STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging.

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.

Assessment of reproductive toxicity in adult zebrafish (Danio rerio) following sublethal exposure to penthiopyrad.

Penthiopyrad (PO), a succinate dehydrogenase inhibitor (SDHI) fungicide, poses a potential risk to fish. Here, we investigated the adverse effects of PO on endocrine regulation and reproductive capacity in zebrafish during a 21-d sublethal exposure to PO concentrations ranging from 0.02 to 2.00 mg/L. Following exposure to PO (0.20 and 2.00 mg/L), female-specific effects including follicle necrosis, structural disturbance of the yolk follicle, fusion of cortical follicles appeared in ovarian tissue of adult females, which led to a significant reduction in fertility. Correspondingly, 0.20 and 2.00 mg/L PO led to a marked reduction in the GSI values of females, and 2.00 mg/L PO caused a 31% decline in the proportion of perinucleolar oocytes (PCO) in oocytes. In addition, testosterone (T) level was obviously suppressed and 17ß-estradiol (E2) level was increased in females after exposure to 2.00 mg/L PO. Male zebrafish treated with 0.20 and 2.00 mg/L of PO exhibited significant interstitial enlargement, edema in the testes, and reduced diameter of seminiferous tubules, along with a thinner basement membrane. The effects of PO on males were associated with significant increase in E2 level, suggesting that PO has an estrogenic effect on male fish. Greater E2 levels in serum were further supported by increased transcription levels of genes linked to the hypothalamic-pituitary-gonad-liver (HPGL) axis. Notably, transcription levels of cyp19a, er2b, era, and cyp19b was remarkably increased, exhibiting a clear link with variations in E2 levels. Overall, the present study demonstrates that PO induces reproductive impairment in zebrafish by promoting steroidogenesis.

Associations between personal noise exposure and heart rate variability were modified by obesity and PM2.5: The study among obese and normal-weight adults (SONA).

Noise pollution has been documented to increase the risks of cardiovascular disorders, which can be predicted by heart rate variability (HRV), nevertheless, there has been limited evidence on the modifiers of noise pollution. Environmental fine particulate matter (PM2.5) and obesity status are both growing major concerns of cardiovascular disease burden. Our study aims to investigate whether these two factors may modify the associations between noise exposure and HRV indices. An investigation was performed on 97 (53 normal-weight and 44 obese) participants aged 18-26 years, with continuous 5-min personal exposure assessment and ambulatory electrocardiogram monitoring for 24 h. This study found that personal exposure to noise was associated with decreased HRV level and imbalanced cardiac autonomic function, as indicated by decreases in standard deviation of normal-to-normal intervals (SDNN), square root of the mean squared differences of successive intervals (rMSSD), the percentage of R-R intervals that differ from each other by more than 50 ms (pNN50), low-frequency (LF) power, high-frequency (HF) power, and increases in LF-HF-Ratio. Stronger associations between personal noise exposure and HRV indices were observed among obese participants and participants with higher PM2.5 exposure levels compared to their counterparts. For SDNN, a 1 dB(A) increment in personal noise exposure at 3h-average was associated with a 1.25% (95%CI: -1.64%, -0.86%) decrease among obese participants, and a 0.11% (95%CI: -0.38%, 0.16%) decrease among normal-weight participants (P for subgroup difference<0.001); and a 0.87% (95%CI: -1.20%, -0.54%) decrease among participants with higher PM2.5 exposure levels, and a 0.22% (95%CI: -0.58%, 0.14%) decrease among participants with lower PM2.5 exposure levels (P for subgroup difference = 0.008). Obesity and PM2.5 may aggravate the adverse effects of noise on HRV, which has implications for targeted prevention of cardiovascular disease burden associated with noise pollution.

Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

Effect of short-term exposure to particulate air pollution on heart rate variability in normal-weight and obese adults.

BACKGROUND: The adverse effects of particulate air pollution on heart rate variability (HRV) have been reported. However, it remains unclear whether they differ by the weight status as well as between wake and sleep. METHODS: A repeated-measure study was conducted in 97 young adults in Beijing, China, and they were classified by body mass index (BMI) as normal-weight (BMI, 18.5-24.0 kg/m2) and obese (BMI ≥ 28.0 kg/m2) groups. Personal exposures to fine particulate matter (PM2.5) and black carbon (BC) were measured with portable exposure monitors, and the ambient PM2.5/BC concentrations were obtained from the fixed monitoring sites near the subjects' residences. HRV and heart rate (HR) were monitored by 24-h Holter electrocardiography. The study period was divided into waking and sleeping hours according to time-activity diaries. Linear mixed-effects models were used to investigate the effects of PM2.5/BC on HRV and HR in both groups during wake and sleep. RESULTS: The effects of short-term exposure to PM2.5/BC on HRV were more pronounced among obese participants. In the normal-weight group, the positive association between personal PM2.5/BC exposure and high-frequency power (HF) as well as the ratio of low-frequency power to high-frequency power (LF/HF) was observed during wakefulness. In the obese group, personal PM2.5/BC exposure was negatively associated with HF but positively associated with LF/HF during wakefulness, whereas it was negatively correlated to total power and standard deviation of all NN intervals (SDNN) during sleep. An interquartile range (IQR) increase in BC at 2-h moving average was associated with 37.64% (95% confidence interval [CI]: 25.03, 51.51%) increases in LF/HF during wakefulness and associated with 6.28% (95% CI: - 17.26, 6.15%) decreases in SDNN during sleep in obese individuals, and the interaction terms between BC and obesity in LF/HF and SDNN were both statistically significant (p <  0.05). The results also suggested that the effects of PM2.5/BC exposure on several HRV indices and HR differed in magnitude or direction between wake and sleep. CONCLUSIONS: Short-term exposure to PM2.5/BC is associated with HRV and HR, especially in obese individuals. The circadian rhythm of HRV should be considered in future studies when HRV is applied.

Protective effect of novel substituted nicotine hydrazide analogues against hypoxic brain injury in neonatal rats via inhibition of caspase.

In hypoxic-ischemic injury of the brain of neonates, the level of caspase-3 was found to be aberrantly activated. Its overexpression leads to the alteration of cytoskeleton protein fodrin and loss of DNA repair enzyme which ultimately results in neurological impairment and disability. Concerning this, the present study was intended to develop novel nicotine hydrazide analogues as caspase inhibitors via efficient synthetic route. These compounds were subsequently tested for inhibitory activity against caspase-3 and -7 where they exhibit highly potent activity against caspase-3 revealing compound 5k as most potent inhibitor (IC50=19.4±2.5µM). In Western blot analysis, 5k considerably inhibits the overexpression of caspase-3. The aryl nicotinate of compound 5k, as indicated by molecular docking was found to engage His121 and critical enzyme thiols, i.e., Cys163 of caspase-3 for its potent activity. Moreover, histopathological examination of brain tissues and hippocampus neurons showed that compound 5k considerably improves the brain injury and exert neuroprotective effects in hypoxic-ischemic (HI). In brain homogenate, 5k significantly improves the activity of MDA, SOD, GSH-Px, CAT and T-AOC to exert its beneficial effect against oxidative stress induced by HI injury.

p85α is a microRNA target and affects chemosensitivity in pancreatic cancer.

BACKGROUND: We previously identified a correlation between increased expression of the phosphoinositide 3-kinase (PI3K) regulatory subunit p85α and improved survival in human pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the impact of changes in p85α expression on response to chemotherapy and the regulation of p85α by microRNA-21 (miR-21). MATERIALS AND METHODS: PDAC tumor cells overexpressing p85α were generated by viral transduction, and the effect of p85α overexpression on sensitivity to gemcitabine was tested by MTT assay. Primary human PDAC tumors were stained for p85α and miR-21 via immunohistochemistry and in situ hybridization, respectively. Additionally, PDAC cells were treated with miR-21 mimic, and changes in p85α and phospho-AKT were assessed by Western blot. Finally, a luciferase reporter assay system was used to test direct regulation of p85α by miR-21. RESULTS: Higher p85α expression resulted in increased sensitivity to gemcitabine (P < 0.01), which correlated with decreased PI3K-AKT activation. Human tumors demonstrated an inverse correlation between miR-21 and p85α expression levels (r = -0.353, P < 0.001). In vitro, overexpression of miR-21 resulted in decreased levels of p85α and increased phosphorylation of AKT. Luciferase reporter assays confirmed the direct regulation of p85α by miR-21 (P < 0.01). CONCLUSIONS: Our results demonstrate that p85α expression is a determinant of chemosensitivity in PDAC. Additionally, we provide novel evidence that miR-21 can influence PI3K-AKT signaling via its direct regulation of p85α. These data provide insight into potential mechanisms for the known relationship between increased p85α expression and improved survival in PDAC.

Stromal microRNA-21 levels predict response to 5-fluorouracil in patients with pancreatic cancer.

BACKGROUND AND OBJECTIVES: MicroRNA-21 (miR-21) is upregulated and inversely associated with survival in many cancer types, including pancreatic ductal adenocarcinoma (PDAC). We studied the predictive value of miR-21 levels for gemcitabine or 5-fluorouracil (5-FU) response in tumor cells (TCs) or cancer associated fibroblasts (CAFs) in a cohort of PDAC patients from the RTOG 9704 trial. METHODS: MiR-21 expression in CAFs and TCs, determined by in situ hybridization, of the 229 PDAC subset from RTOG 9704 was correlated with (i) histopathology characteristics using a chi-square test; and (ii) patient overall survival (OS) using the Cox proportional hazards model. RESULTS: MiR-21 was strongly expressed in TCs and CAFs in 137/182 (75%) and 152/181 (84%) PDACs, respectively. MiR-21 expression in CAFs for the group given 5-FU for OS: (i) approached significance in a univariate analysis (hazard ratio [HR], 1.57; 95% confidence interval [CI], 0.95-2.57; P = 0.07); and (ii) was significant in the multivariate model (HR, 1.70; 95% CI, 1.03-2.82; P = 0.038). CONCLUSIONS: MiR-21 expression in CAFs was associated with decreased OS in PDAC patients who received 5-FU, but not gemcitabine. These findings begin to identify stromal miR-21 as a marker to guide chemotherapy choice in PDAC patients.

Extracellular vesicles from Lacticaseibacillus paracasei PC-H1 inhibit HIF-1α-mediated glycolysis of colon cancer.

Aims: Extracellular vesicles from Lacticaseibacillus paracasei PC-H1 have antiproliferative activity of colon cells, but the effect on glycolytic metabolism of cancer cell remains enigmatic. The authors investigated how Lacticaseibacillus paracasei extracellular vesicles (LpEVs) inhibit the growth of colon cancer cells by affecting tumor metabolism. Materials & methods: HCT116 cells were treated with LpEVs and then differentially expressed genes were analyzed by transcriptome sequencing, the sequencing results were confirmed in vivo and in vitro. Results: LpEVs entered colon cancer cells and inhibited their growth. Transcriptome sequencing revealed differentially expressed genes were related to glycolysis. Lactate production, glucose uptake and lactate dehydrogenase activity were significantly reduced after treatment. LpEVs also reduced HIF-1α, GLUT1 and LDHA expression. Conclusion: LpEVs exert their antiproliferative activity of colon cancer cells by decreasing HIF-1α-mediated glycolysis.

Causal effects of gut microbiota on the risk of erectile dysfunction: a Mendelian randomization study.

Erectile dysfunction ranks among the prevalent sexual disorders in men. Several studies have indicated a potential link between gut microbiota and erectile dysfunction. To validate this potential association, we were to screen statistical data from genome-wide association studies of gut microbiota and erectile dysfunction. p values of less than 1 × 10-5 were set as the threshold for screening instrumental variables that were strongly associated with gut microbiota. At the same time, in order to obtain more convincing findings, we further excluded instrumental variables with possible chain imbalance, instrumental variables with the presence of palindromes, instrumental variables with F-statistics less than 10, and instrumental variables associated with risk factors for erectile dysfunction. Five methods including inverse-variance weighted method, weighted median method, weighted mode, Mendelian randomization egger method and Mendelian randomization pleiotropy residual sum and outlier test were then used to analyse the 2591 instrumental variables obtained from the screening. We identified correlations between six gut microbiota and the risk of erectile dysfunction. The genus Ruminococcaceae UCG-013 exhibited an inverse association with the risk of developing erectile dysfunction (0.79 (0.65-0.97), P = 0.0214). Conversely, the genus Tyzzerella3 (1.13 (1.02-1.26), P = 0.0225), genus Erysipelotrichaceae UCG-003 (1.18 (1.01-1.38), P = 0.0412), genus LachnospiraceaeNC2004group (1.19 (1.03-1.37), P = 0.0191), genus Oscillibacter (1.23 (1.08-1.41), P = 0.0022), and family Lachnospiraceae (1.26 (1.05-1.52), P = 0.0123) demonstrated positive associations with an increased risk of erectile dysfunction. These sensitivity analyses of the gut microbiota were consistent. This study demonstrated a possible causal relationship between gut microbiota and erectile dysfunction risk through Mendelian randomization analysis, providing new potential possibilities for the prevention and treatment of erectile dysfunction.

Exploring the causal association between serum metabolites and erectile dysfunction: a bidirectional Mendelian randomisation study.

Erectile dysfunction is a common sexual disorder in men. Some studies have found a strong association between some serum metabolites and erectile dysfunction. To investigate this association further, we used bidirectional Mendelian randomisation to investigate causality and possible biological mechanisms.Firstly, this study screened the statistics of genome-wide association studies of serum metabolites and erectile dysfunction to obtain instrumental variables. Inverse variance weighting was used as the primary method for causal effect analysis of instrumental variables in forward or reverse Mendelian randomisation, and the results obtained by MR-Egger regression and the weighted median method were used as references. Subsequently, the metabolites causally associated with erectile dysfunction were subjected to replication analyses and meta-analyses, and the results of the meta-analyses were analysed by pathway analyses to find influential pathways. In this process, Mendelian randomisation results need to be assessed for stability and reliability using sensitivity analysis.It was found that a total of six serum metabolites were causally associated with erectile dysfunction in a forward Mendelian randomisation study. 1,3,7-trimethyluraten (0.85 (0.73-0.99), P = 0.0368), ergothioneine (0.65 (0.45-0.94), P = 0.0226) and gamma-glutamylglutamate (0.63 (0.46-0.88), P = 0.0059) were protective against the development of erectile dysfunction, whereas 2-hydroxyhippurate (1.10 (1.02-1.19), P = 0.0152), N2,N2-dimethylguanosine (1.57 (1.02-2.40), P = 0.0395) and octanoylcarnitine (1.38 (1.06-1.82), P = 0.0183) were able to induce the development of erectile dysfunction. In addition, metabolic pathway analysis showed that 1,3,7-trimethylurate was able to influence the development of erectile dysfunction via the caffeine metabolism pathway (P = 0.0454). On the other hand, reverse Mendelian randomisation analysis showed that erectile dysfunction reduced serum homocitrulline levels (0.99 (0.97-1.00), P = 0.0360). Sensitivity analyses, including heterogeneity tests and pleiotropy tests, confirmed the reliability of the results.In conclusion, this study demonstrated a bidirectional causal relationship between serum metabolites and erectile dysfunction using bidirectional Mendelian randomisation analysis and replication meta-analysis. On this basis, this study provides a new direction of thinking and strong evidence for the therapeutic application and adjunctive diagnosis of serum metabolites in erectile dysfunction, and provides a certain reference value for subsequent related studies.

Cardiorespiratory effects of indoor ozone exposure during sleep and the influencing factors: A prospective study among adults in China.

Ambient ozone (O3) is recognized as a significant air pollutant with implications for cardiorespiratory health, yet the effects of indoor O3 exposure have received less consideration. Furthermore, while sleep occupies one-third of life, research on the health consequences of O3 exposure during this crucial period is scarce. This study aimed to investigate associations of indoor O3 during sleep with cardiorespiratory function and potential predisposing factors. A prospective study among 81 adults was conducted in Beijing, China. Repeated measurements of cardiorespiratory indices reflecting lung function, airway inflammation, cardiac autonomic function, blood pressure, systemic inflammation, platelet and glucose were performed on each subject. Real-time concentrations of indoor O3 during sleep were monitored. Associations of O3 with cardiorespiratory indices were evaluated using linear mixed-effect model. Effect modification by baseline lifestyles (diet, physical activity, sleep-related factors) and psychological status (stress and depression) were investigated through interaction analysis. The average indoor O3 concentration during sleep was 20.3 µg/m3, which was well below current Chinese indoor air quality standard of 160 µg/m3. O3 was associated with most respiratory indicators of decreased airway function except airway inflammation; whereas the cardiovascular effects were only manifested in autonomic dysfunction and not in others. An interquartile range increases in O3 at 6-h average was associated with changes of -3.60 % (95 % CI: -6.19 %, -0.93 %) and -9.60 % (95 % CI: -14.53 %, -4.39 %) in FVC and FEF25-75, respectively. Further, stronger effects were noted among participants with specific dietary patterns, poorer sleep and higher level of depression. This study provides the first general population-based evidence that low-level exposure to indoor O3 during sleep has greater effects on the respiratory system than on the cardiovascular system. Our findings identify the respiratory system as an important target for indoor O3 exposure, and particularly highlight the need for greater awareness of indoor air quality, especially during sleep.

Ambient ultrafine particles exacerbate oxygen desaturation during sleep in patients with chronic obstructive pulmonary disease: New insights into the effect spectrum of ultrafine particles on susceptible populations.

The health effects of ultrafine particles (UFPs) are of growing global concern, but the epidemiological evidence remains limited. Sleep-disordered breathing (SDB) characterized by hypoxemia is a prevalent condition linked to many debilitating chronic diseases. However, the role of UFPs in the development of SDB is lacking. Therefore, this prospective panel study was performed to specifically investigate the association of short-term exposure to UFPs with SDB parameters in patients with chronic obstructive pulmonary disease (COPD). Ninety-one COPD patients completed 226 clinical visits in Beijing, China. Personal exposure to ambient UFPs of 0-7 days was estimated based on infiltration factor and time-activity pattern. Real-time monitoring of sleep oxygen saturation, spirometry, respiratory questionnaires and airway inflammation detection were performed at each clinical visit. Generalized estimating equation was used to estimate the effects of UFPs. Exposure to UFPs was significantly associated with increased oxygen desaturation index (ODI) and percent of the time with oxygen saturation below 90 % (T90), with estimates of 21.50 % (95%CI: 6.38 %, 38.76 %) and 18.75 % (95%CI: 2.83 %, 37.14 %), respectively, per 3442 particles/cm3 increment of UFPs at lag 0-3 h. Particularly, UFPs' exposure within 0-7 days was positively associated with the concentration of alveolar nitric oxide (CaNO), and alveolar eosinophilic inflammation measured by CaNO exceeding 5 ppb was associated with 29.63 % and 33.48 % increases in ODI and T90, respectively. In addition, amplified effects on oxygen desaturation were observed in current smokers. Notably, individuals with better lung function and activity tolerance were more affected by ambient UFPs due to longer time spent outdoors. To our knowledge, this is the first study to link UFPs to hypoxemia during sleep and uncover the key role of alveolar eosinophilic inflammation. Our findings provide new insights into the effect spectrum of UFPs and potential environmental and behavioral intervention strategies to protect susceptible populations.

Endoscopically acquired pancreatic cyst fluid microRNA 21 and 221 are associated with invasive cancer.

OBJECTIVES: Pancreatic cysts are a group of lesions with heterogeneous malignant potential. Currently, there are no reliable biomarkers to aid in cyst diagnosis and classification. The objective of this study was to identify potential microRNA (miR) biomarkers in endoscopically acquired pancreatic cyst fluid that could be used to distinguish between benign, premalignant, and malignant cysts. METHODS: A list of candidate miRs was developed using a whole-genome expression array analysis of pancreatic cancer (pancreatic ductal adenocarcinoma) and nonmalignant samples overlapped with existing literature and predicted gene targets. Endoscopically acquired pancreatic cyst fluid samples were obtained from a group of 38 patients who underwent cyst fluid aspiration and surgical resection. Selected miR expression levels in cyst fluid samples were assessed by quantitative real-time-PCR. Additionally, in situ hybridization (ISH) on corresponding cyst tissue samples was performed to identify the source and validate the expression level of fluid miRs. RESULTS: Of the six miRs that were profiled in the study, two showed differential expression in malignant cysts. miR-221 was expressed at significantly higher levels in malignant cysts compared with benign or premalignant cysts (P=0.05). miR-21 was also expressed at significantly higher levels in malignant cysts (P<0.01). Additionally, the expression of miR-21 was significantly higher in premalignant cysts than benign cysts (P=0.03). The differential expression of miR-21 among cyst categories was confirmed by ISH. CONCLUSIONS: In this small single-center study, miRs are potential pancreatic cyst fluid diagnostic biomarkers. In particular, miR-21 is identified as a candidate biomarker to distinguish between benign, premalignant, and malignant cysts. Additionally miR-221 may be of use in the identification of more advanced malignant disease.

The Effect of Fe Addition on the Curie Temperature and Magnetic Entropy of the Gd45Co50Al5 Amorphous Alloy.

The new magnetic refrigeration (MR) technology, which uses the magnetocaloric effect (MCE) of materials for refrigeration, has shown apparent advantages over the compression refrigeration of freon and other gases. Therefore, how to obtain materials with excellent magnetic entropy change near room temperature is of great significance for the realization of MR. In order to achieve high Tc of a Gd-based amorphous alloy, Gd45Co50Al5 amorphous alloy with good room temperature MCE was selected, and a series of Gd45Co50-xFexAl5 (x = 2, 5, 10) amorphous alloys were prepared by adding Fe instead of Co. In this paper, the effect of Fe addition on the Curie temperature, and the magnetic entropy change in the alloys, were studied thoroughly. The results show that the Curie temperature is increased to 281 K by adding 5% Fe elements, which is mainly related to the enhanced 3d-3d interaction of transition elements caused by Fe addition, and the maximum value of magnetic entropy change is 3.24 J/(kg·K) under a field of 5 T. The results are expected to provide guidance for further improving the room temperature MCE of Gd-based amorphous alloys.

Obesity-related cardiometabolic indicators modify the associations of personal noise exposure with heart rate variability: A further investigation on the Study among Obese and Normal-weight Adults (SONA).

Elucidating the associations between environmental noise and heart rate variability (HRV) would be beneficial for the prevention and control of detrimental cardiovascular changes. Obese people have been found to manifest heightened susceptibility to the adverse effects of noise on HRV. However, the underlying mechanisms remain unclear. Based on 53 normal-weight and 44 obese young adults aged 18-26 years in Beijing, China, this study aimed to investigate the role of obesity-related cardiometabolic indicators for associations between short-term environmental noise exposure and HRV in the real-world context. The participants underwent personal noise exposure and ambulatory electrocardiogram monitoring using portable devices at 5-min intervals for 24 continuous hours. Obesity-related blood pressure, glucose and lipid metabolism, and inflammatory indicators were subsequently examined. Generalized mixed-effect models were used to estimate the associations between noise exposure and HRV parameters. The C-peptide, homeostasis model assessment of insulin resistance (HOMA-IR), and leptin levels were higher in obese participants compared to normal-weight participants. We observed amplified associations between short-term noise exposure and decreases in HRV among participants with higher C-peptide, HOMA-IR, and leptin levels. For instance, a 1 dB(A) increment in 3 h-average noise exposure level preceding each measurement was associated with changes of -0.20% (95%CI: -0.45%, 0.04%) and -1.35% (95%CI: -1.85%, -0.86%) in standard deviation of all normal to normal intervals (SDNN) among participants with lower and higher C-peptide levels, respectively (P for interaction <0.05). Meanwhile, co-existing fine particulate matter (PM2.5) could amplify the associations between noise and HRV among obese participants and participants with higher C-peptide, HOMA-IR, and leptin levels. The more apparent associations of short-term exposure to environmental noise with HRV and the effect modification by PM2.5 may be partially explained by the higher C-peptide, HOMA-IR, and leptin levels of obese people.

Wolfberry water extract attenuates blue light-emitting diode damage to ARPE-19 cells and mouse retina by activating the NRF2 signaling pathway.

The wolfberry is believed to improve eyesight in traditional Chinese medicine. Soaking wolfberry in thermos cups has become a common health-preserving practice. The object of this paper was to research the protective effects of wolfberry water extract (WWE) on oxidative injury induced by blue light-emitting diodes (LEDs) in ARPE-19 cells and C57BL/6J mice. Wolfberry water extract significantly increased cell viability, reduced ROS production, stabilized mitochondrial membrane potential, and inhibited apoptosis in blue LED-induced cells (P < 0.05). The protective effects of WWE against blue LED-induced cytotoxicity and ROS accumulation in cells were abolished by transfection with Nrf2 siRNA. In blue LED-exposed C57BL/6J mice, WWE treatment markedly increased the amplitudes of electroretinogram (ERG) waves a and b, increased the thickness of retinal outer nuclear layer (ONL), activated endogenous antioxidant enzymes, and decreased MDA levels in the retina and lens. WWE also promoted NRF2 translocation and the expression of the downstream genes Ho-1, Nqo1, Gclc, and Gclm in the retina. The protection of WWE in ERG a and b wave amplitudes and ROS levels were abrogated in Nrf2 knockout mice. These results suggested that WWE has beneficial effects on retinal injury induced by blue LED, and mechanisms of action at least partly via the NRF2 signaling pathway.

Associations between multiple metals during early pregnancy and gestational diabetes mellitus under four statistical models.

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. Metal exposure is an emerging factor affecting the risk of GDM. However, the effects of metal mixture on GDM and key metals within the mixture remain unclear. This study was aimed at investigating the association between metal mixture during early pregnancy and the risk of GDM using four statistical methods and further at identifying the key metals within the mixture associated with GDM. A nested case-control study including 128 GDM cases and 318 controls was conducted in Beijing, China. Urine samples were collected before 13 gestational weeks and the concentrations of 13 metals were measured. Single-metal analysis (unconditional logistic regression) and mixture analyses (Bayesian kernel machine regression (BKMR), quantile g-computation, and elastic-net regression (ENET) models) were applied to estimate the associations between exposure to multiple metals and GDM. Single-metal analysis showed that Ni was associated with lower risk of GDM, while positive associations of Sr and Sb with GDM were observed. Compared with the lowest quartile of Ni, the ORs of GDM in the highest quartiles were 0.49 (95% CI 0.24, 0.98). In mixture analyses, Ni and Mg showed negative associations with GDM, while Co and Sb were positively associated with GDM in BKMR and quantile g-computation models. No significant joint effect of metal mixture on GDM was observed. However, interestingly, Ni was identified as a key metal within the mixture associated with decreased risk of GDM by all three mixture methods. Our study emphasized that metal exposure during early pregnancy was associated with GDM, and Ni might have important association with decreased GDM risk.

Associations of multiple air pollutants with kidney function in normal-weight and obese adults and effect modification by free fatty acids.

Increasing studies have linked air pollution to kidney dysfunction, however, the associations between the mixture of air pollutants and kidney function and potential effect modifiers remain unclear. We aimed to investigate whether obese adults were more susceptible than normal-weight ones to the joint effects of multiple air pollutants on kidney function and further to explore effect modification by free fatty acids (FFAs). Forty obese and 49 normal-weight adults were recruited from a panel study (252 follow-up visits). Individual exposure levels of air pollutants (PM2.5, PM10, O3, NO2, SO2 and CO) were estimated. Glomerular function (cystatin C (CysC) and estimated glomerular filtration rate (eGFR)) and tubular function (neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1) were evaluated. Plasma levels of FFAs including trans fatty acids (TFAs) and essential fatty acids (EFAs) were quantified using targeted metabolomics. Bayesian kernel machine regression model was applied to estimate the associations between the mixture of air pollutants and kidney function. The results showed significant joint effects of air pollutants on kidney function indicators. In the normal-weight group, the mixture of air pollutants was significantly associated with CysC and eGFRcr-cys when the mixture was at or above its 70 percentile compared with the median, where O3 was identified as the key pollutant. In the obese group, a significantly positive association between the pollutant mixture and NGAL was observed in addition to trends in CysC and eGFRcr-cys, mainly driven by SO2. Interaction analysis suggested that the associations of air pollutants with kidney function were augmented by TFAs in both groups and weakened by EFAs in the normal-weight group. This study highlighted the renal adverse effects of air pollutants and modification of FFAs, which has implications for target prevention for kidney dysfunction associated with air pollution, especially among vulnerable populations.