Mitochondria can be used as important biomarkers of pollutants on human health, and fine particulate matter (PM2.5) has been documented to cause respiratory damage. However, current studies about the ...relationship between PM2.5 and mitochondria in respiratory tract are limited and warrant further detailed investigations. Hence, the study was aimed to evaluate effects of PM2.5 on mitochondrial structure, investigate the link between PM2.5-induced mitochondrial disorder and respiratory damage, and delineate the possible mechanisms using both in vitro and in vivo models. PM2.5 exposure resulted in damage of mitochondrial structure, including mitochondrial dynamic, DNA biogenesis and morphological alteration 16HBE cells. Furthermore, PM2.5 elevated ROS formation. However, DPI and NAC (inhibitor of ROS) in supplement restored PM2.5-induced mitochondrial disorder. PM2.5 also contributed to the 16HBE cells apoptosis via mitochondrial pathway. Additionally, the results coincided with the in vivo data which were obtained from bronchial tissues of SD rats exposed to PM2.5 for 30 days. Collectively, this study uncovers that PM2.5 leads to the disorder of mitochondrial structure via ROS generation, and then results in respiratory damage. It provides further understanding about the detrimental effect of PM2.5 on respiratory damage, and reveals a mechanistic basis for preventing outcomes in polluted environments.
Tumor cells undergo metabolic rewiring from oxidative phosphorylation towards aerobic glycolysis to maintain the increased anabolic requirements for cell proliferation. It is widely accepted that ...specific expression of the M2 type pyruvate kinase (PKM2) in tumor cells contributes to this aerobic glycolysis phenotype. To date, researchers have uncovered myriad forms of functional regulation for PKM2, which confers a growth advantage on the tumor cells to enable them to adapt to various microenvironmental signals. Here the richness of our understanding on the modulations and functions of PKM2 in tumor progression is reviewed, and some new insights into the paradoxical expression and functional differences of PKM2 in distinct cancer types are offered.
•The expression of PKM2 is regulated at different levels.•PKM2 activity is regulated by protein modification, protein interaction and metabolites.•PKM2 exhibits both metabolic and non-metabolic functions.•PKM2 is a molecule of important clinical implications.
The Pathogenesis of Diabetes Guo, Huiqin; Wu, Haili; Li, Zhuoyu
International journal of molecular sciences,
04/2023, Volume:
24, Issue:
8
Journal Article
Peer reviewed
Open access
Diabetes is the most common metabolic disorder, with an extremely serious effect on health systems worldwide. It has become a severe, chronic, non-communicable disease after cardio-cerebrovascular ...diseases. Currently, 90% of diabetic patients suffer from type 2 diabetes. Hyperglycemia is the main hallmark of diabetes. The function of pancreatic cells gradually declines before the onset of clinical hyperglycemia. Understanding the molecular processes involved in the development of diabetes can provide clinical care with much-needed updates. This review provides the current global state of diabetes, the mechanisms involved in glucose homeostasis and diabetic insulin resistance, and the long-chain non-coding RNA (lncRNA) associated with diabetes.
Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in the cure of colon cancer. Therefore, there is an urgent need to explore a safe and effective multidrug ...resistance reversal agent for colorectal cancer, which would be of great significance for improving clinical efficacy. The dietary flavonoid kaempferol plays a key role in the progression of colorectal cancer and 5-Fu resistance. However, the molecular mechanism of kaempferol in reversing 5-Fu resistance in human colorectal cancer cells is still unclear. We found that kaempferol could reverse the drug resistance of HCT8-R cells to 5-Fu, suggesting that kaempferol alone or in combination with 5-Fu has the potential to treat colorectal cancer. It is well known that aerobic glycolysis is related to tumor growth and chemotherapy resistance. Indeed, kaempferol treatment significantly reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells. In terms of mechanism, kaempferol promotes the expression of microRNA-326 (miR-326) in colon cancer cells, and miR-326 could inhibit the process of glycolysis by directly targeting pyruvate kinase M2 isoform (PKM2) 3'-UTR (untranslated region) to inhibit the expression of PKM2 or indirectly block the alternative splicing factors of PKM mRNA, and then reverse the resistance of colorectal cancer cells to 5-Fu. Taken together, our data suggest that kaempferol may play an important role in overcoming resistance to 5-Fu therapy by regulating the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.
Apigenin (AP), as an anticancer agent, has been widely explored. However, the molecular targets of apigenin on tumor metabolism are unclear. Herein, we found that AP could block cellular glycolysis ...through restraining the tumor-specific pyruvate kinase M2 (PKM2) activity and expression and further significantly induce anti-colon cancer effects. The IC50 values of AP against HCT116, HT29, and DLD1 cells were 27.9 ± 2.45, 48.2 ± 3.01 and 89.5 ± 4.89 μM, respectively. Fluorescence spectra and solid-phase AP extraction assays proved that AP could directly bind to PKM2 and markedly inhibit PKM2 activity in vitro and in HCT116 cells. Interestingly, in the presence of d-fructose-1,6-diphosphate (FBP), the inhibitory effect of AP on PKM2 was not reversed, which suggests that AP is a new allosteric inhibitor of PKM2. RT-PCR and Western blot assays showed that AP could ensure a low PKM2/PKM1 ratio in HCT116 cells via blocking the β-catenin/c-Myc/PTBP1 signal pathway. Hence, PKM2 represents a novel potential target of AP against colon cancer.
Exposure to fine particulate matter (PM2.5) has a close association with respiratory damage. Vitamin c and quercetin have been documented to possess antioxidant and anti-inflammation properties. ...However, their potential protective effects against PM2.5-induced respiratory damage have not been evaluated yet. Hence, the study was aimed to investigate their protective effects and delineate the possible mechanisms. The results indicated that PM2.5 depleted the cell viability of 16HBE cells, elevated reactive oxygen species (ROS) generation, and inhibited mitochondrial genes expressions, including fusion proteins Mfn1 and OPA1, along with biogenesis markers SIRT1 and p53R2. Additionally, the damage of mitochondrial morphology was observed upon PM2.5 exposure using both JC-1 and MitoTracker Red staining. Expressions of mitochondrial respiratory chain genes including NDUFS2 and UQCRI1 were also attenuated by PM2.5 exposure. Furthermore, PM2.5 promoted the mRNA levels of NADPH oxidase and inflammation cytokines. However, the addition of vitamin c or quercetin strikingly antagonized the PM2.5-induced toxic effects. Collectively, these findings suggest that vitamin c and quercetin have repressive roles in respiratory oxidative damage incurred by PM2.5, which provide the theoretical basis about intervention and control of food nutrients on PM2.5-induced human adverse health.
•Vitamin c and quercetin can relief the toxicity caused by PM2.5 on 16HBE cells.•Vitamin c and quercetin prominently alleviate the PM2.5-induced ROS generation.•Vitamin c and quercetin supplement significantly counteract the NOX2 and p67phox expressions incurred by PM2.5.•Vitamin c and quercetin have suppressive roles in mitochondrial structure and function damaged by PM2.5.•Vitamin c and quercetin play protective effects on inflammation response affected by PM2.5.
Foxtail millet (Setaria italica) is a whole millet grain that has been considered for improving the disorder of glucose and lipid metabolism. The purpose of the work is to explore the extraction and ...enrichment of polyphenols from foxtail millets which can regulate the disorder of glucose and lipid metabolism by increasing endogenous GLP-1(Glucagon-like peptide-1).
The optimum ultrasound-assisted extraction (UAE) of foxtail millet polyphenols (FMP) was as follows: 70 °C and 400 W and 70% ethanol concentration, further purification using macroporous resin. In vitro, the FMP eluent of 60% ethanol (FMP-60) has the best effect in promoting GLP-1 secretion from L cells among the different active components of FMP. Millet polyphenols (MP) were obtained from finishing foxtail millet with the bran removed by the same extraction and purification method. Compared with MP-60, FMP-60 mainly included eight active phenolic constituents and contained more ferulic acid, p-coumaric acid, 2-Hydroxycinnamic acid, and Coniferaldehyde. After gavage treatment of DIO mice with FMP-60, FMP-60 promoted endogenous GLP-1 secretion in mice and ameliorated disorders of glucolipid metabolism in DIO mice.
FMP-60 could improve glucose homeostasis and ameliorates metabolic disease by promoting the endogenous GLP-1 level and preventing weight gain in diet-induced obese mice. This article is protected by copyright. All rights reserved.
Warning sign plays an important role in risk avoidance. Many studies have found that images are better warnings than text, while others have revealed flaws of image-only warning signs. To better ...understand the factors underlying the effectiveness of different types of warning signs (image only, text only, or image and text), this study adopted event-related potential technology to explore the differences at the neurocognitive level using the oddball paradigm and the Go/No-go paradigm. Together, the behavioral and electroencephalogram results showed that text-only warnings had the lowest effectiveness, but there was little difference between the image-only and image-and-text warnings. The differences in the effects of the three warning signs were mainly in the areas of attention and cognitive control, implying differences in the underlying cognitive processes. Therefore, in the design of warning signs, the effects of different design attributes on cognitive processing should be taken into account based on actual needs in order to improve the effectiveness of the signs.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and has become a growing public health concern worldwide. Polyphenols may improve high-fat diet (HFD)-related NAFLD. Our ...previous study found that ferulic acid (FA) and p-coumaric acid (p-CA) were the polyphenols with the highest content in foxtail millet. In this study, we investigated the mechanism underlying the impact of ferulic acid and p-coumaric acid (FA/p-CA) on non-alcoholic fatty liver (NAFLD). The association of FA and p-CA with fatty liver was first analyzed by network pharmacology. Synergistic ameliorating of NAFLD by FA and p-CA was verified in oleic acid (OA) and palmitic acid (PA) (FFA)-treated hepatocytes. Meanwhile, FA/p-CA suppressed final body weight and TG content and improved liver dysfunction in HFD-induced NAFLD mice. Mechanistically, our data indicated that FA and p-CA bind to histone deacetylase 1 (HDAC1) to inhibit its expression. The results showed that peroxisome proliferator activated receptor gamma (PPARG), which is positively related to HDAC1, was inhibited by FA/p-CA, and further suppressed fatty acid binding protein (FABP) and fatty acid translocase (CD36). It suggests that FA/p-CA ameliorate NAFLD by inhibiting free fatty acid uptake via the HDAC1/PPARG axis, which may provide potential dietary supplements and drugs for prevention of NAFLD.
Nature polyphenols widely present in plants and foods are promising candidates in cancer chemotherapy. Emerging evidence has shown that plant polyphenols regulate the expression of miRNAs to exert ...the anti-Multidrug resistance (MDR) activity, which partly attributes to their regulation on miRNAs methylation. Our previous study found that bound polyphenol from foxtail millet bran (BPIS) had potential as an anti-MDR agent for colorectal cancer (CRC), but its mechanism remains unclear. The present findings demonstrated that BPIS upregulated the expression of miR-149 by reducing the methylation of its CpG islands, which subsequently induced the cell cycle arrest in G2/M phase, resulting in enhancing the chemo-sensitivity of HCT-8/Fu cells. Mechanically, BPIS and its active components (FA and p-CA) reduced miR-149 methylation by inhibiting the expression levels of DNA methyltransferases, promoting a remarkable increase of miR-149 expression. Further, the increased miR-149 induced cell cycle arrest in G
2
/M phase by inhibiting the expression of Akt, Cyclin B1 and CDK1, thus increasing the chemosensitivity of HCT-8/Fu cells. Additionally, a strong inducer of DNA de-methylation (5-aza-dc) treatment markedly increased the chemosensitivity of CRC through elevating miR-149 expression, which indicates the hypermethylation of miR-149 may be the key cause of drug resistance in CRC. The study indicates that the enhanced chemosensitivity of BPIS on CRC is mainly attributed to the increase of miR-149 expression induced by methylation inhibition.
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