Soy protein compared with whey protein ameliorates insulin resistance by regulating lipid metabolism, AMPK/mTOR pathway and gut microbiota in high-fat diet-fed mice.

The findings of soy protein versus whey protein supplementation on glycemic regulation are inconsistent. The aim of the present study was to investigate the preventive effect of soy protein isolate (SPI) and whey protein isolate (WPI) on a high-fat diet (HFD) induced insulin resistance and its potential molecular mechanisms. Male C57BL/6J mice were randomly divided into seven groups (n = 12): normal control, HFD plus 10% SPI, HFD plus 20% SPI, HFD plus 30% SPI, HFD plus 10% WPI, HFD plus 20% WPI, and HFD plus 30% WPI. After 12 weeks of feeding, compared with the WPI groups, serum concentration of insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and liver weight were significantly lower in the SPI groups. Compared with the WPI groups, the mRNA levels of CD36, SLC27A1, PPARγ and AMPKα were significantly higher, and those of LPL, SREBP1c, FASN and ACC1 were significantly lower in the liver in the SPI groups. In the liver or gastrocnemius muscle, compared with the WPI groups, the mRNA levels of GLUT4, IRS-1, PI3K and AKT were significantly higher, and those of mTOR and S6K1 were significantly lower, and the protein levels of GLUT4, p-AMPKα/AMPKα, p-PI3K/PI3K and p-AKT/AKT were significantly higher, and those of p-IRS-1Ser307/IRS-1, p-mTOR/mTOR and p-S6K1/S6K1 were significantly lower in the SPI groups. The Chao1 and ACE indices were higher, and the relative abundance of Staphylococcus and Weissella was lower in the SPI groups than those in the WPI groups. In conclusion, soy protein was more effective than whey protein in preventing IR in HFD-fed mice by regulating lipid metabolism, the AMPK/mTOR pathway, and gut microbiota.

Real-ambient particulate matter exposure-induced FGFR1 methylation contributes to cardiac dysfunction via lipid metabolism disruption.

Particulate matter (PM)-induced cardiometabolic disorder contributes to the progression of cardiac diseases, but its epigenetic mechanisms are largely unknown. This study used bioinformatic analysis, in vivo and in vitro multiple models to investigate the role of PM-induced cardiac fibroblast growth factor 1 (FGFR1) methylation and its impact on cardiomyocyte lipid metabolic disruption. Bioinformatic analysis revealed that FGFR1 was associated with cardiac pathologies, mitochondrial function and metabolism, supporting the possibility that FGFR1 may play regulatory roles in PM-induced cardiac functional impairment and lipid metabolism disorders. Individually ventilated cage (IVC)-based real-ambient PM exposure system mouse models were used to expose C57/BL6 mice for six and fifteen weeks. The results showed that PM induced cardiac lipid metabolism disorder, DNA nucleotide methyltransferases (DNMTs) alterations and FGFR1 expression declines in mouse heart. Lipidomics analysis revealed that carnitines, phosphoglycerides and lysophosphoglycerides were most significantly affected by PM exposure. At the cellular level, AC16 cells treated with FGFR1 inhibitor (PD173074) led to impaired mitochondrial and metabolic functions in cardiomyocytes. Inhibition of DNA methylation in cells by 5-AZA partially restored the FGFR1 expression, ameliorated cardiomyocyte injury and mitochondrial functions. These changes involved alterations in AMP-activated protein kinase (AMPK)-peroxisome proliferator activated receptors gamma, coactivator 1 alpha (PGC1α) pathways. Bisulfite sequencing PCR (BSP) and DNA methylation specific PCR (MSP) confirmed that PM exposure induced FGFR1 gene promoter region methylation. These results suggested that, by inducing FGFR1 methylation, PM exposure would affect cardiac injury and deranged lipid metabolism. Overexpression of FGFR1 in mouse heart using adeno-associated virus 9 (AAV9) effectively alleviated PM-induced cardiac impairment and metabolic disorder. Our findings identified that FGFR1 methylation might be one of the potential indicators for PM-induced cardiac mitochondrial and metabolic dysfunction, providing novel insights into underlying PM-related cardiotoxic mechanisms.

Whey protein and soy protein prevent obesity by upregulating uncoupling protein 1 to activate brown adipose tissue and promote white adipose tissue browning in high-fat diet-fed mice.

There are inconsistent conclusions regarding the effect of whey protein and soy protein supplementation on obesity, and the underlying mechanisms of a high-protein diet for reducing weight gain remain to be elucidated. The aim of the present study was to investigate the preventive effect of whey protein and soy protein on obesity and its possible mechanism. Eighty-four male C57BL/6J mice were randomly divided into seven dietary groups: control group (10% fat) and 6 groups fed with a high-fat diet (HFD): 10% whey protein isolate (WPI), 20% WPI, 30% WPI, 10% soy protein isolate (SPI), 20% SPI and 30% SPI for 12 weeks. Compared with the 20% SPI group, the 20% WPI group had a significantly lower body weight, serum levels of insulin, total cholesterol and leptin, weight of inguinal white adipose tissue (iWAT), and size of adipocytes in iWAT and epididymal white adipose tissue (eWAT). The body mass index (BMI) and the Lee index were significantly lower in the WPI groups than those in the SPI groups at the same protein level. The body weight, body weight gain and BMI were significantly lower with the decreasing ratio of protein to carbohydrate (P/C). Compared with the 20% SPI group, the expressions of browning-related genes such as UCP1 (uncoupling protein 1), PGC-1α, AMPKα and Cidea and the protein expression of UCP1 were significantly higher in brown adipose tissue (BAT) and iWAT in the 20% WPI group. Moreover, the expressions of lipogenesis-related genes such as SREBP1c, PPARγ, LPL and DGAT1 in BAT, iWAT and eWAT in the 10% WPI group were significantly lower compared with the 10% SPI group. In conclusion, whey protein was more effective than soy protein in preventing obesity in mice, probably by suppressing lipogenesis in adipose tissues, activating BAT and promoting the browning of iWAT. In addition, lowering the P/C ratio was beneficial for combating obesity in the context of a HFD.

Real ambient particulate matter-induced lipid metabolism disorder: Roles of peroxisome proliferators-activated receptor alpha.

A growing body of evidence associated particulate matter (PM) exposure with lipid metabolism disorders, yet, the underlying mechanism remains to be elucidated. Among the major lipid metabolism modulators, peroxisome proliferator-activated receptor (PPAR) alpha plays an important role. In the current study, an individually ventilated cage (IVC) system was used to expose C57/B6 mice to real-ambient PM for six weeks, with or without co-treatment of PPAR alpha agonist WY14,643. The general parameters, liver and adipose tissue pathology, serum lipids, metal deposition and lipid profile of liver were assessed. The results indicated that six weeks of real-ambient PM exposure induced dyslipidemia, including increased serum triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C) level, along with steatosis in liver, increased size of adipocytes in white adipose tissue (WAT) and whitening of brown adipose tissue (BAT). ICP-MS results indicated increased Cr and As deposition in liver. Lipidomics analysis revealed that glycerophospholipids and cytochrome P450 pathway were most significantly affected by PM exposure. Several lipid metabolism-related genes, including CYP4A14 in liver and UCP1 in BAT were downregulated following PM exposure. WY14,643 treatment alleviated PM-induced dyslipidemia, liver steatosis and whitening of BAT, while enhancing CD36, SLC27A1, CYP4A14 and UCP1 expression. In conclusion, PPAR alpha pathway participates in PM-induced lipid metabolism disorder, PPAR alpha agonist WY14,643 treatment exerted protective effects on PM-induced dyslipidemia, liver steatosis and whitening of BAT, but not on increased adipocyte size of WAT.

Mitochondria damage in ambient particulate matter induced cardiotoxicity: Roles of PPAR alpha/PGC-1 alpha signaling.

Particulate matter (PM) had been associated with cardiotoxicity, while the mechanism of toxicity has yet to be elucidated, with mitochondria dysfunction as a potential candidate. To investigate the potential cardiotoxic effects of ambient PM exposure and assess the damage to cardiac mitochondria, C57/B6 mice were exposed to filtered air or real ambient PM for three or six weeks. Furthermore, to reveal the role of peroxisome proliferators-activated receptor alpha (PPAR alpha) in PM exposure induced cardiotoxicity/mitochondria damage, animals were also co-treated with PPAR alpha agonist WY 14,643 or PPAR alpha antagonist GW 6471. Cardiotoxicity was assessed with echocardiography and histopathology, while mitochondria damage was evaluated with mitochondria membrane potential measurement and transmission electron microscopy. Potential impacts of PM exposure to PPAR alpha signaling were detected with co-immunoprecipitation and western blotting. The results indicated that exposure to ambient PM exposure induced cardiotoxicity in C57/B6 mice, including altered cardiac functional parameters and morphology. Cardiac mitochondria damage is detected, in the form of compromised mitochondria membrane potential and morphology. Molecular investigations revealed disruption of PPAR alpha interaction with peroxisome proliferator-activated receptor gamma coactivator-1A (PGC-1a) as well as altered expression levels of PPAR alpha downstream genes. Co-treatment with WY 14,643 alleviated the observed toxicities, while co-treatment with GW 6471 had mixed results, exaggerating most cardiotoxicity and mitochondrial damage endpoints but alleviating some cardiac functional parameters. Interestingly, WY 14,643 and GW 6471 co-treatment seemed to exhibit similar regulative effects towards PPAR alpha signaling in animals exposed to PM. In conclusion, ambient PM exposure indeed induced cardiotoxicity in C57/B6 mice, in which cardiac mitochondria damage and disrupted PPAR alpha signaling are contributors.

In ovo very early-in-life exposure to diesel exhaust induced cardiopulmonary toxicity in a hatchling chick model.

Diesel exhaust (DE) had been associated with cardiopulmonary toxicity and developmental toxicity. However, neonatal very early-in-life exposure had not been extensively studied previously. To investigate the potential effects of neonatal very early-in-life exposure to DE, a brand-new chicken embryo in ovo exposure model had been established, with which the cardiopulmonary effects of DE exposure via air cell infusion at embryonic day 18/19 (ED18/19) were assessed in hatchling chicks post-hatch 0-, 1-, or 2-weeks. Heart rates were assessed with electrocardiography. Cardiac and pulmonary morphologies were investigated with histopathological methods. Cardiopulmonary effects were explored with immunohistochemistry for alpha smooth muscle actin (alpha-SMA). In further investigations, the expression levels of phosphorylated AhR, serum levels of TGF-ß1, phosphorylated SMAD2/3 and phosphorylated p38MAPK were assessed in the lung tissues. Significantly elevated heart rates, increased right ventricular wall thickness and cardiac collagen deposition were observed in the hearts of exposed hatchling chicks. Significantly increased collagen deposition as well as increased vascular alpha-SMA layer thickness/decreased cavity area were observed in exposed animal lungs. These effects persisted up to two weeks post-hatch. Mechanistic studies revealed elevated phosphorylated AhR expression levels in 0-week and 1-week chicken lungs, while phosphorylated SMAD2/3 levels significantly increased in 0-week chicken lungs but decreased in 2-week chicken lungs following DE exposure. Phosphorylation of p38MAPK did not remarkably increase until 2-week post-hatch. In summary, the novel chicken neonatal very early-in-life exposure model effectively exposed the chicken embryos during the neonatal initial breathing, resulting in cardiopulmonary toxicity, which is associated with AHR, TGF-ß1 and MAPK signaling.

Real-Ambient Particulate Matter Exposure-Induced Cardiotoxicity in C57/B6 Mice.

It is generally accepted that exposure to particulate matter (PM) increases the risk of cardiovascular-related morbidity and mortality, though the exact mechanism behind this has yet to be elucidated. Oxidative stress plays a potentially important role in the mechanism of toxicity, with Nrf2 serving as a major antioxidant gene. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential cardiotoxicity induced by real-ambient PM exposure and the potential role of Nrf2 and related signaling in this endpoint. After 6- or 11-weeks exposure to PM, ICP-mass spectrometry was used to assess the metal depositions in the heart tissue following PM exposure. Functional and morphological changes in the hearts were investigated with echocardiography and histopathology, and oxidative stress levels were assessed with a serum malondialdehyde content assay. In the further mechanistic study, an RNA-seq technique was utilized to assess the gene transcription status in the hearts of C57/B6 mice exposed to PM with or without Nrf2 knockout. The expression levels of genes of interest were then further investigated with quantitative real-time PCR and western blotting. The results indicated that PM exposure resulted in significant elevation of sodium, potassium, selenium, and ferrum levels in mouse heart tissue. Meanwhile, significantly altered heart function and morphology were observed. Interestingly, Nrf2 knockout led to abolishment of PM-induced effects in several functional parameters but not the morphological changes. Meanwhile, elevated malondialdehyde content was observed in Nrf2 knockout animals. RNA-seq results revealed thousands of genes altered by PM exposure and/or Nrf2 knockout, and this affected several pathways, such as MAPK, phagosome, calcium signaling, and JAK-STAT. In subsequent molecular studies, enhanced nuclear translocation of Nrf2 was also observed following PM exposure, while the MAPK signaling pathway along with related JAK-STAT and TGF-ß1 pathway genes, such as p38MAPK, AKT, TAK1, JAK1, STAT3, GRB2, TGFb1, and SMAD2, were confirmed to be affected by PM exposure and/or Nrf2 knockout. The data suggested that PM may induce cardiotoxicity in C57/B6 mice in which Nrf2 plays both protective and detrimental roles involving cardiac-related pathways, such as MAPK, JAK-STAT, and TGF-ß1.

Morphological Evolution of Tetrachlorinated Perylene Bisimides with Lengthy Alkyl Substituent Polycrystalline Thin Films during Reversible Phase Transitions.

The phase behavior and related morphological evolution of thin films of lengthy alkyl substituted core-tetrachlorinated perylene bisimide (C18-4ClPBI), a large π-conjugated molecule, have been studied. It is found that the C18-4ClPBI can exist in two different crystalline phases depending on temperature, which transform reversibly in heating and cooling processes. The X-ray diffraction results demonstrate that the two crystalline forms of C18-4ClPBI exhibit a similar packing geometry but with different unit cell dimensions. It is confirmed that the low-temperature phase is packed more compactly than its high-temperature counterpart. During high-temperature to low-temperature crystalline phase transition, nonbirefringent protrusions were observed, which disassembled in the reverse crystalline phase transition process during heating. The exact formation mechanism of the protrusions is not clear at the moment. Nevertheless, their influence on the transfer characteristics of the polycrystalline C18-4ClPBI thin film has been clearly illustrated.

Prevalence and Associated Risk Factors of Chronic Kidney Disease in an Elderly Population from Eastern China.

Chronic kidney disease (CKD) is a global major public health problem. Almost all of previous studies evaluating the prevalence of CKD focused on adults, while studies among the elderly were relatively rare, especially in China. The aim of this study was to investigate the prevalence and associated risk factors of CKD among the elderly in Qingdao, China. This was a cross-sectional study with 38,038 inhabitants (aged 60-109) randomly recruited in Qingdao, China. All participants were required to complete a questionnaire for their demographic characteristics. Blood and urine samples of participants were collected, and the albumin and creatinine levels were measured for albuminuria and estimated glomerular filtration rate (eGFR) assessment. The associations between risk factors and indicators of kidney damage were analyzed by logistic regression. A total of 34,588 inhabitants completed the survey. The overall prevalence of CKD was 11.41% (95% confidence interval (CI): 11.07-11.74%) in the elders from Qingdao in 2016. The prevalence of albuminuria and low eGFR (<60 mL/min per 1·73 m²) were 8.47% (95% CI: 8.17-8.76%) and 3.98% (95% CI: 3.78-4.19%), respectively. Older age, hypertension, diabetes, anemia, hyperuricemia, hyperhomocysteinemia, hypertriglyceridemia, obesity, and LDL-C ≥ 4.1 mmol/L were independently associated with the presence of CKD. In conclusion, common chronic non-communicable diseases, including hypertension, diabetes, obesity, hyperhomocysteinemia, hyperuricemia, and hypertriglyceridemia, were associated with greater prevalence of CKD.

Perfluorooctanoic acid-induced toxicities in chicken embryo primary cardiomyocytes: Roles of PPAR alpha and Wnt5a/Frizzled2.

Perfluorooctanoic acid (PFOA) is a widespread persistent organic pollutant and may induce developmental toxicities, including developmental cardiotoxicity. To explore the potential mechanism of developmental cardiotoxicity induced by PFOA exposure, chicken embryo primary cardiomyocytes were extracted either from chicken embryos pretreated with PFOA (2 mg/kg), or from untreated embryos and then directly exposed cells to PFOA (1, 10, 30 or 100 µg/ml) in culture. Additionally, peroxisome proliferator activated receptor alpha (PPAR alpha) silencing lentivirus was applied to the embryos on embryonic day (ED2). Cell viability was measured with CCK-8 kit, morphology was assessed with hematoxylin and eosin staining, and intracellular Ca2+ concentrations were determined with Fluo-4 AM probe. Western blotting was utilized to confirm PPAR alpha silencing efficiency and the protein abundance of Wnt5a and Frizzled2. The results indicated that both PFOA pretreatment and direct exposure decreased primary cardiomyocyte viability, altered cell morphology and increased intracellular Ca2+ concentrations. While l-carnitine co-treatment effectively abolished such changes, PPAR alpha silencing only abolished most of the changes in PFOA pretreatment group, but not in cells directly exposed to relatively high doses of PFOA. The protein abundance of Wnt5a and Frizzled2 was increased by PFOA pretreatment, while direct exposure to PFOA increased Frizzled2 abundance but decreased Wnt5a abundance. PPAR alpha silencing resulted in over 50% decrease of PPAR alpha expression level, which abolished the Wnt5a/Frizzled2 expression alterations following PFOA exposure. In conclusion, PFOA-induced primary cardiomyocyte toxicity is associated with PPAR alpha and Wnt5a/Frizzled2, in which PPAR alpha seems to play regulatory roles towards Wnt5a/Frizzled2.