Unraveling the Molecular Regulation of Ferroptosis in Respiratory Diseases.

Ferroptosis, a type of programmed cell death that relies on iron, is distinct in terms of its morphological, biochemical and genetic features. Unlike other forms of cell death, such as autophagy, apoptosis, necrosis, and pyroptosis, ferroptosis is primarily caused by lipid peroxidation. Cells that die due to iron can potentially trigger an immune response which intensifies inflammation and causes severe inflammatory reactions that eventually lead to multiple organ failure. In recent years, ferroptosis has been identified in an increasing number of medical fields, including neurological pathologies, chronic liver diseases and sepsis. Ferroptosis has the potential to cause an inflammatory tempest, with many of the catalysts and pathological indications of respiratory ailments being linked to inflammatory reactions. The growing investigation into ferroptosis in respiratory disorders has also garnered significant interest to better understand the mechanism of ferroptosis in these diseases. In this review, the recent progress in understanding the molecular control of ferroptosis and its mechanism in different respiratory disorders is examined. In addition, this review discusses current challenges and prospects for understanding the link between respiratory diseases and ferroptosis.

Aging related obesity and type 2 diabetes mellitus suppress neuromuscular communication and aggravate skeletal muscle dysfunction in rhesus monkeys.

Age-related functional deterioration in skeletal muscle raises the risk for falls, disability, and mortality in the elderly, particularly in obese people or those with type 2 diabetes mellitus (T2D). However, the response of the skeletal muscle to transitioning from obesity to diabetes remains poorly defined, despite that obesity is classified as a stage of pre-diabetes. We screened and selected spontaneously obese and diabetic rhesus monkeys and examined altered protein expression in skeletal muscle of healthy aging (CON), obesity aging (OB), and type 2 diabetes mellitus aging (T2D) rhesus monkeys using Tandem Mass Tags (TMT)-based quantitative proteomic analysis. In total, we identified 142 differentially expressed proteins. Muscle-nerve communication proteins were firstly suppressed at obese-stage. With the disintegration of skeletal muscle, mitochondrial complex I and other energy homeostasis relate proteins were significantly disordered at T2D stage. Indicating that aging related obesity suppressed muscle-nerve communication and contribute to T2D related functional deterioration of skeletal muscles in elderly rhesus monkeys. Some alterations of muscular functional regulator are detected in both obesity and T2D samples, suggesting some T2D related skeletal muscular hypofunctions are occurring at obesity or pre-obesity stage. Muscle-nerve communication proteins and muscular function related proteins could be potential therapy target or early diagnose marker of for skeletal muscular hypofunctions in aging obesity populations.

Soil warming-induced reduction in water content enhanced methane uptake at different soil depths in a subtropical forest.

Global warming can significantly impact soil CH4 uptake in subtropical forests due to changes in soil moisture, temperature sensitivity of methane-oxidizing bacteria (MOB), and shifts in microbial communities. However, the specific effects of climate warming and the underlying mechanisms on soil CH4 uptake at different soil depths remain poorly understood. To address this knowledge gap, we conducted a soil warming experiment (+4 °C) in a natural forest. From August 2020 to October 2021, we measured soil temperature, soil moisture, and CH4 uptake rates at four different soil depths: 0-10 cm, 10-20 cm, 20-40 cm, and 40-60 cm. Additionally, we assessed the soil MOB community structure and pmoA gene (with qPCR) at the 0-10 and 10-20 cm depths. Our findings revealed that warming significantly enhanced soil net CH4 uptake rate by 12.28 %, 29.51 %, and 61.05 % in the 0-10, 20-40, and 40-60 cm soil layers, respectively. The warming also led to reduced soil moisture levels, with more pronounced reductions observed at the 20-40 cm depth compared to the 0-20 cm depth. At the 0-10 cm depth, warming increased the relative abundance of upland soil cluster α (a type of MOB) and decreased the relative abundance of Methylocystis, but it did not significantly increase the pmoA gene copies. Our structural equation model analysis indicated that warming directly regulated soil CH4 uptake rate through the decrease in soil moisture, rather than through changes in the pmoA gene and MOB community structure at the 0-20 cm depth. In summary, our results demonstrate that warming enhances soil CH4 uptake at different depths, with soil moisture playing a crucial role in this process. Under warming conditions, the drier soil pores allow for better CH4 penetration, thereby promoting more efficient activity of MOB.

Survival and neurological function in patients treated with extracorporeal membrane oxygenation and therapeutic hypothermia: a protocol for updating a systematic review.

INTRODUCTION: The widespread application of extracorporeal membrane oxygenation (ECMO) has enhanced clinical outcomes for patients experiencing cardiac arrest. However, its effectiveness is still limited and falls short of the desired level. Therapeutic hypothermia, which maintains body temperatures between 32°C and 36°C in cardiac arrest patients treated with ECMO, has been proposed as a potential means of neuroprotection and increased survival rates. Nevertheless, it remains controversial, and its impact on patient complications has yet to be fully understood. Thus, this paper aims to update the protocol for a systematic review of patients treated with ECMO and therapeutic hypothermia, in order to explore its effects on survival and neurological function. METHOD AND ANALYSIS: This protocol has been developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols 2015. The following databases will be systematically searched: PubMed, Web of Science, Cochrane Library, Embase, Ovid, CNKI, Wanfang and China Biology Medicine Disc. The database search strategy will use a combination of subject terms and free-text keywords. The search will encompass articles from the inception of each database up to 15 June 2023. Inclusion criteria encompass randomised controlled trials, cohort studies, case-control studies and quasi-experimental studies. Two researchers will independently review articles and extract relevant data based on these criteria. Any disagreements will be resolved through discussion. Data analysis will be performed using Review Manager software. ETHICS AND DISSEMINATION: Since no patient data were collected in this study, ethical approval was not required. Research findings will be released in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023435353.

LET-767 determines lipid droplet protein targeting and lipid homeostasis.

Lipid droplets (LDs) are composed of a core of neutral lipids wrapped by a phospholipid (PL) monolayer containing several hundred proteins that vary between different cells or organisms. How LD proteins target to LDs is still largely unknown. Here, we show that RNAi knockdown or gene mutation of let-767, encoding a member of hydroxysteroid dehydrogenase (HSD), displaced the LD localization of three well-known LD proteins: DHS-3 (dehydrogenase/reductase), PLIN-1 (perilipin), and DGAT-2 (diacylglycerol O-acyltransferase 2), and also prevented LD growth in Caenorhabditis elegans. LET-767 interacts with ARF-1 (ADP-ribosylation factor 1) to prevent ARF-1 LD translocation for appropriate LD protein targeting and lipid homeostasis. Deficiency of LET-767 leads to the release of ARF-1, which further recruits and promotes translocation of ATGL-1 (adipose triglyceride lipase) to LDs for lipolysis. The displacement of LD proteins caused by LET-767 deficiency could be reversed by inhibition of either ARF-1 or ATGL-1. Our work uncovers a unique LET-767 for determining LD protein targeting and maintaining lipid homeostasis.

The Effects of Serious Games on Cardiopulmonary Resuscitation Training and Education: Systematic Review With Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Serious games have emerged as an innovative educational strategy with the potential to significantly enhance the quality and effectiveness of cardiopulmonary resuscitation (CPR) training. Despite their promise, there remains a degree of controversy when comparing the advantages of serious games with traditional CPR training methods. This study seeks to provide a comprehensive assessment of the impact of serious games on CPR training and education by systematically analyzing the results of previous research. OBJECTIVE: This study aimed to assess the effect of serious games on CPR training and education by summarizing and pooling the results of previous studies. METHODS: We conducted a thorough and systematic search across 9 prominent web-based databases, encompassing the period from the inception of these databases until April 1, 2023. The databases included in our search were PubMed, Cochrane Library, Wiley Online Library, EBSCO (PsycInfo), SpringerLink, Chinese Biology Medicine Disc, Vip Journal Integration Platform, Wanfang Database, and Chinese National Knowledge Infrastructure. The studies selected adhered to the following criteria: (1) being a randomized controlled trial comparing serious games and traditional methods for CPR training; (2) having participants aged 12 years or older in CPR; (3) having an experimental group using serious games and a control group using nongame methods for CPR instruction; and (4) having outcomes including theoretical and skill assessments, compression depth, and rate. The Cochrane risk of bias assessment tool was used to evaluate the risk of bias. Data analysis was performed using RevMan (version 5.3; Cochrane Training), and mean differences (MDs) and standardized mean differences (SMDs) with 95% CIs were used to calculate continuous variables. RESULTS: A total of 9 articles were included, involving 791 study participants, of whom 395 in the experimental group taught CPR training using serious games and 396 in the control group taught CPR training using traditional methods. The results of our meta-analysis indicate that the use of serious games in CPR training yields outcomes that are comparable in effectiveness to traditional training methods across several key areas. Specifically, serious games demonstrated equivalence to traditional formats in theory assessment (SMD -0.22, 95% CI - 0.96 to 0.51; P=.55), skill assessment (SMD -0.49, 95% CI -1.52 to 0.55; P=.36), compression depth (MD -3.17, 95% CI -0.18 to 6.53; P=.06), and compression rate (MD -0.20, 95% CI -7.29 to 6.89; P=.96). CONCLUSIONS: In summary, serious games offer a viable and effective CPR education approach, yielding results comparable to traditional formats. This modality is a valuable addition to CPR training methodologies. However, caution is warranted in interpreting these findings due to limited controlled trials, small sample sizes, and low-quality meta-analyzed evidence.

Nutrient composition and functional constituents of daylily from different producing areas based on widely targeted metabolomics.

Daylily is a functional food with high nutritional value in China. Datong (DT) in Shanxi Province is one of the four main production areas of daylily. Therefore, Linfen (LF), Lvliang (LL), and Yangquan (YQ) in Shanxi Province have also introduced daylily from DT. However, geographical and climatic conditions and producing patterns cause variations in the daylily quality. In the present study, we found that the nutrient composition of daylilies from different producing areas of Shanxi Province varied. The key environmental factors affecting the nutrition of daylily in different regions were altitude and temperature. The widely targeted metabolomics results showed that 1642 metabolites were found in daylily. The differential metabolites between DT and YQ, LL and LF were 557, 667, and 359, respectively. Notably, 9 metabolic pathways and 59 metabolite markers were associated with daylily from different areas. This study provides a theoretical basis for the quality maintenance and health efficacy research of daylily.

The longitudinal associations between internet addiction and ADHD symptoms among adolescents.

Background and aims: Internet addiction has been linked to ADHD-related symptoms. However, the direction of the relationship and its potential for reciprocal relations is not well understood. This study examined the potential reciprocal relations between the three components of ADHD and Internet addiction, as well as the moderating effects of gender on these relations. Methods: Using a longitudinal design, we collected data of 865 Chinese adolescents across three waves (Mage = 13.78, SD = 1.56 in wave 1), with a time interval of 6 months. Results: Cross-lagged analyses revealed bidirectional associations between hyperactivity, inattention, impulsivity, and Internet addiction over time. Multi-group analyses did not yield any significant gender differences in these relationships. Discussion and conclusions: These findings enhance our understanding of the complex link between ADHD components and Internet addiction and have implications for interventions aimed at reducing the prevalence of Internet addiction and ADHD.

An image deblurring method using improved U-Net model based on multilayer fusion and attention mechanism.

The investigation of image deblurring techniques in dynamic scenes represents a prominent area of research. Recently, deep learning technology has gained extensive traction within the field of image deblurring methodologies. However, such methods often suffer from limited inherent interconnections across various hierarchical levels, resulting in inadequate receptive fields and suboptimal deblurring outcomes. In U-Net, a more adaptable approach is employed, integrating diverse levels of features effectively. Such design not only significantly reduces the number of parameters but also maintains an acceptable accuracy range. Based on such advantages, an improved U-Net model for enhancing the image deblurring effect was proposed in the present study. Firstly, the model structure was designed, incorporating two key components: the MLFF (multilayer feature fusion) module and the DMRFAB (dense multi-receptive field attention block). The aim of these modules is to improve the feature extraction ability. The MLFF module facilitates the integration of feature information across various layers, while the DMRFAB module, enriched with an attention mechanism, extracts crucial and intricate image details, thereby enhancing the overall information extraction process. Finally, in combination with fast Fourier transform, the FRLF (Frequency Reconstruction Loss Function) was proposed. The FRLF obtains the frequency value of the image by reducing the frequency difference. The present experiment results reveal that the proposed method exhibited higher-quality visual effects. Specifically, for the GoPro dataset, the PSNR (peak signal-to-noise ratio) reached 31.53, while the SSIM (structural similarity index) attained a value of 0.948. Additionally, for the Real Blur dataset, the PSNR achieved 31.32, accompanied by an SSIM score of 0.934.

Moringa oleifera leaf improves meat quality by modulating intestinal microbes in white feather broilers.

Moringa oleifera addition to animal diets can improve the growth performance, intestinal health, and immunity of animals, without adverse effects. We investigated the effects of Moringa oleifera on the growth performance, meat quality, and intestinal health of broilers. Moringa oleifera and fermented Moringa oleifera could improve the flesh color and breast muscle tenderness of broilers (p < 0.05). The contents of essential amino acids, unsaturated fatty acids, ΣMUFA, P/S and n-3 ratio in breast muscle of broilers were dose-increased, and the effect of fermented Moringa oleifera was better. Moringa oleifera and fermented Moringa oleifera regulated chicken flavor metabolism by increasing the relative abundance and Short-chain fatty acid (SCFA) contents of Bacteroides, Spirillum, and lactic acid bacteria. Overall, supplementation with 1 % fermented Moringa oleifera can significantly increase essential amino acid and unsaturated fatty acid contents in broilers and participate in the synthesis and transformation of amino acids and fatty acids regulated by beneficial bacteria.

FITM2 deficiency results in ER lipid accumulation, ER stress, reduced apolipoprotein B lipidation, and VLDL triglyceride secretion in vitro and in mouse liver.

Objectives: Triglyceride (TG) association with apolipoprotein B100 (apoB100) serves to form very low density lipoproteins (VLDL) in the liver. The repertoire of factors that facilitate this association is incompletely defined. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytoplasmic lipid droplets (LDs) in tissues that do not form VLDL. We hypothesized that in the liver, in addition to promoting cytosolic LD formation, FITM2 would also transfer TG from its site of synthesis in the ER membrane to nascent VLDL particles within the ER lumen. Methods: Experiments were conducted using a rat hepatic cell line (McArdle-RH7777, or McA cells), an established model of mammalian lipoprotein metabolism, and mice. FITM2 expression was reduced using siRNA in cells and by liver specific cre-recombinase mediated deletion of the Fitm2 gene in mice. Effects of FITM2 deficiency on VLDL assembly and secretion in vitro and in vivo were measured by multiple methods, including density gradient ultracentrifugation, chromatography, mass spectrometry, simulated Raman spectroscopy (SRS) microscopy, sub-cellular fractionation, immunoprecipitation, immunofluorescence, and electron microscopy. Main findings: 1) FITM2-deficient hepatic cells in vitro and in vivo secrete TG-depleted VLDL particles, but the number of particles is unchanged compared to controls; 2) FITM2 deficiency in mice on a high fat diet (HFD) results in decreased plasma TG levels. The number of apoB100-containing lipoproteins remains similar, but shift from VLDL to LDL density; 3) Both in vitro and in vivo , when TG synthesis is stimulated and FITM2 is deficient, TG accumulates in the ER, and despite its availability this pool is unable to fully lipidate apoB100 particles; 4) FITM2 deficiency disrupts ER morphology and results in ER stress. Principal conclusions: The results suggest that FITM2 contributes to VLDL lipidation, especially when newly synthesized hepatic TG is in abundance. In addition to its fundamental importance in VLDL assembly, the results also suggest that under dysmetabolic conditions, FITM2 may be a limiting factor that ultimately contributes to non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH).

Prediction Models for Return of Spontaneous Circulation in Patients with Cardiac Arrest: A Systematic Review and Critical Appraisal.

Objectives: Prediction models for the return of spontaneous circulation (ROSC) in patients with cardiac arrest play an important role in helping physicians evaluate the survival probability and providing medical decision-making reference. Although relevant models have been developed, their methodological rigor and model applicability are still unclear. Therefore, this study aims to summarize the evidence for ROSC prediction models and provide a reference for the development, validation, and application of ROSC prediction models. Methods: PubMed, Cochrane Library, Embase, Elsevier, Web of Science, SpringerLink, Ovid, CNKI, Wanfang, and SinoMed were systematically searched for studies on ROSC prediction models. The search time limit was from the establishment of the database to August 30, 2022. Two reviewers independently screened the literature and extracted the data. The PROBAST was used to evaluate the quality of the included literature. Results: A total of 8 relevant prediction models were included, and 6 models reported the AUC of 0.662-0.830 in the modeling population, which showed good overall applicability but high risk of bias. The main reasons were improper handling of missing values and variable screening, lack of external validation of the model, and insufficient information of overfitting. Age, gender, etiology, initial heart rhythm, EMS arrival time/BLS intervention time, location, bystander CPR, witnessed during sudden arrest, and ACLS duration/compression duration were the most commonly included predictors. Obvious chest injury, body temperature below 33°C, and possible etiologies were predictive factors for ROSC failure in patients with TOHCA. Age, gender, initial heart rhythm, reason for the hospital visit, length of hospital stay, and the location of occurrence in hospital were the predictors of ROSC in IHCA patients. Conclusion: The performance of current ROSC prediction models varies greatly and has a high risk of bias, which should be selected with caution. Future studies can further optimize and externally validate the existing models.

CDKs Functional Analysis in Low Proliferating Early-Stage Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a poor prognosis and growing incidence. In this study, we explored the potential roles of CDK1, CDK2, CDK4, and CDK6 in the progression of early-stage PDAC. Clinicopathologic and mRNA expression data and treatment information of 140 patients identified with stage I/II PDAC who underwent pancreaticoduodenectomy were obtained from the Cancer Genome Atlas data set. Our bioinformatic analysis showed that higher CDK1, CDK2, CDK4, or CDK6 expression was associated with a shorter median survival of the early-stage PDAC patients. Of note, in the low-proliferating pancreatic cancer group, CDKs expressions were significantly associated with proteins functioning in apoptosis, metastasis, immunity, or stemness. Among the low-proliferating PDAC, higher expression of CDK1 was associated with the shorter survival of patients, suggesting that CDK1 may regulate PDAC progression through cell cycle-independent mechanisms. Our experimental data showed that CDK1 knockdown/inhibition significantly suppressed the expression levels of AHR and POU5F1, two critical proteins functioning in cancer cell metastasis and stemness, in low-proliferating, but not in high-proliferating pancreatic cancer cells. In all, our study suggests that CDKs regulate PDAC progression not only through cell proliferation but also through apoptosis, metastasis, immunity, and stemness.

TanshinoneIIA inhibits melanocyte pyroptosis by regulating the ROS/NLRP3 signaling axis.

BACKGROUND: Pyroptosis has been implicated in the development of human diseases, including vitiligo. TanshinoneIIA has been confirmed to play anti-vitiligo role. However, whether tanshinoneIIA inhibits vitiligo progression via regulating cell pyroptosis remains unclear. METHODS: Hydrogen peroxide (H2 O2 )-induced melanocytes were used to mimic vitiligo cell model in vitro. Cell viability was assessed by cell counting kit 8 assay, and reactive oxygen species (ROS) production was detected by DCFH-DA staining. Nod-like receptor protein 3 (NLRP3) expression was detected by quantitative real-time PCR, western blot and immunofluorescence staining. Cell pyroptosis was measured using flow cytometry, and the contents of interleukin-1ß and interleukin-18 were determined by ELISA. Besides, the protein levels of apoptosis-associated speck-like protein containing CARD (ASC) and cleaved-Caspase-1 were examined by western blot analysis. RESULTS: H2 O2 could induce ROS production, NLRP3 expression and pyroptosis in melanocytes. TanshinoneIIA inhibited ROS production, pyroptosis, and the expression of NLRP3, ASC and cleaved-caspase-1 in H2 O2 -induced melanocytes. Compared with the function of ROS inhibitor (NAC), tanshinoneIIA acted as a ROS scavenger to relieve melanocyte pyroptosis. In addition, NLRP3 inhibitor (MCC950) also could aggravate the inhibition effect of tanshinoneIIA on melanocyte pyroptosis. CONCLUSION: TanshinoneIIA suppressed melanocyte pyroptosis probably through modulating the ROS/NLRP3 signaling axis, which provides the evidence for therapeutic effect in vitiligo.

The relationship between parenting styles and adolescent problematic Internet use: A three-level meta-analysis.

Background and aims: Problematic Internet use (PIU) has become a global public health problem. It has been suggested that parenting style is associated with adolescent PIU. However, the evidence in favor of this view is mixed. Based on the PRISMA method, the present study employed three-level meta-analysis approach to investigate the relationship between these two variables and further explore potential moderators. Methods: After a systematic search for published articles, 35 studies were included, reporting 171 effect sizes (N = 40,587). Results: The results showed that positive parenting styles were significantly negatively related to PIU. This association was moderated by gender, age, publication year, and measurements of PIU, but was not by culture and measurements of parenting styles. Negative parenting styles were significantly positively related to PIU, which was moderated by publication year, culture, and sub-types of negative parenting, but not by gender, age, and measurements of both parenting styles and PIU. In addition, the correlation of PIU with negative parenting styles was stronger than that with positive parenting styles. Discussion and Conclusions: The present results demonstrated that parenting styles, especially punitive parenting styles, should be attached to more important when treating adolescent PIU.

PFKP: More than phosphofructokinase.

Phosphofructokinase (PFK) is one of the key enzymes that functions in glycolysis. Studies show that PFKP regulates cell proliferation, apoptosis, autophagy, cell migration/metastasis, and stemness through glycolysis and glycolysis-independent functions. PFKP performs its function not only in the cytoplasm, but also at the cell membrane, on the mitochondria, at the lysosomal membrane, and in the nucleus. The functions of PFKP are extensively studied in cancer cells. PFKP is also highly expressed in certain immune cells; nevertheless, the study of the PFKP's role in immune cells is limited. In this review, we summarize how the expression and activity of PFKP are regulated in cancer cells. PFKP may be applied as a prognostic marker due to its overexpression and significant functions in cancer cells. As such, specifically targeting/inhibiting PFKP may be a critical and promising strategy for cancer therapy.

Role of iron manganese plaque in the safe production of rice (Oryza sativa L.) grains: Field evidence at plot and regional scales in cadmium-contaminated paddy soils.

The relationship between iron manganese plaque (IP) and cadmium (Cd) accumulation by rice in the microenvironment of rice rhizosphere at varying field scales needs to be further explored. In this study, we selected different rice varieties and implemented tailored amendments to ensure the safe production of rice grains in heavily Cd-contaminated farmland situated around an E-waste dismantling site. Through regional surveys, we elucidated the role of IP in facilitating safe rice production. The selection of low-Cd accumulating rice varieties and application of appropriate amendments with sufficient dosages allowed for the effective reduction of Cd transport from soil to rice, resulting in a safe concentration of Cd in rice grains. Analysis using a random forest algorithm indicated that iron (Fe) played a more pivotal role than manganese in soil-rice systems in mitigating Cd accumulation in brown rice. The presence of Fe in IP (IP-Fe) at a low loading mass was unfavorable to the Cd-safe production of rice, while at an IP-Fe loading mass of 52 g/kg, the Cd content in brown rice decreased to a safe level. Furthermore, precipitation, coprecipitation, and complexation of surface functional groups contributed to Cd fixation on IP, as indicated by scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy, electron probe microanalysis, and Fourier-transform infrared spectroscopy with attenuated total reflection. Our results highlighted the key role of IP in the production of Cd-safe rice at different field scales.

Generating a Murine PTEN Null Cell Line to Discover the Key Role of p110ß-PAK1 in Castration-Resistant Prostate Cancer Invasion.

Although androgen deprivation treatment often effectively decreases prostate cancer, incurable metastatic castration-resistant prostate cancer (CRPC) eventually occurs. It is important to understand how CRPC metastasis progresses, which is not clearly defined. The loss of PTEN, a phosphatase to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate in the PI3K pathway, occurs in up to 70% to 80% of CRPC. We generated a mouse androgen-independent prostate cancer cell line (PKO) from PTEN null and Hi-Myc transgenic mice in C57BL/6 background. We confirmed that this PKO cell line has an activated PI3K pathway and can metastasize into the femur and tibia of immunodeficient nude and immunocompetent C57BL/6 mice. In vitro, we found that androgen deprivation significantly enhanced PKO cell migration/invasion via the p110ß isoform-depended PAK1-MAPK activation. Inhibition of the p110ß-PAK1 axis significantly decreased prostate cancer cell migration/invasion. Of note, our analysis using clinical samples showed that PAK1 is more activated in CRPC than in advanced prostate cancer; high PAK1/phosphorylated-PAK1 levels are associated with decreased survival rates in patients with CRPC. All the information suggests that this cell line reflects the characteristics of CRPC cells and can be applied to dissect the mechanism of CRPC initiation and progression. This study also shows that PAK1 is a potential target for CRPC treatment. IMPLICATIONS: This study uses a newly generated PTEN null prostate cancer cell line to define a critical functional role of p110ß-PAK1 in CRPC migration/invasion. This study also shows that the p110ß-PAK1 axis can potentially be a therapeutic target in CRPC metastasis.

NEK2 overexpression aggravates IL-22-induced keratinocyte proliferation and cytokine level increases and IMQ-induced psoriasis-like dermatitis.

BACKGROUND: Psoriasis is a common inflammatory skin disease characterized by the excessive proliferation and abnormal differentiation of keratinocytes. Protein kinases could act on intracellular signaling pathways associated with cell proliferation. OBJECTIVE: Identifying more hub protein kinases affecting cellular and molecular processes in psoriasis, and exploring the dynamic effects of baicalin and NEK2 on the IL-22-induced cellular inflammation and IMQ-induced psoriasis-like mice. METHODS AND RESULTS: In this study, differentially expressed protein kinases playing a hub role in psoriasis initiation and development were identified using integrative bioinformatics analyses, and NEK2 has been chosen. NEK2 was significantly up-regulated in psoriatic samples according to online datasets and experimental analyses. In IL-22-induced cellular inflammation model in HaCaT cells, NEK2 overexpression promoted, whereas NEK2 knockdown partially abolished IL-22-induced alterations in cell viability, DNA synthesis, cytokine levels, as well as STAT3 phosphorylation and p-RB, cyclin D1, CDK4, and CDK6 protein contents. Baicalin treatment partially suppressed IL-22-induced HaCaT cell viability, DNA synthesis, and increases in cytokine levels, whereas NEK2 overexpression significantly abolished Baicalin-induced protection against cellular inflammation. In IMQ-induced psoriasis-like skin inflammation model in mice, baicalin markedly ameliorated IMQ-induced psoriasis-like symptoms and local skin inflammation, whereas NEK2 overexpression partially eliminated the therapeutic effects of baicalin. CONCLUSION: NEK2, up-regulated in psoriatic lesion skin, could aggravate IMQ-induced psoriasis-like dermatitis and attenuate the therapeutic efficiency of baicalin through promoting keratinocyte proliferation and cytokine levels. The STAT3 signaling might be involved.