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.

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.

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 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.

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.

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.

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.

Association of multiple air pollutants with oxygen saturation during sleep in COPD patients: Effect modification by smoking status and airway inflammatory phenotypes.

Air pollution contributes substantially to the development of chronic obstructive pulmonary disease (COPD). To date, the effect of air pollution on oxygen saturation (SpO2) during sleep and potential susceptibility factors remain unknown. In this longitudinal panel study, real-time SpO2 was monitored in 132 COPD patients, with 270 nights (1615 h) of sleep SpO2 recorded. Exhaled nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) were measured to assess airway inflammatory characteristics. Exposure levels of air pollutants were estimated by infiltration factor method. Generalized estimating equation was used to investigate the effect of air pollutants on sleep SpO2. Ozone, even at low levels (<60 µg/m3), was significantly associated with decreased SpO2 and extended time of oxygen desaturation (SpO2 < 90%), especially in the warm season. The associations of other pollutants with SpO2 were weak, but significant adverse effects of PM10 and SO2 were observed in the cold season. Notably, stronger effects of ozone were observed in current smokers. Consistently, smoking-related airway inflammation, characterized by higher levels of exhaled CO and H2S but lower NO, significantly augmented the effect of ozone on SpO2 during sleep. This study highlights the importance of ozone control in protecting sleep health in COPD patients.

MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell-intrinsic Amplification of Type I IFN Signaling.

PURPOSE: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL DESIGN: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. RESULTS: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation. CONCLUSIONS: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

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.

Generation of liver metastases in a mouse model using ultrasound-guided intravenous injection.

Here, we present a protocol to generate a murine model of liver metastasis by directly injecting tumor cells into the portal vein under ultrasound guidance. We describe steps for animal and cell preparation and two techniques for injecting tumor cells. One technique is freehand, while the other technique is device-assisted using a 3D-printed prototype device. Finally, we describe tumor surveillance with bioluminescent imaging.

18F-FDG PET Visualizes Systemic STING Agonist-Induced Lymphocyte Activation in Preclinical Models.

Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with 18F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. 18F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on 18F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased 18F-FDG uptake in the spleen. The average spleen SUVmax in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in STING agonist-treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased 18F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that 18F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development.

Joint effect of multiple air pollutants on cardiometabolic health in normal-weight and obese adults: A novel insight into the role of circulating free fatty acids.

The cardiometabolic effects of air pollution in the context of mixtures and the underlying mechanisms remain not fully understood. This study aims to investigate the joint effect of air pollutant mixtures on a broad range of cardiometabolic parameters, examine the susceptibility of obese individuals, and determine the role of circulating fatty acids. In this panel study, metabolically healthy normal-weight (MH-NW, n = 49) and obese (MHO, n = 39) adults completed three longitudinal visits (257 person-visits in total). Personal exposure levels of PM2.5, PM10, O3, NO2, SO2, CO and BC were estimated based on fixed-site monitoring data, time-activity logs and infiltration factor method. Blood pressure, glycemic homeostasis, lipid profiles, systematic inflammation and coagulation biomarkers were measured. Targeted metabolomics was used to quantify twenty-eight plasma free fatty acids (FFAs). Bayesian kernel machine regression models were applied to establish the exposure-response relationships and identify key pollutants. Significant joint effects of measured air pollutants on systematic inflammation and coagulation biomarkers were observed in the MHO group, instead of the MH-NW group. Lipid profiles showed the most significant changes in both groups and O3 contributed the most to the total effect. Specific FFA patterns were identified, and de novo lipogenesis (DNL)-related pattern was most closely related to blood lipid profiles. In particular, interaction analysis suggested that DNL-related FFA pattern augmented the effects of O3 on triglyceride (TG, Pinteraction = 0.040), high-density lipoprotein cholesterol (HDL-C, Pinteraction = 0.106) and TG/HDL-C (Pinteraction = 0.020) in the MHO group but not MH-NW group. This modification was further confirmed by interaction analysis with estimated activity of SCD1, a key enzyme in the DNL pathway. Therefore, despite being metabolically healthy, obese subjects have a higher cardiometabolic susceptibility to air pollution, especially O3, and the DNL pathway may represent an intrinsic driver of lipid susceptibility. This study provides new insights into the cardiometabolic susceptibility of obese individuals to air pollution.

Hawthorn fruit extract ameliorates H2O2-induced oxidative damage in neuronal PC12 cells and prolongs the lifespan of Caenorhabditis elegans via the IIS signaling pathway.

Hawthorn (Crataegus pinnatifida) fruit has a long history of use as traditional Chinese medicine and is shown to have many health benefits including antioxidant and anti-aging. In this study, the anti-aging mechanism of hawthorn fruit extract (HFE) is predicted by network pharmacology and further verified in H2O2-induced PC12 cells and Caenorhabditis elegans. Network pharmacology predicted that the antiaging mechanism of HFE is mainly involved in phosphoinositide 3-kinase (PI3K)/AKT and the insulin/insulin-like growth factor-1 (IIS) signaling pathway. HFE significantly improved cell viability, increased superoxide dismutase, catalase, and glutathione peroxidase activity, decreased lactate dehydrogenase release, the level of reactive oxygen species (ROS), and malondialdehyde content in H2O2-induced PC12 cells (p < 0.05). HFE significantly increased the mean lifespan of C. elegans by 28.43% (100 µg mL-1) and enhanced the stress resistance to H2O2, paraquat, juglone, ultraviolet radiation, and heat shock. HFE also suppressed the accumulation of aging pigments, improved the body bending ability, increased antioxidant enzyme activities, and reduced the contents of ROS and malondialdehyde. In addition, relevant gene expression, lifespan experiments with mutant strains, and molecular docking studies supported the results that HFE might extend lifespan through the IIS signal pathway.

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.

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity.

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.

Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells.

We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.

Short-term ozone exposure and metabolic status in metabolically healthy obese and normal-weight young adults: A viewpoint of inflammatory pathways.

Unhealthy metabolic status increases risks of cardiovascular and other diseases. This study aims to explore whether there is a link between O3 and metabolic health indicators through a viewpoint of inflammatory pathways. 49 metabolically healthy normal-weight (MH-NW) and 39 metabolically healthy obese (MHO) young adults aged 18-26 years were recruited from a panel study with three visits. O3 exposure were estimated based on fixed-site environmental monitoring data and time-activity diary for each participant. Compared to MH-NW people, MHO people were more susceptible to the adverse effects on metabolic status, including blood pressure, glucose, and lipid indicators when exposed to O3. For instance, O3 exposure was associated with significant decreases in high-density lipoprotein cholesterol (HDL-C), and increases in C-peptide and low-density lipoprotein cholesterol (LDL-C) among MHO people, while only weaker changes in HDL-C and LDL-C among MH-NW people. Mediation analyses indicated that leptin mediated the metabolic health effects in both groups, while eosinophils and MCP-1 were also important mediating factors for the MHO people. Although both with a metabolically healthy status, compared to normal-weight people, obese people might be more susceptible to the negative effects of O3 on metabolic status, possibly through inflammatory indicators such as leptin, eosinophils, and MCP-1.

Joint effect of multiple air pollutants on lipid profiles in obese and normal-weight young adults: The key role of ozone.

Dyslipidemia may be a potential mechanism linking air pollution to adverse cardiovascular outcomes and this may differ among obese and normal-weight populations. However, the joint effect of multiple air pollutants on lipid profiles and the role of each pollutant are still unclear. This panel study aims to investigate and compare the overall associations of major air pollutants with lipid parameters in obese and normal-weight adults, and assess the relative importance of each pollutant for lipid parameters. Forty-four obese and 53 normal-weight young adults were recruited from December 2017 to June 2018 in Beijing, China. Their fasting blood was collected and serum lipid levels were measured in three visits. Six major air pollutants were included in this study, which were PM2.5, PM10, NO2, SO2, O3 and CO. Bayesian kernel machine regression (BKMR) was implemented to estimate the joint effect of the six air pollutants on various lipid parameters. We found that decreased high-density lipoprotein cholesterol (HDL-C) in the obese group and increased low-density lipoprotein cholesterol (LDL-C) and non-HDL-C in the normal-weight group were associated with the exposure to the mixture of six air pollutants above. Significant increases in total cholesterol (TC)/HDL-C and non-HDL-C/HDL-C were observed in both groups, and the effect was stronger in obese group. Of the six air pollutants above, O3 had the largest posterior inclusion probability in above lipid indices, ranging from 0.75 to 1.00. In the obese group, approximately linear exposure-response relationships were observed over the whole range of logarithmic O3-8 h max concentration, while in the normal-weight group, these relationships existed when the logarithmic concentration exceeded about 2.8. Therefore, lipid profiles of obese adults may be more sensitive to air pollution and this study highlights the importance of strengthening emissions control efforts for O3 in the future.