Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.

Lipin1 expression was induced at a late stage of differentiation of 3T3-L1 preadipocytes and maintained at high levels in mature adipocytes. Knockdown of expression of lipin1 by small interfering RNA in 3T3-L1 preadipocytes almost completely inhibited differentiation into adipocytes, whereas overexpression of lipin1 accelerated adipocyte differentiation, demonstrating that lipin1 is required for adipocyte differentiation. In mature adipocytes, transfection of lipin1-small interfering RNA decreased the expression of adipocyte functional genes, indicating the involvement of lipin1 in the maintenance of adipocyte function. Lipin1 increases the transcription-activating function of peroxisome proliferator-activated receptor ␥ 2 (PPAR␥ 2 ) via direct physical interaction, whereas lipin1 did not affect the function of other adipocyte-related transcription factors such as C/EBP␣, liver X-activated receptor ␣, or sterol regulatory element binding protein 1c. In mature adipocytes, lipin1 was specifically recruited to the PPAR␥-response elements of the phosphoenolpyruvate carboxykinase gene, an adipocyte-specific gene. C/EBP␣ up-regulates lipin1 transcription by directly binding to the lipin1 promoter. Based on the existence of a positive feedback loop between C/EBP␣ and PPAR␥ 2 , we propose that lipin1 functions as an amplifier of the network between these factors, resulting in the maintenance of high levels of the specific gene expression that are required for adipogenesis and mature adipocyte functions.Adipose tissue plays an essential role in maintaining metabolic homeostasis (1). White adipose tissue takes up fatty acids derived from the diet or the liver as well as increases the uptake of glucose in response to insulin by recruiting glucose transporter 4 (GLUT4) 2 to the plasma membrane. Then white adipose tissue stores the glucose or fatty acids as a form of triacylglyceride and releases free fatty acids during states of starvation. Recent studies have shown that adipose tissue secretes various humoral factors called adipocytokines which play numerous functions associated with food intake, insulin sensitivity, energy homeostasis, inflammatory responses, and atherogenesis (2). In obese subjects adipocytes cannot function adequately, thereby causing various metabolic syndromes including insulin resistance, dyslipidemia, and coronary-vascular disease (3-6). Lipodystrophy leads to the same condition as obesity due to lack of adipocyte function (7-9). Thus, studying the molecular mechanisms that control adipose tissue development and function is important for understanding the pathophysiology of metabolic syndromes.Adipogenesis is a process in which premature cells acquire adipocyte-specific functions. A complex network of transcription factors is developed during this process in response to extracellular adipogenic stimuli. In 3T3-L1 preadipocyte cells the CCAAT/enhancer-binding proteins ␤ and ␦ (C/EBP␤ and C/EBP␦) are induced immediately upon adipogenic hormonal stimuli, and they are expressed for approximately 2 days ...

Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. Damaged mitochondria DNA (mtDNA) may have a role in regulating hyperglycemia during type 2 diabetes. Circulating cell-free mitochondria DNA (ccf-mtDNA) was found in serum and plasma from patients and has been linked to the prognosis factors in various human diseases. However, the role of ccf-mtDNA in chronic inflammation in type 2 diabetes is unclear. In this study, we hypothesized that the ccf-mtDNA levels are associated with chronic inflammation in patients with type 2 diabetes. The mtDNA levels were elevated in the plasma from patients with type 2 diabetes compared to healthy subjects. The elevated mtDNA levels were associated with interleukin-1 (IL-1)β levels in patients with type 2 diabetes. The mtDNA, from patients with type 2 diabetes, induced absent in melanoma 2 (AIM2) inflammasome-dependent caspase-1 activation and IL-1β and IL-18 secretion in macrophages. Our results suggest that the ccf-mtDNA might contribute to AIM2 inflammasome-mediated chronic inflammation in type 2 diabetes.

Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells.

Extracellular vesicles (EVs) are nanovesicles of endocytic origin released by cells and found in human bodily fluids. EVs contain both mRNA and microRNA (miRNA), which can be shuttled between cells, indicating their role in cell communication. This study investigated whether nasal secretions contain EVs and whether these EVs contain RNA. EVs were isolated from nasal lavage fluid (NLF) using sequential centrifugation. EVs were characterized and EV sizes were identified by transmission electron microscopy (TEM). In addition, EV miRNA expression was different in the chronic rhinosinusitis without nasal polyp (CRSsNP) and chronic rhinosinusitis with nasal polyp (CRSwNP) groups. The Kyoto encyclopedia gene and genome database (KEGG) database was used to identify pathways associated with changed miRNAs in each analysis group. Twelve miRNAs were differentially expressed in NLF-EVs of CRS patients versus HCs. In addition, eight miRNAs were differentially expressed in NLF-EVs of CRSwNP versus CRSsNP patients. The mucin-type O-glycan biosynthesis was a high-ranked predicted pathway in CRS patients versus healthy controls (HCs), and the Transforming growth factor beta (TGF-β) signaling pathway was a high-ranked predicted pathway in CRSwNP versus CRSsNP patients. We demonstrated the presence of and differences in NLF-EV miRNAs between CRS patients and HCs. These findings open up a broad and novel area of research on CRS pathophysiology as driven by miRNA cell communication.