4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

Objectives: The aim of this study was to investigate the mechanism of itaconate's potential effect in diabetic kidney disease.Methods: Renal immune responsive gene 1 (IRG1) levels were measured in db/db mice and streptozotocin (STZ) + high-fat diet (HFD)-induced diabetic mice. Irg1 knockout mice were generated. db/db mice were treated with 4-octyl itaconate (4-OI, 50 mg/kg), a derivative of itaconate, for 4 weeks. Renal function and morphological changes were investigated. Ultrastructural alterations were determined by transmission electron microscopy.Results: Renal IRG1 levels were reduced in two diabetic models. STZ+HFD-treated Irg1 knockout mice exhibited aggravated renal tubular injury and worsened renal function. Treatment with 4-OI lowered urinary albumin-to-creatinine ratio and blood urea nitrogen levels, and restored renal histological changes in db/db mice. It improved mitochondrial damage, increased expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the renal cortex of db/db mice. These were confirmed in vitro; 4-OI improved high glucose-induced abnormal mitochondrial morphology and TFAM expression in HK-2 cells, effects that were inhibited by PGC-1α silencing. Moreover, 4-OI reduced the number of apoptotic cells in the renal cortex of db/db mice. Further study showed that 4-OI increased renal Nrf2 expression and decreased oxidative stress levels in db/db mice. In HK-2 cells, 4-OI decreased high glucose-induced mitochondrial ROS production, which was reversed by Nrf2 silencing. Nrf2 depletion also inhibited 4-OI-mediated regulation of PGC-1α, TFAM, and mitochondrial apoptotic protein expressions.Conclusions: 4-OI attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis.

Resveratrol stimulates brown of white adipose via regulating ERK/DRP1-mediated mitochondrial fission and improves systemic glucose homeostasis.

PURPOSE: Diabetes mellitus and metabolic homeostasis disorders may benefit from white adipose tissue (WAT) browning, which is associated with mitochondrial fission. Resveratrol, a dietary polyphenol, exhibits beneficial effects against abnormalities related to metabolic diseases. However, it remains unknown whether resveratrol contributes to WAT browning by regulating mitochondrial fission. METHODS: We administered resveratrol (0.4% mixed with control) to db/db mice for 12 weeks, measuring body weight, oral glucose tolerance, insulin tolerance, and histological changes. The uncoupling protein 1 (UCP1) and dynamin-related protein 1 (DRP1) expressions in the epididymal WAT were assessed via immunoblotting. RESULTS: We found that resveratrol improved systemic glucose homeostasis and insulin resistance in db/db mice, which was associated with increased UCP1 in epididymal WAT. Resveratrol-treated mice exhibited more fragmented mitochondria and increased phosphorylation of DRP1 in the epididymal WAT of the db/db mice. These results were further confirmed in vitro, where resveratrol induced extracellular signal-regulated kinase (ERK) signaling activation, leading to phosphorylation of DRP1 at the S616 site (p-DRP1S616) and mitochondrial fission, which was reversed by an ERK inhibitor in 3T3-L1 adipocytes. CONCLUSION: Resveratrol plays a role in regulating the phosphorylation of ERK and DRP1, resulting in the promotion of beige cells with epididymal WAT and the improvement of glucose homeostasis. Our present study provides novel insights into the potential mechanism of resveratrol-mediated effects on WAT browning, suggesting that it is, at least in part, mediated through ERK/DRP1-mediated mitochondrial fission.

Long-Term High-Fat Diet Decreases Renal Insulin-Degrading Enzyme Expression and Function by Inhibiting the PPARγ Pathway.

SCOPE: Long-term high-fat diet (HFD) causes insulin resistance, which is a primary etiological factor in the development of obesity and type 2 diabetes mellitus. Impaired insulin clearance is not only a consequence but also a cause of insulin resistance. The kidney is a major site of insulin clearance, where the insulin-degrading enzyme (IDE) plays a vital role in the proximal tubule. Thus, the study investigates the role of renal IDE in the regulation of insulin resistance in HFD-induced obese mice. METHODS AND RESULTS: Twenty four-weeks of HFD in C57BL/6 mice causes insulin resistance and impaires insulin clearance, accompanied by a decrease in renal IDE expression and activity. Palmitic acid decreases IDE mRNA and protein expressions in HK-2 cells. RNA-Seq analysis found that the PPAR pathway is involved. 24-weeks of HFD decreases renal PPARγ, but not PPARα or PPARß/δ mRNA expression. The inhibition of IDE expression by palmitic acid is prevented by the PPARγ agonist rosiglitazone. The amount of PPARγ bound to the promoters of IDE is decreased in palmitic acid-treated cells. Rosiglitazone improves insulin clearance and insulin resistance and increases renal IDE expression in HFD fed-mice. CONCLUSION: Long-term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPARγ.

Curcumin suppresses cell proliferation and reduces cholesterol absorption in Caco-2 cells by activating the TRPA1 channel.

BACKGROUND: Curcumin (Cur) is a bioactive dietary polyphenol of turmeric with various biological activities against several cancers. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Intestinal cholesterol homeostasis is associated with CRC. Chemotherapy for CRC is related to varied adverse effects. Therefore, natural products with anti-cancer properties represent a potential strategy for primary prevention of CRC. METHODS: The present study used Cur as a therapeutic approach against CRC using the Caco-2 cell line. The cells were treated with different concentrations of Cur for different duration of time and then the proliferation ability of cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine assays. Oil red O staining and cholesterol assay kit were used to evaluate cellular lipid content and cholesterol outward transportation. Finally, the protein expressions of cholesterol transport-related protein and signal transduction molecules were assessed using Western blot assay. RESULTS: Cur inhibited cell proliferation in Caco-2 cells in a dose- and time-dependent manner by activating the transient receptor potential cation channel subfamily A member 1 (TRPA1) channel. Activation of the TRPA1 channel led to increased intracellular calcium, peroxisome proliferator-activated receptor gamma (PPARγ) upregulation, and the subsequent downregulation of the specificity protein-1 (SP-1)/sterol regulatory element-binding protein-2 (SREBP-2)/Niemann-Pick C1-like 1 (NPC1L1) signaling pathway-related proteins, and finally reduced cholesterol absorption in Caco-2 cells. CONCLUSIONS: Cur inhibits cell proliferation and reduces cholesterol absorption in Caco-2 cells through the Ca2+/PPARγ/SP-1/SREBP-2/NPC1L1 signaling by activating the TRPA1 channel, suggesting that Cur can be used as a dietary supplement for the primary prevention of CRC. In Caco-2 cells, Cur first stimulates calcium influx by activating the TRPA1 channel, further upregulates PPARγ and downregulates SP-1/SREBP-2/NPC1L1 signaling pathway, and finally inhibits the absorption of cholesterol. TRPA1, transient receptor potential cation channel subfamily A member 1; NPC1L1, Niemann-Pick C1-like 1; PPARγ, peroxisome proliferator-activated receptor gamma; SP-1, specificity protein-1; SREBP-2, sterol regulatory element-binding protein-2; Cur, curcumin.

The effect of angiotensin-converting enzyme polymorphism on hemodynamic response to endotracheal intubation in hypertensive patients.

Endotracheal intubation elicits a hemodynamic response associated with increased heart rate and blood pressure that is influenced by the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) genetic polymorphism which may be of importance also for the pressure response to anesthesia. A total of 337 patients underwent abdominal surgery in general anesthesia and 16% were D/D-homozygotes, 45% were I/D heterozygotes and 39% of the patients were I/I homozygotes. Before surgery most patients were in treatment for arterial hypertension. Systolic and diastolic pressure, heart rate and concentrations of catecholamines in blood were determined before and after induction of anesthesia and for up to 10 minutes following endotracheal intubation. Anesthesia decreased blood pressure and for patients presenting ID and DD, blood pressure and heart rate reached similar levels but compared to II-homozygotes, D-carriers demonstrated significantly higher levels for systolic pressure and heart rate before and after intubation (p < 0.05). The blood levels of catercholamines were similar in the three genotype groups. The incidence of ECG-determined myocardial ischemia was higher in D-allele carriers compared to I-allele homozygotes (DD 22%, ID 25% vs. II 5%). In response to anesthesia and intubation and independent of sympathetic nervous activity, D-allele carriers for ACE polymorphism increased blood pressure response and higher risk for development of cardiovascular complications compared to patients homozygous for the I-allele.