CXCL6 promotes the progression of NAFLD through regulation of PPARα.

An increasing number of studies have shown that Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, insulin resistance, dyslipidemia, hypertension and metabolic syndrome, but its specific pathogenesis remains unclear. By analyzing GEO database, we found CXCL6 was upregulated in liver tissues of patients with NAFLD. We also confirmed with qPCR that CXCL6 is highly expressed in serum of patients with NAFLD. To identify the underlying impact of CXCL6 on NAFLD, we established animal and cell models of NAFLD. Similarly, we confirmed by qPCR and Western blot that CXCL6 was upregulated in the NAFLD model in vitro and vivo. After transfecting NAFLD cells with siRNA targeting CXCL6 (si-CXCL6), a series of functional experiments were carried out, and these data indicated that the inhibition of CXCL6 reduced intracellular lipid deposition, decreased AST, ALT and TG level, facilitate cell proliferation and suppress their apoptosis. Furthermore, western blot and qPCR analyses displayed that the suppression of CXCL6 could raise the PPARα expression, but PPAR α inhibitor, GW6471 could partially counteract this effect. What's more, Oil Red O staining, biochemical analyzer and TG detection kit revealed that GW6471 could reverse the inhibitory effect of si-CXCL6 on NAFLD. In summary, we provide convincing evidence that CXCL6 is markedly elevated in NAFLD, and the CXCL6/PPARα regulatory network mediates disease progression of NAFLD.

The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.

Epigenetic regulation of lineage-specific genes is important for the differentiation and function of T cells. Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5 mC) conversion to 5-hydroxymethylcytosine (5 hmC) to mediate DNA demethylation. However, the roles of Tet proteins in the immune response are unknown. Here, we characterized the genome-wide distribution of 5 hmC in CD4(+) T cells and found that 5 hmC marks putative regulatory elements in signature genes associated with effector cell differentiation. Moreover, Tet2 protein was recruited to 5 hmC-containing regions, dependent on lineage-specific transcription factors. Deletion of Tet2 in T cells decreased their cytokine expression, associated with reduced p300 recruitment. In vivo, Tet2 plays a critical role in the control of cytokine gene expression in autoimmune disease. Collectively, our findings suggest that Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.

Predicting Braess's paradox of power grids using graph neural networks.

As an increasing number of renewable energy generators are integrated into the electrical grid, the necessity to add new transmission lines to facilitate power transfer and ensure grid stability becomes paramount. However, the addition of new transmission lines to the existing grid topology can lead to the emergence of Braess's paradox or even trigger grid failures. Hence, predicting where to add transmission lines to guarantee stable grid operation is of utmost importance. In this context, we employ deep learning to address this challenge and propose a graph neural network-based method for predicting Braess's paradox in electrical grids, framing the problem of adding new transmission lines causing Braess's paradox as a graph classification task. Taking into consideration the topological and electrical attributes of the grid, we select node features such as degree, closeness centrality, and power values. This approach assists the model in better understanding the relationships between nodes, enhancing the model's representational capabilities. Furthermore, we apply layered adaptive weighting to the output of the graph isomorphism network to emphasize the significance of hierarchical information that has a greater impact on the output, thus improving the model's generalization across electrical grids of varying scales. Experimental results on the IEEE 39, IEEE 57, and IEEE 118 standard test systems demonstrate the efficiency of the proposed method, achieving prediction accuracies of 93.8%, 88.8%, and 88.1%, respectively. Model visualization and ablation studies further validate the effectiveness of this approach.

LINC00115 promotes gastric cancer partly by the miR-212-5p/ATPAF1 axis.

LncRNAs are known to be key regulators in the initiation and development of diverse cancers. Whether LINC00115 is involved in the regulation of gastric cancer (GC) progression remains unclear. Here, we aimed to show the function of LINC00115 in GC. RT-qPCR was used to measure gene expression in GC tissues and cells. Colony formation, EdU, TUNEL, and wound healing assays were used to analyze cellular processes in GC. The in vivo GC xenograft model was established. We observed that LINC00115 was highly expressed in GC. Functionally, silencing LINC00115 inhibited GC cell proliferation, and migration but facilitated GC apoptosis. Mechanistically, LINC00115 sponged miR-212-5p, while miR-212-5p targeted ATPAF1 in GC cells. Rescue assays showed ATPAF1 overexpression countervailed the inhibitory role of LINC00115 depletion in GC progression in vitro and in vivo. Overall, LINC00115 promoted GC progression by upregulating ATPAF1 via miR-212-5p.

Cuticular lipids and associated gene expression analysis under NaCl stress in Thellungiella salsuginea.

Cuticular lipids, including wax and cutin, protect plants against external environmental stress. The relationship between the cuticle properties and salt tolerance is not clear. In this article, photosynthetic and physiological characteristics related to water use and cuticle permeability were assessed in the leaves of Thellungiella salsuginea under NaCl stress. The chemical composition of wax and cutin monomers, and the expression of cuticle-associated genes were also analyzed. The results showed that the net photosynthetic rate and stomatal conductance in the leaves of T. salsuginea decreased, and the water use efficiency increased with increasing NaCl concentration. Salt stress caused a significant increase in total wax, but total cutin monomers only increased under high salt. Transcriptome sequencing and lipid metabolism pathway analysis were performed on rosette leaves of T. salsuginea after 24 h of NaCl treatment. We analyzed the expression of 42 genes involved in cuticle lipid metabolism, and found that most of them exhibited higher expression levels at 0.15 mol L-1 NaCl, but lower expression levels at 0.3 mol L-1 NaCl. The expression of 12 of these genes was further detected by qRT-PCR after 1 week of NaCl treatment: most of them were upregulated both under low and high NaCl stress. Hence, we speculate that the cuticle acts as an adaptive trait in T. salsuginea in salty environments.

Chip Pad Inspection Method Based on an Improved YOLOv5 Algorithm.

Chip pad inspection is of great practical importance for chip alignment inspection and correction. It is one of the key technologies for automated chip inspection in semiconductor manufacturing. When applying deep learning methods for chip pad inspection, the main problem to be solved is how to ensure the accuracy of small target pad detection and, at the same time, achieve a lightweight inspection model. The attention mechanism is widely used to improve the accuracy of small target detection by finding the attention region of the network. However, conventional attention mechanisms capture feature information locally, which makes it difficult to effectively improve the detection efficiency of small targets from complex backgrounds in target detection tasks. In this paper, an OCAM (Object Convolution Attention Module) attention module is proposed to build long-range dependencies between channel features and position features by constructing feature contextual relationships to enhance the correlation between features. By adding the OCAM attention module to the feature extraction layer of the YOLOv5 network, the detection performance of chip pads is effectively improved. In addition, a design guideline for the attention layer is proposed in the paper. The attention layer is adjusted by network scaling to avoid network characterization bottlenecks, balance network parameters, and network detection performance, and reduce the hardware device requirements for the improved YOLOv5 network in practical scenarios. Extensive experiments on chip pad datasets, VOC datasets, and COCO datasets show that the approach in this paper is more general and superior to several state-of-the-art methods.

A colloidal gold test strip assay for the detection of African swine fever virus based on two monoclonal antibodies against P30.

African swine fever (ASF), caused by African swine fever virus (ASFV), was first reported in Kenya in 1921, but an effective vaccine or antiviral drug is still not available for ASFV control. Rapid and effective diagnostics are key steps in managing ASF. We generated two monoclonal antibodies (MAbs) against the ASFV phosphoprotein P30 and designated these as 3H7A7 and 6H9A10. Epitope mapping revealed that MAb 3H7A7 and 6H9A10 recognized aa 144-154 and aa 12-18 of P30, respectively. A signal-amplified sandwich colloidal gold test strip for rapid detection of ASFV was developed based using these MAbs. Sensitivity and specificity analysis showed that the detection limit of the strip was 2.16 ng of P30. The strip only reacted with ASFV and did not react with other common porcine viruses. In detection tests using 153 clinical field samples including sera, plasma, anticoagulant-treated blood, and tissue, the strip had 95.42% concordance with real-time PCR. The new MAbs specific for P30 and the rapid colloidal gold test strip helped to reveal novel B cell epitopes in P30 and provide an efficient diagnostic test for on-site clinical detection of ASF.

Chemical and Transcriptomic Analysis of Cuticle Lipids under Cold Stress in Thellungiella salsuginea.

Plant cuticle lipids form outer protective layers to resist environmental stresses; however, the relationship between cuticle properties and cold tolerance is unclear. Here, the extremophyte Thellungiella salsuginea was stressed under cold conditions (4 °C) and the cuticle of rosette leaves was examined in terms of epicuticular wax crystal morphology, chemical composition, and cuticle-associated gene expression. The results show that cold induced formation of distinct lamellas within the cuticle ultrastructure. Cold stress caused 14.58% and 12.04% increases in the amount of total waxes and cutin monomer per unit of leaf area, respectively, probably associated with the increase in total fatty acids. The transcriptomic analysis was performed on rosette leaves of Thellungiella exposed to cold for 24 h. We analyzed the expression of 72 genes putatively involved in cuticle lipid metabolism, some of which were validated by qRT-PCR (quantitative reverse transcription PCR) after both 24 h and one week of cold exposure. Most cuticle-associated genes exhibited higher expression levels under cold conditions, and some key genes increased more dramatically over the one week than after just 24 h, which could be associated with increased amounts of some cuticle components. These results demonstrate that the cuticle provides some aspects of cold adaptation in T. salsuginea.

Major mutation events in structural genes of peste des petits ruminants virus through serial passages in vitro.

Peste des petits ruminants (PPR) is an highly contagious disease of small ruminants, and caused by peste des petits ruminants virus (PPRV), a member of the genus Morbillivirus in the family Paramyxoviridae. The first outbreak of PPR in China was officially reported in July 2007, when a PPRV strain was successfully isolated from a sick goat in Tibet, followed by sequencing at a full-genome level (China/Tibet/Geg/07-30, GenBank: FJ905304.1). To date, this isolate has been virulently attenuated by more than 90 serial passages in Vero-Dog-SLAM cells at our laboratory. In this study, a total of nine strains by serial passages (namely the 10th, 20th, 30th, 40th, 50th, 60th, 70th, 80th, and 90th passages) were chosen for sequencing of six structural genes in PPRV. The sequence analysis showed that mutation rates in all viral genes were relatively low, and only a few identical mutations within certain genes were stably maintained after an earlier passage, perhaps indicating a predominance of mutants after such a passage.

IL-17 plays a central role in initiating experimental Candida albicans infection in mouse corneas.

The pathogenesis of fungal infection in the cornea remains largely unclear. To understand how the immune system influences the progression of fungal infection in corneas, we inoculated immunocompetent BALB/c mice, neutrophil- or CD4⁺ T-cell-depleted BALB/c mice, and nude mice with Candida albicans. We found that only immunocompetent BALB/c mice developed typical Candida keratitis (CaK), while the other mouse strains lacked obvious clinical manifestations. Furthermore, CaK development was blocked in immunocompetent mice treated with anti-IL-17A or anti-IL-23p19 to neutralize IL-17 activity. However, no significant effects were observed when Treg cells, γδ T cells, or IFN-γ were immunodepleted. Upon infection, the corneas of BALB/c mice were infiltrated with IL-17-producing leukocytes, including neutrophils and, to a lesser degree, CD4⁺ T cells. In contrast, leukocyte recruitment to corneas was significantly diminished in nude mice. Indeed, nude mice produced much less chemokines (e.g. CXCL1, CXCL2, CXCL10, CXCL12, CCL2, and IL-6) in response to inoculation. Remarkably, addition of CXCL2 during inoculation restored CaK induction in nude mice. In contrast to its therapeutic effect on CaK, neutralization of IL-17 exacerbated Candida-induced dermatitis in skin. We conclude that IL-17, mainly produced by neutrophils and CD4⁺ T cells in the corneas, is essential in the pathogenesis of CaK.

Establishment of a RAA-CRISPR Cas12a based diagnostic method for peste des petits ruminants virus N gene and M gene.

Peste des petis ruminants (PPR) is an acute, highly contagious fatal disease affecting both domestic and wild small ruminants, caused by Morbillivirus caprinae (also known as peste des petis ruminants virus (PPRV)). Herein, a rapid method based on recombinase aided amplification-clustered regularly interspaced short palindromic repeats-Cas12a (RAA-CRISPR Cas12a) to detect PPRV was developed. CRISPR RNAs and RAA primers for PPRV-N (nucleocapsid) and PPRV-M (matrix) fragments were designed. The reaction system was constructed following screening and optimization. Detection could be completed within in 50 minutes at 37°C. Detection of gradient dilutions of plasmids carrying of PPRV N and M gene fragments indicated a minimum limit of detection of 10 copies/µL. There were no cross-reactions with related viruses and all tested lineages of PPRV were detected successfully. The method also showed good repeatability. The detection of clinical samples (previously detected using reverse transcription polymerase chain reaction (RT-PCR)) indicated good consistency between the RAA-CRISPR Cas12a method and RT-PCR. Thus, the RAA-CRISPR Cas12a method for rapid PPRV diagnosis has strong specificity, high sensitivity, and stable repeatability. Moreover, the results can be observed visually under blue or UV light or using lateral flow strips without complex instruments.

Tetrandrine (TET) inhibits African swine fever virus entry into cells by blocking the PI3K/Akt pathway.

African Swine Fever Virus (ASFV) infection causes an acute and highly contagious disease in swine, resulting in significant economic losses and societal harm worldwide. Currently, there are no effective vaccines or antiviral drugs available for ASFV. Tetrandrine (TET) is extracted from the traditional Chinese herb Stephania tetrandrae, possesses diverse biological functions such as anti-inflammatory, anti-tumor, and antiviral activities. The study comprehensively evaluated the anti-ASFV effect of TET and validated it through biological assays. The dose-dependent inhibition of TET against ASFV was confirmed and a novel mechanism of TET's anti-ASFV activity was elucidated. TET effectively inhibits ASFV during internalization by blocking macropinocytosis through the inhibition of the PI3K/Akt pathway. The specific inhibitor LY294002, targeting the PI3K/Akt pathway, exhibits similar antiviral activity against ASFV as TET. Furthermore, the inhibitory effect of TET against other viruses such as Lumpy Skin Disease Virus (LSDV) and Porcine Epidemic Diarrhea Virus (PEDV) was also identified. Our findings suggest that TET effectively inhibits ASFV and reveal the potential for broad-spectrum antiviral drugs targeting the PI3K/Akt pathway.

A Dynamic-Memory Event-Triggered Protocol to Multiarea Power Systems With Semi-Markov Jumping Parameter.

This work deals with the dynamic-memory event-triggered-based load frequency control issue for interconnected multiarea power systems (IMAPSs) associated with random abrupt variations and deception attacks. To facilitate the transient faults, a semi-Markov process is addressed to model the dynamic behavior of IMAPSs. In order to modulate transmission frequency, a novel area-dependent dynamic-memory event-triggered protocol (DMETP) is scheduled by resorting to a set of the historically released packets (HRPs), which ensures better dynamic performance. From the viewpoint of the defender, the randomly occurring deception attack is taken into account, which is regulated by a Bernoulli-distributed scalar. Benefitting from the DMETP scheduling, a novel framework of the memory-based asynchronous control strategy is formulated, in which the hidden semi-Markov model is adopted to reveal the mode mismatches. Based on the Lyapunov theory, sufficient conditions are established to ensure the stochastic stability of the resulting systems. In the end, the simulation result is presented to reveal the efficiency of the proposed dynamic-memory event-triggered-based approach.

Deep Learner System Based on Focal Color Retinal Fundus Images to Assist in Diagnosis.

Retinal diseases are a serious and widespread ophthalmic disease that seriously affects patients' vision and quality of life. With the aging of the population and the change in lifestyle, the incidence rate of retinal diseases has increased year by year. However, traditional diagnostic methods often require experienced doctors to analyze and judge fundus images, which carries the risk of subjectivity and misdiagnosis. This paper will analyze an intelligent medical system based on focal retinal image-aided diagnosis and use a convolutional neural network (CNN) to recognize, classify, and detect hard exudates (HEs) in fundus images (FIs). The research results indicate that under the same other conditions, the accuracy, recall, and precision of the system in diagnosing five types of patients with pathological changes under color retinal FIs range from 86.4% to 98.6%. Under conventional retinopathy FIs, the accuracy, recall, and accuracy of the system in diagnosing five types of patients ranged from 70.1% to 85%. The results show that the application of focus color retinal FIs in the intelligent medical system has high accuracy and reliability for the early detection and diagnosis of diabetic retinopathy and has important clinical applications.

Population genetics of Camellia granthamiana, an endangered plant species with extremely small populations in China.

Introduction: Camellia, the largest genus of Theaceae, is well-known for having high economic values. Camellia granthamiana demonstrates large beautiful flowers with some primitive characters, such as multiple large and persistent bracteoles and sepals, was listed as Vulnerable species on the IUCN Red List. Methods: In this study, we investigated all possible records of the species, and sampled four natural populations and five cultivated individuals. By applying shallow-genome sequencing for nine individuals and RAD-seq sequencing for all the sampled 77 individuals, we investigated population genetic diversity and population structure of the species. Results and discussion: The results showed that the population sampled from Fengkai, previously identified as C. albogigias, possessed different plastid genome from other species possibly due to plastid capture; the species possesses strong population structure possibly due to the effect of isolation by distance, habitat fragmentation, and self-crossing tendency of the species, whose effective population size declined quickly in the past 4,000 years. Nevertheless, C. granthamiana maintains a medium level of genetic diversity within population, and significant differentiation was observed among the four investigated populations, it is anticipated that more populations are expected to be found and all these extant populations should be taken into instant protection.

Strain-dependent production of interleukin-17/interferon-γ and matrix remodeling-associated genes in experimental Candida albicans keratitis.

PURPOSE: The aim of this study was to investigate the role of genetic background in determining the development or prognosis of experimental fungal keratitis by comparing the disease courses and related molecules of experimental Candida albicans in two common mouse strains. METHODS: After intrastromal inoculation of 1 × 10(5)C. albicans blastospores into corneas of Balb/c and C57BL/6 mice, all mice developed typical keratitis. The disease was monitored using a slit lamp microscope and scored for comparison of symptoms. At desired time points, blood was collected and corneal homogenates were prepared for enzyme-linked immunosorbent assay measurement of interferon (IFN)γ or interleukin (IL)17. Other corneas were processed for histological evaluation, pathogen load measurement, or total RNA extraction, the last of which was subjected to reverse transcription in conjunction with real-time PCR to measure genes of interest in terms of collagens, matrix metalloproteinases (MMPs), and the tissue inhibitors of MMPs (TIMPs). RESULTS: The infected corneas from the two strains presented different manifestations. Corneal transparency was less affected in Balb/c mice than in C57BL/6 mice, and Balb/c corneas contained fewer pathogens than C57BL/6 corneas during the measured period (10 days). In both strains, keratitis started to resolve around days 7-10, but C57BL/6 mice healed slower than Balb/c mice as indicated by disease presentation, histology, and pathogen burden assay. By day 7 post infection, pseudohyphae were rare but cellular infiltration remained intensive in both strains. The surface of the Balb/c corneas remained relatively intact and smooth, and C57BL/6 corneal lesions produced open erosion areas. Perforation was never seen in the current study setting. In both sera and corneas, IL17 expression increased earlier than IFNγ, and C57BL/6 mice produced higher IL17 levels and lower IFNγ levels than Balb/c mice. Compared with C57BL/6 mice, Balb/c corneas produced more MMP-2, Col3a1, and Col4a1, and less or equivalent TIMP-2 at all detected time points. They also produced more MMP-13, less MMP-8, MMP-9, and TIMP-1 at day 3 post infection, but less MMP-13, basically equivalent MMP-8, and more MMP-9 at later time points. CONCLUSIONS: The disease course of experimental C. albicans keratitis depends on the genetic background of the host animals. The balance between IL17 and IFNγ, as well as among the common injury- and wound healing-related proteins, may contribute to the pathogenesis of C. albicans keratitis. This study suggests that great variance of disease presentation should be expected for human subjects with Candida keratitis.

Low-density lipoprotein particles in atherosclerosis.

Among the diseases causing human death, cardiovascular disease (CVD) remains number one according to the World Health Organization report in 2021. It is known that atherosclerosis is the pathological basis of CVD. Low-density lipoprotein (LDL) plays a pivotal role in the initiation and progression of atherosclerotic CVD (ASCVD). LDL cholesterol (LDL-C) is the traditional biological marker of LDL. However, large numbers of patients who have achieved the recommended LDL-C goals still have ASCVD risk. In multiple prospective studies, LDL particle (LDL-P) is reported to be more accurate in predicting CVD risk than LDL-C. LDL-Ps differ in size, density and chemical composition. Numerous clinical studies have proved that the atherogenic mechanisms of LDL-Ps are determined not only by LDL number and size but also by LDL modifications. Of note, small dense LDL (sdLDL) particles possess stronger atherogenic ability compared with large and intermediate LDL subfractions. Besides, oxidized LDL (ox-LDL) is another risk factor in atherosclerosis. Among the traditional lipid-lowering drugs, statins induce dramatic reductions in LDL-C and LDL-P to a lesser extend. Recently, proprotein convertase subtilsin/kexin type 9 inhibitors (PCSK9i) have been demonstrated to be effective in lowering the levels of LDL-C, LDL-P, as well as CVD events. In this article, we will make a short review of LDL metabolism, discuss the discordance between LDL-C and LDL-P, outline the atherogenic mechanisms of action of LDL by focusing on sdLDL and ox-LDL, summarize the methods used for measurement of LDL subclasses, and conclude the advances in LDL-lowering therapies using statins and PCSK9i.

School bullying among Chinese third to fifth grade primary school students in a cross-sectional study: The protective effect of psychological resilience.

School bullying is a major concern for school-aged youth and has great impacts on children's health and well-being, and an increasing number of school bullying cases have been reported in China. Many studies have indicated that psychological resilience may have a well-established association with school bullying. However, only a limited number of studies have explored this association, especially among primary school students. The present study aimed to investigate the relationship between school bullying and psychological resilience among primary school students from a Chinese city. The participants were 6,011 primary school students aged 7-14 years who were recruited in a cross-sectional survey in Luzhou, China. The statistical significance of differences between groups was tested using the χ2 test or t test. Binary logistic regression analyses were conducted to explore the association between psychological resilience and school bullying. The incidence rates of bullies and victims were 30.00% (1803/6011; 95% CI: 28.84%-31.16%) and 69.89% (4201/6011; 95% CI: 68.73%-71.05%), respectively. Psychological resilience was a protective factor of school bullying among primary school students (for bullying perpetrators, OR = 0.76, 95%CI:0.62-0.93, and for bully victims OR = 0.74, 95%CI:0.61-0.90), especially among female students (for bullying perpetrators, OR = 0.63, 95%CI: 0.47-0.85, and for bully victims, OR = 0.69, 95%CI: 0.53-0.90). School bullying among primary school students in Luzhou City was highly prevalent. High levels of psychological resilience might be a protective factor in preventing primary students from being involved in school bullying, especially among females.

Psychological Resilience May Be Related to Students' Responses to Victims of School Bullying: A Cross-Sectional Study of Chinese Grade 3-5 Primary School Students.

BACKGROUND: School bullying is a major public health problem with a large impact on children's health. There is an increasing number of cases of school bullying reported in China. Studies have shown that the health consequences of different ways of responding to school bullying may be quite different and that psychological resilience is also closely related to aggressive behaviors. However, there has been little research on whether individuals with different psychological resilience levels respond differently. OBJECTIVE: To explore the relationship between responses to school bullying and psychological resilience, which may provide new ideas and strategies to better prevent and intervene in school bullying. METHODS: A random sample of 5425 primary school students aged 7-14 years were recruited in Luzhou, China. All students completed a questionnaire anonymously. The statistical significance of differences between groups was tested using the χ2 test or t test. Binary logistic regression was conducted to explore the relationship between responses and psychological resilience. RESULTS: Over two-thirds of primary school students in this study reported experiencing bullying in the past year. The rate of positive responses among victims was 69.10% (2596/3757, 95% CI: 67.62~70.58%). There was a positive relationship between psychological resilience and positive responses. This relationship was observed for all victims (OR = 1.605, 95% CI: 1.254~2.055), especially male victims (OR = 2.300, 95% CI: 1.624~3.259). CONCLUSIONS: There was a positive relationship between primary school bullying responses and psychological resilience among victims, with differences by sex. Therefore, increasing students' level of psychological resilience, possibly by improving their responses, is important for preventing school bullying. Meanwhile, effective interventions for school bullying should be developed from multiple perspectives, particularly sex, bullying roles, and psychological resilience.

Inhibition of p38 MAPK increases the sensitivity of 5-fluorouracil-resistant SW480 human colon cancer cells to noscapine.

A major cause of treatment failure in advanced colon cancer is resistance to chemotherapy. p38 mitogen-activated protein kinase (MAPK) has been associated with cellular apoptosis and plays an important role in multidrug resistance (MDR) in cancer cells. In the present study the effect of p38 MAPK on the sensitivity of 5-fluorouracil (5-FU)-resistant SW480 (SW480/5-FU) human colon cancer cells to noscapine was investigated. Following p38 MAPK interference, the inhibitory effect of noscapine on cell viability and proliferation was increased in the SW480/5-FU cells and there was also a decrease in the expression level of minichromosome maintenance proteins, recombinant Ki-67 and proliferating cell nuclear antigen. Inhibition of p38 MAPK also enhanced noscapine-induced G1-phase cell cycle arrest in the SW480/5-FU cells and there was also a decrease in the protein and mRNA expression level of cyclin D, cyclin E and cyclin-dependent kinase 2, and an increase in the expression level of P57. Furthermore, p38 MAPK interference increased noscapine-induced apoptosis of the SW480/5-FU cells and there was an increase in the protein and mRNA expression level of caspases-3 and 8 and Bax, and decreased Bcl-2 expression level. The sensitivity of the SW480/5-FU cells to noscapine was also increased following p38 MAPK interference, as demonstrated by MDR inhibition via decreased Akt activity and reduced protein expression level of the MDR proteins P-glycoprotein, multidrug resistance protein 1 and ATP-binding cassette G2. These observations indicated that inhibition of p38 MAPK increased the sensitivity of the SW480/5-FU cells to noscapine by suppressing proliferation, induction of cell cycle arrest and apoptosis, and reversal of MDR in the SW480/5-FU cells.