'-untranslated region (UTR), thereby inhibiting irradiation-induced apoptosis and decreasing G2/M block. The role of miR-181a in conferring cellular resistance to radiation treatment was validated both in cell culture models and in mouse tumor xenograft models. The effect of miR-181a on radio-resistance was mediated through targeting the 3'-UTR of PRKCD gene. Thus, the expression level of miR-181a in cervical cancer may serve as a biomarker for sensitivity to radiation therapy, and targeting miR-181a may represent a new approach to sensitizing cervical cancer to radiation treatment.

Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to have important roles in proliferation and growth of tumor cells and in chemotherapy resistance. Yet, the mechanisms underlying how NAC1 contributes to drug resistance remain largely unclear. We report here that autophagy was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. We found that treatment with cisplatin caused an activation of autophagy in ovarian cancer cell lines, A2780, OVCAR3 and SKOV3. We further demonstrated that knockdown of NAC1 by RNA interference or inactivation of NAC1 by inducing the expression of a NAC1 deletion mutant that contains only the BTB/POZ domain significantly inhibited the cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity. Moreover, inhibition of autophagy and sensitization to cisplatin by NAC1 knockdown or inactivation were accompanied by induction of apoptosis. To confirm that the sensitizing effect of NAC1 inhibition on the cytotoxicity of cisplatin was attributed to suppression of autophagy, we assessed the effects of the autophagy inhibitors 3-methyladenosine and chloroquine, and small interfering RNAs (siRNAs) targeting beclin 1 or Atg5 on the cytotoxicity of cisplatin. Treatment with 3-methyladenosine, chloroquine or beclin 1 and Atg5-targeted siRNA also enhanced the sensitivity of SKOV3, A2780 and OVCAR3 cells to cisplatin, indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Regulation of autophagy by NAC1 was mediated by the high-mobility group box 1 (HMGB1), as the functional status of NAC1 was associated with the expression, translocation and release of HMGB1. The results of our study not only revealed a new mechanism determining cisplatin sensitivity but also identified NAC1 as a novel regulator of autophagy. Thus, the NAC1-mediated autophagy may be exploited as a new target for enhancing the efficacy of cisplatin against ovarian cancer and other types of malignancies.

Cellular senescence is defined as the physiological program of terminal growth arrest, which can be triggered by various endogenous or exogenous stress signals. Cellular senescence can be induced in response to oncogenic activation and acts as a barrier to tumorigenesis. Moreover, tumor cells can undergo senescence when exposed to chemotherapeutic agents. In addition to suppressing tumorigenesis, senescent cells remain metabolically active and may contribute to tumor formation and to therapy resistance. In the current review, we discuss the molecular regulation of cellular senescence, the potential implications of senescence in human cancers, and the possibility of exploiting cellular senescence for the treatment of cancers.

Aim: To determine whether elongation factor-2 kinase (eEF-2 kinase) contributes to the malignant phenotype of glioblastoma multiforme by promoting the migration and invasion of glioma cells. The mechanism involved was also explored., Methods: Human glioma cell lines T98G and LN-229 were used. The expression of eEF-2 kinase was silenced using siRNA, and the invasive potential of tumor cells was assessed using a wound-healing assay and a Matrigel invasion assay. Apoptosis was determined using propidium iodide (PI) staining and Western blot analysis of cleaved caspase-3., Results: Silencing the expression of eEF-2 kinase by siRNA significantly suppressed both the migration and invasion of human glioma cells. Silencing eEF-2 kinase expression also sensitized glioma cells to anoikis, thereby decreasing tumor cell viability in the absence of attachment. Treatment of tumor cells with the caspase inhibitor z-VAD-fmk down-regulated Bim accumulation and abolished glioma cell sensitivity to anoikis., Conclusion: The results suggest that the expression of eEF-2 kinase contributes to migration and invasion of human glioma cells by protecting them from anoikis. eEF-2 kinase expression may serve as a prognostic marker and a novel target for cancer therapy.

Autophagy is an evolutionarily conserved lysosomal self-digestion process involved in degradation of long-lived proteins and damaged organelles. In recent years, increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. In this review, we focus on the recent studies of the evolutionarily conserved autophagy-related genes (ATGs) that are implicated in autophagosome formation and the pathways involved. We discuss several key autophagic mediators (eg, Beclin-1, UVRAG, Bcl-2, Class III and I PI3K, mTOR, and p53) that play pivotal roles in autophagic signaling networks in cancer. We discuss the Janus roles of autophagy in cancer and highlighted their relationship to tumor suppression and tumor progression. We also present some examples of targeting ATGs and several protein kinases as anticancer strategy, and discuss some autophagy-modulating agents as antitumor agents. A better understanding of the relationship between autophagy and cancer would ultimately allow us to harness autophagic pathways as new targets for drug discovery in cancer therapeutics.

Aim: To study the influence of beta-receptor activation on sodium channel current and the physiological significance of increased sodium current with regard to the increased cardiac output caused by sympathetic excitation., Methods: Multiple experimental approaches, including ECG, action potential recording with conventional microelectrodes, whole-cell current measurements, single-channel recordings, and pumping-force measurements, were applied to guinea pig hearts and isolated ventricular myocytes., Results: Isoprenaline was found to dose-dependently shorten QRS waves, increase the amplitude and the V(max) of action potentials, augment the fast sodium current, and increase the occurrence frequencies and open time constants of the long-open and burst modes of the sodium channel. Increased levels of membrane-permeable cAMP have similar effects. In the presence of a calcium channel blocker, TTX reversed the increased pumping force produced by isoprenaline., Conclusion: Beta-adrenergic modulation increases the inward sodium current and accelerates the conduction velocity within the ventricles by changing the sodium channel modes, which might both be conducive to the synchronous contraction of the heart and enhance its pumping function.