Sleep deprivation induced fat accumulation in the visceral white adipose tissue by suppressing SIRT1/FOXO1/ATGL pathway activation.

Sleep is critical for maintaining overall health. Insufficient sleep duration and poor sleep quality are associated with various physical and mental health risks and chronic diseases. To date, plenty of epidemiological research has shown that sleep disorders are associated with the risk of obesity, which is usually featured by the expansion of adipose tissue. However, the underlying mechanism of increased fat accumulation upon sleep disorders remains unclear. Here we demonstrated that sleep deprivation (SD) caused triglycerides (TG) accumulation in the visceral white adipose tissue (vWAT), accompanied by a remarkable decrease in the expression of adipose triglyceride lipase (ATGL) and other two rate-limiting lipolytic enzymes. Due to the key role of ATGL in initiating and controlling lipolysis, we focused on investigating the signaling pathway leading to attenuated ATGL expression in vWAT upon SD in the following study. We observed that ATGL downregulation resulted from the suppression of ATGL transcription, which was mediated by the reduction of the transcriptional factor FOXO1 and its upstream regulator SIRT1 expression in vWAT after SD. Furthermore, impairment of SIRT1/FOXO1/ATGL pathway activation and lipolysis induced by SIRT1 inhibitor EX527 in the 3 T3-L1 adipocytes were efficiently rescued by the SIRT1 activator resveratrol. Most notably, resveratrol administration in SD mice revitalized the SIRT1/FOXO1/ATGL pathway activation and lipid mobilization in vWAT. These findings suggest that targeting the SIRT1/FOXO1/ATGL pathway may offer a promising strategy to mitigate fat accumulation in vWAT and reduce obesity risk associated with sleep disorders.

Ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation mediates female reproductive dysfunction induced by cold exposure.

Ambient air temperature is a key factor affecting human health. Female reproductive disorders are representative health risk events under low temperature. However, the mechanism involving in cold-induced female reproductive disorders remains largely unknown. Female mice were intermittently exposed to cold conditions (4 °C) to address the health risk of low temperature on female reproductive system. Primary granulosa cells (GCs) were prepared and cultured under low temperature (35 °C) or exposed to ß3-adrenoreceptor agonist, isoproterenol, to mimic the condition of cold exposure. Western-blot, RT-PCR, co-IP, ELISA, pharmacological inhibition or siRNA-mediated knockdown of target gene were performed to investigate the possible role of hormones, gap conjunction proteins, and ER stress sensor protein in regulating female reproductive disorders under cold exposure. Cold exposure induced estrous cycle disorder and follicular dysplasia in female mice, accompanying with abnormal upregulation of progesterone and its synthetic rate-limiting enzyme, StAR, in the ovarian granulosa cells. Under the same conditions, an increase in connexin 43 (CX43) expressions in the GCs was also observed, which contributed to elevated progesterone levels in the ovary. Moreover, ER stress sensor protein, PERK, was activated in the ovarian GCs after cold exposure, leading to the upregulation of downstream NRF2-dependent CX43 transcription and aberrant increase in progesterone synthesis. Most importantly, blocking PERK expression in vivo significantly inhibited NRF2/CX43/StAR/progesterone pathway activation in the ovary and efficiently rescued the prolongation of estrous cycle and the increase in follicular atresia of the female mice induced by cold stress. We have elucidated the mechanism of ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation in mediating female reproductive disorder under cold exposure. Targeting PERK might be helpful for maintaining female reproductive health under cold conditions.

A comprehensive AI model development framework for consistent Gleason grading.

BACKGROUND: Artificial Intelligence(AI)-based solutions for Gleason grading hold promise for pathologists, while image quality inconsistency, continuous data integration needs, and limited generalizability hinder their adoption and scalability. METHODS: We present a comprehensive digital pathology workflow for AI-assisted Gleason grading. It incorporates A!MagQC (image quality control), A!HistoClouds (cloud-based annotation), Pathologist-AI Interaction (PAI) for continuous model improvement, Trained on Akoya-scanned images only, the model utilizes color augmentation and image appearance migration to address scanner variations. We evaluate it on Whole Slide Images (WSI) from another five scanners and conduct validations with pathologists to assess AI efficacy and PAI. RESULTS: Our model achieves an average F1 score of 0.80 on annotations and 0.71 Quadratic Weighted Kappa on WSIs for Akoya-scanned images. Applying our generalization solution increases the average F1 score for Gleason pattern detection from 0.73 to 0.88 on images from other scanners. The model accelerates Gleason scoring time by 43% while maintaining accuracy. Additionally, PAI improve annotation efficiency by 2.5 times and led to further improvements in model performance. CONCLUSIONS: This pipeline represents a notable advancement in AI-assisted Gleason grading for improved consistency, accuracy, and efficiency. Unlike previous methods limited by scanner specificity, our model achieves outstanding performance across diverse scanners. This improvement paves the way for its seamless integration into clinical workflows.

Gleason grading is a well-accepted diagnostic standard to assess the severity of prostate cancer in patients' tissue samples, based on how abnormal the cells in their prostate tumor look under a microscope. This process can be complex and time-consuming. We explore how artificial intelligence (AI) can help pathologists perform Gleason grading more efficiently and consistently. We build an AI-based system which automatically checks image quality, standardizes the appearance of images from different equipment, learns from pathologists' feedback, and constantly improves model performance. Testing shows that our approach achieves consistent results across different equipment and improves efficiency of the grading process. With further testing and implementation in the clinic, our approach could potentially improve prostate cancer diagnosis and management.

Sleep deprivation reduced LPS-induced IgG2b production by up-regulating BMAL1 and CLOCK expression.

Sleep deprivation (SD) weakens the immune system and leads to increased susceptibility to infectious or inflammatory diseases. However, it is still unclear how SD affects humoral immunity. In the present study, sleep disturbance was conducted using an sleep deprivation instrument, and the bacterial endotoxin lipopolysaccharide (LPS) was used to activate the immune response. It was found that SD-pretreatment reduced LPS-induced IgG2b+ B cells and IgG2b isotype antibody production in lymphocytes of spleen. And, SD-pretreatment decreased the proportion of CD4+T cells, production of CD4+T cells derived TGF-ß1 and its contribution in helping IgG2b production. Additionally, BMAL1 and CLOCK were selectively up-regulated in lymphocytes after SD. Importantly, BMAL1 and CLOCK deficiency contributed to TGF-ß1 expression and production of IgG2b+ B cells. Thus, our results provide a novel insight to explain the involvement of BMAL1 and CLOCK under SD stress condition, and their roles in inhibiting TGF-ß1 expression and contributing to reduction of LPS induced IgG2b production.

Induction of heme oxygenase-1 antagonizes PM2.5-induced pulmonary VEGFA expression through regulating HIF-1α.

Particulate matter (PM) 2.5 has long been regarded as a major risk factor of the respiratory system, which constitutes a threat to human health. Although the positive relationship between PM2.5 exposure and the development of respiratory diseases has been well established, limited studies investigate the intrinsic self-protection mechanisms against PM2.5-induced respiratory injuries. Excessive pulmonary inflammation served as a key pathogenic mechanism in PM2.5-induced airway dysfunction, and we have previously shown that PM2.5 induced the production of vascular endothelial growth factor A (VEGFA) in the bronchial epithelial cells, which subsequently led to pulmonary inflammatory responses. In the current study, we found that PM2.5 also concurrently induced the expression of the stress-responsive protein heme oxygenase-1 (HO-1) along with VEGFA in the bronchial epithelial cells both in vivo and in vitro. Importantly, knocking down of HO-1 expression significantly increased the synthesis and secretion of VEGFA; while overexpression of HO-1 showed the opposite effects, indicating that HO-1 induction can antagonize VEGFA production in the bronchial epithelial cells upon PM2.5 exposure. Mechanistically, HO-1 inhibited PM2.5-evoked VEGFA induction through modulating hypoxia-inducible factor 1 alpha (HIF-1α), which was the upstream transcriptional factor of VEGFA. More specifically, HO-1 could not only inhibit HIF-1α expression, but also suppress its transactivity. Taken together, our results suggested that HO-1 was an intrinsic protective factor against PM2.5-induced pulmonary VEGFA production with a mechanism relating to HIF-1α, thus providing a potential treatment strategy against PM2.5 triggered airway injuries.

Design, Synthesis, and Antifungal Activities of Novel Carboxamides Derivatives Bearing a Chalcone Scaffold as Potential SDHIs.

In search for SDHIs fungicides, twenty-five novel carboxamides containing a chalcone scaffold were designed, synthesized, and evaluated for antifungal activities against five pathogenic fungi. The results showed that compound 5 k exhibited outstanding antifungal activity against R. solani with an EC50 value of 0.20 µg/mL, which was much better than that of commercial SDHIs Boscalid (EC50 =0.74 µg/mL). Moreover, compound 5 k also displayed promising antifungal activities against S. sclerotiorum, B. cinerea, and A. alternate (IC50 =2.53-4.06 µg/mL), indicating that 5 k had broad-spectrum antifungal activity. Additionally, in vivo antifungal activities results showed that 5 k could significantly inhibit the growth of R. solani in rice leaves with good protective efficacy (57.78 %) and curative efficacy (58.45 %) at 100 µg/mL, both of which were much better than those of Boscalid, indicating a promising application prospect. Moreover, SEM analysis showed that compound 5 k could remarkably disrupt the typical structure and morphology of R. solani hyphae. Further SDH enzyme inhibition assay and molecular docking study revealed that lead compound 5 k had a similar mechanism of action as commercial SDHI Boscalid. These results indicated that compound 5 k showed potential as a SDHIs fungicide and deserved further investigation.

ISG20L1 acts as a co-activator of DAPK1 in the activation of the p53-dependent cell death pathway.

Our previous studies have revealed that GADD45α is a liable proapoptotic protein, which undergoes MDM2-dependent constitutive ubiquitylation and degradation in resting cancer cells. Under chemotherapeutic agent (such as arsenite, 5-Fu and VP-16) exposure, DAPK1 functions as a novel p53 (also known as TP53) kinase, which induces phosphorylation of p53 at Ser15 and transactivates the p53 target Ets-1, to synergistically repress IKKß-dependent MDM2 stability, and ultimately removes the inhibitory effect of MDM2 on GADD45α, resulting in GADD45α accumulation and cell apoptosis. In the current study, we show that there is a strong induction of ISG20L1 (also known as AEN) expression in several cancer cell lines under exposure of arsenite and other chemotherapeutic agents. Surprisingly, although originally identified as a transcriptional target of p53, ISG20L1 induction was not controlled by p53. Instead, ISG20L1 functioned as upstream activator of p53 by interacting with DAPK1, and plays an essential role in promoting DAPK1-p53 complex formation and the subsequent activation of Ets-1/IKKß/MDM2/GADD45α cascade. Therefore, our findings have revealed novel function of ISG20L1 in mediating cancer cell apoptosis induced by chemotherapeutic agents via modulating activation of the DAPK1- and p53-dependent cell death pathway.

Interface catalytic regulation via electron rearrangement and hydroxyl radicals triggered by oxygen vacancies and heavy metal ions.

Although the enhanced intrinsic activities of some nano-metal oxides are obtained by manufacturing oxygen vacancies (OVs), the effect of multiple roles of OVs is ambiguous. Herein, an interface catalytic regulation via electron rearrangement and hydroxyl radicals (˙OH) was proposed with the designed ZrO2 hollow sphere rich in OVs (Vo-rich ZrO2). Surprisingly, it was shown that the catalytic ability of Vo-rich ZrO2 was 9.9 times higher than that of ZrO2 with little OVs in electrochemical catalytic reduction of Pb(ii). It was found that the generation of Zr2+ and Zr3+ caused by OVs results in the rearrangement of abundant free electrons to facilitate the catalytic reaction rates. The longer bond length between Vo-rich ZrO2 and reactants, and the lower adsorption energy are beneficial for reactants to desorb, improving the conversion rates. Besides, the produced ˙OH were captured which were induced by OVs and trace divalent heavy metal ions in in situ electron paramagnetic resonance (EPR) experiments, contributing to lowering the energy barriers. This study not only revealed the enhanced interface catalytic effect of electron rearrangement and generated ˙OH triggered by OVs, but also provided unique insights into interface catalytic regulation on nano-metal oxides simulated by OVs.

Heme oxygenase-1 protects against PM2.5 induced endothelial dysfunction through inhibition of HIF1α.

PM2.5 has been accepted as a strong risk factor for cardiovascular diseases. Activation of the renin-angiotensin system (RAS) has been proved to be a key factor in triggering vascular endothelial dysfunction upon PM2.5 exposure in our previous reports. In the current study, we observed the concurrent induction of hemoxygenase (HO)- 1 and RAS components (ANGII and AT1R) expression both in the vascular endothelial cell lines and in rat lung tissue after PM2.5 exposure. Furthermore, HO-1 inhibited RAS activation by suppressing the expression and activity of HIF1α, the upstream transcriptional activator of ANGII and AT1R. In addition, HO-1 blocked significantly increased the release of cell adhesion molecules and chemokines (VCAM-1, E-Selectin, P-Selectin, IL-8, MCP-1) that drive monocyte-endothelium adhesion, along with the enhanced the generation of oxidative stress response mediators in the vascular endothelium. These data together indicate that PM2.5 induced HO-1 upregulation functions as a self-defense response to antagonize endothelial dysfunction by inhibiting HIF1α-mediated RAS activation. Targeting endogenous protective pathway might be helpful to protect from PM2.5-induced cardiovascular injury.

REVIO: Range- and Event-Based Visual-Inertial Odometry for Bio-Inspired Sensors.

Visual-inertial odometry is critical for Unmanned Aerial Vehicles (UAVs) and robotics. However, there are problems of motion drift and motion blur in sharp brightness changes and fast-motion scenes. It may cause the degradation of image quality, which leads to poor location. Event cameras are bio-inspired vision sensors that offer significant advantages in high-dynamic scenes. Leveraging this property, this paper presents a new range and event-based visual-inertial odometry (REVIO). Firstly, we propose an event-based visual-inertial odometry (EVIO) using sliding window nonlinear optimization. Secondly, REVIO is developed on the basis of EVIO, which fuses events and distances to obtain clear event images and improves the accuracy of position estimation by constructing additional range constraints. Finally, the EVIO and REVIO are tested in three experiments-dataset, handheld and flight-to evaluate the localization performance. The error of REVIO can be reduced by nearly 29% compared with EVIO in the handheld experiment and almost 28% compared with VINS-Mono in the flight experiment, which demonstrates the higher accuracy of REVIO in some fast-motion and high-dynamic scenes.

[Chemical Characteristics and Sources of Atmospheric Aerosols in the Surrounding District of a Heavily Polluted City in the Southern Part of North China].

In order to explore the chemical composition and source profiles of atmospheric particulate matter in winter in the northern area of Handan, a heavily polluted city in the southern part of North China, PM1 and PM2.5 samples were collected and analyzed from November 23 to December 12, 2020. During the observation period, the daily average ρ(PM1)and ρ(PM2.5) were 114.53 µg·m-3 and 124.25 µg·m-3, respectively, and the ratio of PM1/PM2.5 was 83.3%-95.3%, which was significantly higher than those of other cities in the Beijing-Tianjin-Hebei region, indicating that air pollution of fine particulate matter, especially sub-micron particulate matter, was more serious in Handan. Compared with that during clean days, SNA (SO42-, NO3-, and NH4+) in PM1 increased by 14.5% during heavy pollution, and SNA in PM2.5 increased by 15.2%; the nitrogen oxidation rate (NOR) in particular increased by three times on heavy pollution days. With the deepening of pollution, the proportion of secondary organic carbon (SOC) in PM1 and PM2.5 increased by 22.0% and 12.5%, respectively. SOC tended to accumulate in small particles, whereas the proportion of primary organic carbon (POC) and elemental carbon (EC) in PM1 decreased by 15.4% and 6.6%, and the POC and EC in PM2.5 decreased by 8.2% and 4.3%, respectively. The above results indicated that secondary formation played an important role in the heavy pollution of particulate matter. With the aggravation of air pollution, the liquid water content of the particles increased, and both the sulfur oxidation ratio (SOR) and nitrogen oxidation ratio (NOR) increased, indicating that the aqueous phase chemical reaction made an important contribution to the formation of secondary inorganics. With the deepening of pollution, inorganic elements were on the rise; Se, As, Pb, and Zn were highly enriched in inorganic elements. The results of principal component analysis (PCA) showed that secondary formation, industrial emissions, vehicle exhaust, and biomass burning emissions were the main sources of particulate pollutants. The results of potential source contribution factor analysis (PSCF) showed that the high value areas of SO42-, NO3-, EC, OC, and inorganic elements were mainly from the north and southwest directions of the observation area.

Acute hypoxia induced dysregulation of clock-controlled ovary functions.

High altitudes or exposure to hypoxia leads to female reproductive disorders. Circadian clocks are intrinsic time-tracking systems that enable organisms to adapt to the Earth's 24-h light/dark cycle, which can be entrained by other environmental stimuli to regulate physiological and pathological responses. In this study, we focused on whether ovarian circadian clock proteins were involved in regulating female reproductive dysfunction under hypoxic conditions. Hypobaric hypoxia was found to induce a significantly prolonged estrous cycle in female mice, accompanied by follicular atresia, pituitary/ovarian hormone synthesis disorder, and decreased LHCGR expression in the ovaries. Under the same conditions, the levels of the ovarian circadian clock proteins, CLOCK and BMAL1, were suppressed, whereas E4BP4 levels were upregulated. Results from granulosa cells (GCs) further demonstrated that CLOCK: BMAL1 and E4BP4 function as transcriptional activators and repressors of LHCGR in ovarian GCs, respectively, whose responses were mediated by HIF1ɑ-dependent (E4BP4 upregulation) and ɑ-independent (CLOCK and BMAL1 downregulation) manners. The LHCGR agonist was shown to efficiently recover the impairment of ovulation-related gene (EREG and PGR) expression in GCs induced by hypoxia. We conclude that hypoxia exposure causes dysregulation of ovarian circadian clock protein (CLOCK, BMAL1, and E4BP4) expression, which mediates female reproductive dysfunction by impairing LHCGR-dependent signaling events. Adjusting the timing system or recovering the LHCGR level in the ovaries may be helpful in overcoming female reproductive disorders occurring in the highlands.

IKKα mediates UVB-induced cell apoptosis by regulating p53 pathway activation.

Exposure to ultraviolet B (UVB) has been demonstrated to induce DNA damage as well as angiogenesis-related photo-damages, which are implicated in a variety of medical problems, including sunburn, photo-aging and skin cancers. However, the molecular mechanism related to UVB-induced photo-injuries remained fully elucidated. Here we revealed that one of the catalytic subunits of the IKK complex, IKKα, played a critical role in mediating UVB-induced apoptotic responses in two kinds of UVB sensitive cells, human keratinocyte (HaCat) and mouse embryonic fibroblasts (MEFs). This function of IKKα was unrelated to NF-κB activity, but was delivered by inducing phosphorylation and acetylation of p53 and upregulating the expression of the pro-apoptotic p53 target gene, PERP. Although IKKα kinase activity was required for mediating post-translational modifications and transactivation of 53 and PERP induction, IKKα did not show direct binding ability toward p53. Instead, IKKα could interact with CHK1, the protein kinase leading to p53 phosphorylation, and trigger CHK1 activation and CHK1/p53 complex formation. At the same time, IKKα could also interact with p300 and CBP, the acetyltransferases responsible for p53 acetylation, and trigger p300/CBP activation and p300/p53 or CBP/p53 complex formation under UVB exposure. Taken together, we have identified a novel NF-κB-independent role of IKKα in mediating UVB-induced apoptosis by regulating p53 pathway activation. Targeting IKKα/p53/PERP pathway might be helpful to prevent skin photo-damages induced by sunlight.

Circadian oscillation expression of ornithine carbamoyltransferase and its significance in sleep disturbance.

Ornithine transcarbamylases (OTC), a key enzyme in urea cycle, is an important marker for some liver injury or diseases. However, whether OTC could be a sensitive indicator for liver dysfunction under sleep disturbance condition remains unknown. The present study aimed to explore the circadian oscillation expression of OTC and its significance in disturbed sleep condition. Sleep disturbance was conducted by a sleep deprivation (SD) instrument. Our results found that SD for 72h induced abnormal increasing of OTC levels in serum and liver of rats. And, serum OTC concentration and liver OTC expression could return to normal levels after recovery sleep following SD. Moreover, hepatic OTC expression showed circadian oscillation in day and night, characterized with occurrence of a peak between ZT 22 and ZT 2, and a nadir between ZT 14 and ZT 18. Further analysis suggested the existence of ROR response element (RORE) for potential RORɑ binding sites in OTC promoter region, and elevated RORɑ expression in rat livers under sleep disturbance condition. Additionally, oscillation expression of OTC induced by serum shock in HepG2 cells was characterized with a peak occurred between ZT 12 and ZT 16, and RORɑ knockdown at ZT 16 significantly lowered OTC expression. The results together indicate that OTC is closely correlated with circadian clock, and could be a sensitive indicator for sleep disturbance stress.

Autophagic feedback-mediated degradation of IKKα requires CHK1- and p300/CBP-dependent acetylation of p53.

In our previous report, we demonstrated that one of the catalytic subunits of the IκB kinase (IKK) complex, IKKα (encoded by CHUK), performs an NF-κB-independent cytoprotective role in human hepatoma cells under the treatment of the anti-tumor therapeutic reagent arsenite. IKKα triggers its own degradation, as a feedback loop, by activating p53-dependent autophagy, and therefore contributes substantially to hepatoma cell apoptosis induced by arsenite. Interestingly, IKKα is unable to interact with p53 directly but plays a critical role in mediating p53 phosphorylation (at Ser15) by promoting CHK1 activation and CHK1-p53 complex formation. In the current study, we found that p53 acetylation (at Lys373 and/or Lys382) was also critical for the induction of autophagy and the autophagic degradation of IKKα during the arsenite response. Furthermore, IKKα was involved in p53 acetylation through interaction with the acetyltransferases for p53, p300 (also known as EP300) and CBP (also known as CREBBP) (collectively p300/CBP), inducing CHK1-dependent p300/CBP activation and promoting p300-p53 or CBP-p53 complex formation. Therefore, taken together with the previous report, we conclude that both IKKα- and CHK1-dependent p53 phosphorylation and acetylation contribute to mediating selective autophagy feedback degradation of IKKα during the arsenite-induced proapoptotic responses.

Sleep Disturbance Induces Increased Cholesterol Level by NR1D1 Mediated CYP7A1 Inhibition.

Disturbed sleep is closely associated with an increased risk of metabolic diseases. However, the underlying mechanisms of circadian clock genes linking sleep and lipid profile abnormalities have not been fully elucidated. This study aimed to explore the important role of the circadian clock in regulating impaired cholesterol metabolism at an early stage of sleep deprivation (SD). Sleep disturbance was conducted using an SD instrument. Our results showed that SD increased the serum cholesterol levels. Concentrations of serum leptin and resistin were much lower after SD, but other metabolic hormone concentrations (adiponectin, glucagon, insulin, thyroxine, norepinephrine, and epinephrine) were unchanged before and after SD. Warning signs of cardiovascular diseases [decreased high density lipoprotein (HDL)-cholesterol and increased corticosterone and 8-hydroxyguanosine levels] and hepatic cholestasis (elevated total bile acids and bilirubin levels) were observed after SD. Cholesterol accumulation was also observed in the liver after SD. The expression levels of HMGCR, the critical enzyme for cholesterol synthesis, remained unchanged in the liver. However, the expression levels of liver CYP7A1, the enzyme responsible for the conversion of cholesterol into bile acids, significantly reduced after SD. Furthermore, expression of NR1D1, a circadian oscillator and transcriptional regulator of CYP7A1, strikingly decreased after SD. Moreover, NR1D1 deficiency decreased liver CYP7A1 levels, and SD could exacerbate the reduction of CYP7A1 expression in NR1D1-/- mouse livers. Additionally, NR1D1 deficiency could further increase serum cholesterol levels under SD. These results suggest that sleep disturbance can induce increased serum cholesterol levels and liver cholesterol accumulation by NR1D1 mediated CYP7A1 inhibition.

LKB1/p53/TIGAR/autophagy-dependent VEGF expression contributes to PM2.5-induced pulmonary inflammatory responses.

One of the health hazards of PM2.5 exposure is to induce pulmonary inflammatory responses. In our previous study, we demonstrated that exposing both the immortalized and primary human bronchial epithelial cells to PM2.5 results in a significant upregulation of VEGF production, a typical signaling event to trigger chronic airway inflammation. Further investigations showed that PM2.5 exposure strongly induces ATR/CHK1/p53 cascade activation, leading to the induction of DRAM1-dependent autophagy to mediate VEGF expression by activating Src/STAT3 pathway. In the current study, we further revealed that TIGAR was another transcriptional target of p53 to trigger autophagy and VEGF upregulation in Beas-2B cells after PM2.5 exposure. Furthermore, LKB1, but not ATR and CHK1, played a critical role in mediating p53/TIGAR/autophagy/VEGF pathway activation also by linking to Src/STAT3 signaling cascade. Therefore, on combination of the previous report, we have identified both ATR/CHK1/p53/DRAM1- and LKB1/p53/TIGAR- dependent autophagy in mediating VEGF production in the bronchial epithelial cells under PM2.5 exposure. Moreover, the in vivo study further confirmed VEGF induction in the airway potentially contributed to the inflammatory responses in the pulmonary vascular endothelium of PM2.5-treated rats. Therefore, blocking VEGF expression or autophagy induction might be the valuable strategies to alleviating PM2.5-induced respiratory injuries.

Association between microRNA-125b expression in formalin-fixed paraffin-embedded tumor tissues and prognosis in patients with melanoma.

Melanoma is an invasive and malignant type of tumor with unsatisfactory therapeutic outcomes. The present study aimed to detect the expression levels of microRNA (miR)-125b in formalin-fixed paraffin-embedded (FFPE) melanoma tissues and the association of its expression levels with the clinical features, diagnosis and prognosis of melanoma. Expression levels of miR-125b in 29 FFPE melanoma specimens (16 primary and 13 metastatic tumors), and 16 intradermal nevus (IDN) specimens as a control, were detected by reverse transcription-quantitative PCR. Associations among miR-125b expression and mortality, patient age and sex, tumor location and size, lymph node metastasis (LNM) and TNM stage were analyzed by t-test. The diagnostic value of miR-125b for melanoma was evaluated by receiver operating characteristic (ROC) curve analysis. Prognosis of patients in the microRNA-125b low- and high-expression groups was analyzed by Fisher's exact test. The association between miR-125b expression and the overall survival of patients with melanoma was assessed using Kaplan-Meier curve analysis and a Cox proportional hazards model. The results revealed that the expression levels of miR-125b in primary and metastatic melanomas were significantly lower than those in the IDN control group (P<0.05), and the expression levels of miR-125b in the metastatic group were significantly lower than those in the primary group (P<0.05). In addition, the expression levels of miR-125b were significantly associated with LNM (P=0.001) and TNM stage (P=0.004), but not with age, sex, tumor size or location (P>0.05). ROC curve analysis revealed that the area under the curve (AUC) was 0.880, with a 95% CI of 0.777-0.984 (P<0.05). The overall survival rate of the patients with a low expression level of miR-125b (20.0%) was lower than that of patients with a high expression level of miR-125b (64.3%) (P<0.05). miR-125b expression was an independent predictor of overall survival in patients with melanoma [hazard ratio (HR), 0.252; 95% CI, 0.087-0.729]. Overall, these findings indicated that a low expression level of miR-125b was associated with higher LNM and TNM stage in patients with melanoma, and that this has a certain diagnostic value. miR-125b may be used for the early screening of melanoma and determining the prognosis of patients with melanoma, and may be a potential target for the treatment of the disease.