Desipramine ameliorates fine particulate matter-induced hepatic insulin resistance by modulating the ceramide metabolism in mice.

Recent research has highlighted a correlation between exposure to ambient fine particulate matter (PM2.5) and the development of systemic insulin resistance (IR) along with an elevated risk of diabetes. Ceramide has emerged as one of the pathogenic mechanisms contributing to IR. The inhibition of acid sphingomyelinase (ASMase) activity by desipramine (DES) has been shown to effectively reduce ceramide levels. In the present study, 24 female C57BL/6 N mice were randomized into one of the four groups: the filtered air exposure (FA) group, the concentrated PM2.5 exposure (PM) group, the concentrated PM2.5 treated with low-dose DES (DL) group, and the concentrated PM2.5 treated with high-dose DES (DH) group. The PM, DL and DH groups were exposed to PM2.5 for an 8-week period within a whole-body exposure system. The study encompassed extensive examinations of glucose homeostasis, liver lipid profile, ceramide pathway, and insulin signaling pathway. Our results demonstrated that PM2.5 exposure caused impaired glucose tolerance, elevated ceramide levels, increased phosphorylation PP2A, reduced Akt phosphorylation, and hindered GLUT2 expression. Remarkably, DES administration mitigated PM2.5-induced IR by effectively lowering ceramide levels. In conclusion, the reduction of ceramide levels by DES may be a promising therapeutic strategy for coping PM2.5-induced IR.

Exposure memory and susceptibility to ambient PM2.5: A perspective from hepatic cholesterol and bile acid metabolism.

Both epidemiological and experimental studies increasingly show that exposure to ambient fine particulate matter (PM2.5) is related to the occurrence and development of chronic diseases, such as metabolic diseases. However, whether PM2.5 has "exposure memory" and how these memories affect chronic disease development like hepatic metabolic homeostasis are unknown. Therefore, we aimed to explore the effects of exposure transition on liver cholesterol and bile acids (BAs) metabolism in mice. In this study, C57BL/6 mice were exposed to concentrated ambient PM2.5 or filtered air (FA) in a whole-body exposure facility for an initial period of 10 weeks, followed by another 8 weeks of exposure switch (PM2.5 to FA and FA to PM2.5) comparing to non-switch groups (FA to FA and PM2.5 to PM2.5), which were finally divided into four groups (FF of FA to FA, PP of PM2.5 to PM2.5, PF of PM2.5 to FA, and FP of FA to PM2.5). Our results showed no significant difference in food intake, body composition, glucose homeostasis, and lipid metabolism between FA and PM2.5 groups after the initial exposure before the exposure switch. At the end of the exposure switch, the mice switched from FA to PM2.5 exposure exhibited a high sensitivity to late-onset PM2.5 exposure, as indicated by significantly elevated hepatic cholesterol levels and disturbed BAs metabolism. However, the mice switched from PM2.5 to FA exposure retained a certain memorial effects of previous PM2.5 exposure in hepatic cholesterol levels, cholesterol metabolism, and BAs metabolism. Furthermore, 18-week PM2.5 exposure significantly increased hepatic free BAs levels, which were completely reversed by the FA exposure switch. Finally, the changes in small heterodimeric partner (SHP) and nuclear receptor subfamily 5 group A member 2 (LRH1) in response to exposure switch mechanistically explained the above alterations. Therefore, mice switching from PM2.5 exposure to FA showed only a weak memory of prior PM2.5 exposure. In contrast, the early FA caused mice to be more susceptible to subsequent PM2.5 exposure.

PM2.5-induced cellular senescence drives brown adipose tissue impairment in middle-aged mice.

Airborne fine particulate matter (PM2.5) exposure is closely associated with metabolic disturbance, in which brown adipose tissue (BAT) is one of the main contributing organs. However, knowledge of the phenotype and mechanism of PM2.5 exposure-impaired BAT is quite limited. In the study, male C57BL/6 mice at three different life phases (young, adult, and middle-aged) were simultaneously exposed to concentrated ambient PM2.5 or filtered air for 8 weeks using a whole-body inhalational exposure system. H&E staining and high-resolution respirometry were used to assess the size of adipocytes and mitochondrial function. Transcriptomics was performed to determine the differentially expressed genes in BAT. Quantitative RT-PCR, immunohistochemistry staining, and immunoblots were performed to verify the transcriptomics and explore the mechanism for BAT mitochondrial dysfunction. Firstly, PM2.5 exposure caused altered BAT morphology and mitochondrial dysfunction in middle-aged but not young or adult mice. Furthermore, PM2.5 exposure increased cellular senescence in BAT of middle-aged mice, accompanied by cell cycle arrest, impaired DNA replication, and inhibited AKT signaling pathway. Moreover, PM2.5 exposure disrupted apoptosis and autophagy homeostasis in BAT of middle-aged mice. Therefore, BAT in middle-aged mice was more vulnerable to PM2.5 exposure, and the cellular senescence-initiated apoptosis, autophagy, and mitochondrial dysfunction may be the mechanism of PM2.5 exposure-induced BAT impairment.

Early Pulmonary Fibrosis-like Changes in the Setting of Heat Exposure: DNA Damage and Cell Senescence.

It is well known that extreme heat events happen frequently due to climate change. However, studies examining the direct health impacts of increased temperature and heat waves are lacking. Previous reports revealed that heatstroke induced acute lung injury and pulmonary dysfunction. This study aimed to investigate whether heat exposure induced lung fibrosis and to explore the underlying mechanisms. Male C57BL/6 mice were exposed to an ambient temperature of 39.5 ± 0.5 °C until their core temperature reached the maximum or heat exhaustion state. Lung fibrosis was observed in the lungs of heat-exposed mice, with extensive collagen deposition and the elevated expression of fibrosis molecules, including transforming growth factor-ß1 (TGF-ß1) and Fibronectin (Fn1) (p < 0.05). Moreover, epithelial-mesenchymal transition (EMT) occurred in response to heat exposure, evidenced by E-cadherin, an epithelial marker, which was downregulated, whereas markers of EMT, such as connective tissue growth factor (CTGF) and the zinc finger transcriptional repressor protein Slug, were upregulated in the heat-exposed lung tissues of mice (p < 0.05). Subsequently, cell senescence examination revealed that the levels of both senescence-associated ß-galactosidase (SA-ß-gal) staining and the cell cycle protein kinase inhibitor p21 were significantly elevated (p < 0.05). Mechanistically, the cGAS-STING signaling pathway evoked by DNA damage was activated in response to heat exposure (p < 0.05). In summary, we reported a new finding that heat exposure contributed to the development of early pulmonary fibrosis-like changes through the DNA damage-activated cGAS-STING pathway followed by cellular senescence.

Metabolic Profile and Lipid Metabolism Phenotype in Mice with Conditional Deletion of Hepatic BMAL1.

The disruption of circadian rhythms (CRs) has been linked to metabolic disorders, yet the role of hepatic BMAL1, a key circadian regulator, in the whole-body metabolism and the associated lipid metabolic phenotype in the liver remains unclear. Bmal1 floxed (Bmal1f/f) and hepatocyte-specific Bmal1 knockout (Bmal1hep-/-) C57BL/6J mice underwent a regular feeding regimen. Hepatic CR, lipid content, mitochondrial function, and systemic metabolism were assessed at zeitgeber time (ZT) 0 and ZT12. Relevant molecules were examined to elucidate the metabolic phenotype. Hepatocyte-specific knockout of Bmal1 disrupted the expression of rhythmic genes in the liver. Bmal1hep-/- mice exhibited decreased hepatic TG content at ZT0, primarily due to enhanced lipolysis, reduced lipogenesis, and diminished lipid uptake. The ß-oxidation function of liver mitochondria decreased at both ZT0 and ZT12. Our findings on the metabolic profile and associated hepatic lipid metabolism in the absence of Bmal1 in hepatocytes provides new insights into metabolic syndromes from the perspective of liver CR disturbances.

Hawthorn total flavonoids ameliorate ambient fine particulate matter-induced insulin resistance and metabolic abnormalities of lipids in mice.

Recent studies have shown a strong correlation between ambient fine particulate matter (PM2.5) exposure and diabetes risk, including abnormal lipid accumulation and systemic insulin resistance (IR). Hawthorn total flavonoids (HF) are the main groups of active substances in Hawthorn, which showed anti-hyperlipidemic and anti-hyperglycemic effects. Therefore, we hypothesized that HF may attenuate PM2.5-induced IR and abnormal lipid accumulation. Female C57BL/6 N mice were randomly assigned to the filtered air exposure (FA) group, concentrated PM2.5 exposure (PM) group, PM2.5 exposure maintained on a low-dose HF diet (LHF) group, and PM2.5 exposure maintained on a high-dose HF diet (HHF) group for an 8-week PM2.5 exposure using a whole-body exposure device. Body glucose homeostasis, lipid profiles in the liver and serum, and enzymes responsible for hepatic lipid metabolism were measured. We found that exposure to PM2.5 impaired glucose tolerance and insulin sensitivity. In addition, triacylglycerol (TAG) in serum elevated, whereas hepatic TAG levels were decreased after PM2.5 exposure, accompanied by inhibited fatty acid uptake, lipogenesis, and lipolysis in the liver. HF administration, on the other hand, balanced the hepatic TAG levels by increasing fatty acid uptake and decreasing lipid export, leading to alleviated systemic IR and hyperlipidemia in PM2.5-exposed mice. Therefore, HF administration may be an effective strategy to protect against PM2.5-induced IR and metabolic abnormalities of lipids.

Gestational exposure to PM2.5 disrupts fetal development by suppressing placental trophoblast syncytialization via progranulin/mTOR signaling.

Recent epidemiological and animal studies have indicated that ambient fine particulate matter (PM2.5) exposure during pregnancy is closely associated with intrauterine growth restriction (IUGR). However, the underlying mechanisms remain to be revealed. In this study, we found that gestational exposure to PM2.5 significantly decreased fetal weight and crown-rump length in mice, accompanied by insufficient placental trophoblast syncytialization and increased expression of progranulin (PGRN) in mice placenta. Administering PGRN neutralizing antibody to pregnant mice alleviated growth restriction and insufficient placental trophoblast syncytialization caused by PM2.5, accompanied with suppressed activation of the mTOR signaling pathway. Furthermore, in vitro experiments using human placental BeWo cells showed that 10 µg·mL-1 PM2.5 activated PGRN/mTOR signaling and suppressed forskolin-induced cell fusion, which was blocked by knockdown of PGRN. Taken together, our results demonstrated that PM2.5 exposure during pregnancy inhibited placental trophoblast syncytialization by activating PGRN/mTOR signaling, leading to abnormal placental development and IUGR. This study reveals a novel mechanism underlying the developmental toxicity of PM2.5 exposure during pregnancy.

LRRK2 is involved in heat exposure-induced acute lung injury and alveolar type II epithelial cell dysfunction.

Heat exposure induces excessive hyperthermia associated with systemic inflammatory response that leads to multiple organ dysfunction including acute lung injury. However, how heat impairs the lung remains elusive so far. We aimed to explore the underlying mechanism by focusing on leucine-rich repeat kinase 2 (LRRK2), which was associated with lung homeostasis. Both in vivo and in vitro models were induced by heat exposure. Firstly, heat exposure exerted core temperature (Tc) disturbance, pulmonary dysfunction, atelectasis, inflammation, impaired energy metabolism, and reduced surfactant proteins in the lung of mice. In addition, decreased LRRK2 expression and increased heat shock proteins (HSPs) 70 were observed with heat exposure in both the lung of mice and alveolar type II epithelial cells (AT2). Furthermore, LRRK2 inhibition aggravated heat exposure-initiated Tc dysregulation, injury in the lung and AT2 cells, and enhanced HSP70 expression. In conclusion, LRRK2 is involved in heat-induced acute lung injury and AT2 cell dysfunction.

Lung function benefits of traditional Chinese medicine Qiju granules against fine particulate air pollution exposure: a randomized controlled trial.

Introduction: Multiple targets are considered as the causes of ambient fine particulate matter [aerodynamic diameters of < 2.5 µm (PM2.5)] induced lung function injury. Qiju granules are derived from the traditional Chinese medicine (TCM) formula known as Qi-Ju-Di-Huang-Wan (Lycium, Chrysanthemum, and Rehmannia Formula, QJDHW), which has been traditionally used to treat symptoms such as cough with phlegm, dry mouth and throat, and liver heat. This treatment approach involves attenuating inflammation, oxidative stress, and fibrosis response. This study investigated the effects of Qiju granules on protecting lung function against PM2.5 exposure in a clinical trial. Methods: A randomized, double-blinded, and placebo-controlled trial was performed among 47 healthy college students in Hangzhou, Zhejiang Province in China. The participants were randomly assigned to the Qiju granules group or the control group based on gender. Clinical follow-ups were conducted once every 2 weeks during a total of 4 weeks of intervention. Real-time monitoring of PM2.5 concentrations in the individually exposed participants was carried out. Data on individual characteristics, heart rate (HR), blood pressure (BP), and lung function at baseline and during the follow-ups were collected. The effects of PM2.5 exposure on lung function were assessed within each group using linear mixed-effect models. Results: In total, 40 eligible participants completed the scheduled follow-ups. The average PM2.5 level was found to be 64.72 µg/m3 during the study period. A significant negative correlation of lung function with PM2.5 exposure concentrations was observed, and a 1-week lag effect was observed. Forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), maximal mid-expiratory flow (MMEF), forced expiratory flow at 75% of forced vital capacity (FVC) (FEF75), forced expiratory flow at 50% of FVC (FEF50), and forced expiratory flow at 25% of FVC (FEF25) were significantly decreased due to PM2.5 exposure in the control group. Small airway function was impaired more seriously than large airway function when PM2.5 exposure concentrations were increased. In the Qiju granules group, the associations between lung function and PM2.5 exposure were much weaker, and no statistical significance was observed. Conclusion: The results of the study showed that PM2.5 exposure was associated with reduced lung function. Qiju granules could potentially be effective in protecting lung functions from the adverse effects of PM2.5 exposure. Clinical Trial Registration: identifier: ChiCTR1900021235.