Upregulated FOXM1 stimulates chondrocyte senescence in Acot12-/-Nudt7-/- double knockout mice.

Rationale: One of the hallmarks of osteoarthritis (OA), the most common degenerative joint disease, is increased numbers of senescent chondrocytes. Targeting senescent chondrocytes or signaling mechanisms leading to senescence could be a promising new therapeutic approach for OA treatment. However, understanding the key targets and links between chondrocyte senescence and OA remains unclear. Methods: Senescent chondrocytes were identified from Nudt7-/-, Acot12-/-, double-knockout mice lacking Acot12 and Nudt7 (dKO) and applied to microarray. The presence of forkhead transcription factor M1 (FOXM1) was detected in aged, dKO, and destabilization of the medial meniscus (DMM) cartilages and articular chondrocytes, and the effect of FoxM1 overexpression and acetyl-CoA treatment on cartilage homeostasis was examined using immunohistochemistry, quantitative real-time PCR (qRT-PCR), cell apoptosis and proliferation assay, and safranin O staining. Delivery of Rho@PAA-MnO2 (MnO2 nanosheet) or heparin-ACBP/COS-GA-siFoxM1 (ACBP-siFoxM1) nanoparticles into DMM cartilage was performed. Results: Here, we propose the specific capture of acetyl-CoA with the delivery of (FoxM1 siRNA (siFoxM1) to prevent cartilage degradation by inhibiting the axis of chondrocyte senescence. dKO stimulate chondrocyte senescence via the upregulation of FoxM1 and contribute to severe cartilage breakdown. We found that the accumulation of acetyl-CoA in the dKO mice may be responsible for the upregulation of FoxM1 during OA pathogenesis. Moreover, scavenging reactive oxygen species (ROS) induced by chondrocyte senescence via the implantation of MnO2 nanosheets or delivery of siFoxM1 functionalized with acetyl-CoA binding protein (ACBP) to capture acetyl-CoA using an injectable bioactive nanoparticle (siFoxM1-ACBP-NP) significantly suppressed DMM-induced cartilage destruction. Conclusion: We found that the loss of Acot12 and Nudt7 stimulates chondrocyte senescence via the upregulation of FoxM1 and accumulation of acetyl-CoA, and the application of siFoxM1-ACBP-NP is a potential therapeutic strategy for OA treatment.

Heukcha, naturally post-fermented green tea extract, ameliorates diet-induced hypercholesterolemia and NAFLD in hamster.

Hypercholesterolemia, characterized by an increase in plasma low-density lipoprotein (LDL) cholesterol and total cholesterol (TC), is the leading cause of non-alcoholic fatty liver disease (NAFLD). The present study examined the effect of Heukcha extract (HCE), a naturally post-fermented green tea extract, on diet-induced hypercholesterolemia and related NAFLD in hamsters that metabolize lipids in a similar fashion to humans. The 10-week-old golden Syrian hamsters were fed a normal diet (ND) or a high cholesterol diet (HCD) containing 0.2% cholesterol and 10% lard, and some were also given HCE (200 or 500 mg/kg/day) orally for 12 weeks. The HCE did not affect the body weight gain, food intake, or the calorie intake. HCD significantly (p < 0.05) increased LDL (0.9 to 2.1 mmol/L), TC (2.7 to 7.8 mmol/L), and triglyceride (TG; 2.3 to 4.0 mmol/L), which was significantly decreased by 27.7%, 17.3%, and 60%, respectively, by HCE. HDL was significantly increased by HCD (0.6 to 1.6 mmol/L), but it was not affected by HCE administration. Furthermore, HCE suppressed HCD-induced liver oxidative stress, fibrosis, and lipid accumulation almost to control levels. Interestingly, HCE significantly increased the protein level of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis, by 1.5-fold in the liver. The present data suggest that HCE could be a functional food ingredient that can suppress the occurrence of diet-induced hypercholesterolemia and NAFLD, possibly by increasing the expression of CYP7A1.

Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling.

The global burden of chronic kidney disease (CKD) intertwined with cardiovascular disease has become a major health problem. Oxidative stress (OS) plays an important role in the pathophysiology of CKD. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) antioxidant system plays a critical role in kidney protection by regulating antioxidants during OS. Heme oxygenase-1 (HO-1), one of the targets of Nrf2-ARE, plays an important role in regulating OS and is protective in a variety of human and animal models of kidney disease. Thus, activation of Nrf2-HO-1 signaling may offer a potential approach to the design of novel therapeutic agents for kidney diseases. In this review, we have discussed the association between OS and the pathogenesis of CKD. We propose Nrf2-HO-1 signaling-mediated cell survival systems be explored as pharmacological targets for the treatment of CKD and have reviewed the literature on the beneficial effects of small molecule natural products that may provide protection against CKD.

TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury.

In response to liver injury, the liver undergoes a regeneration process to retain its mass and function. However, the regeneration mechanism has not been fully clarified. This study investigated the role of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo-signaling effector, in liver regeneration. We observed that TAZ stimulates liver regeneration after liver injury. After partial hepatectomy (PHx) or carbon tetrachloride damage, TAZ was required for liver regeneration to increase hepatic cell proliferation and resist hepatic apoptosis, which were decreased in liver-specific TAZ knockout (LKO) mice. TAZ stimulated macrophage infiltration, resulting in IL-6 production, which induced liver regeneration. In LKO mice, IL-6-induced activation of signal transducer and activator of transcription 3, ERK, and PKB was decreased. We also observed that periductal fibrogenesis was significantly increased in LKO mice during liver regeneration after PHx, which was caused by increased hepatic apoptosis. Our results suggest that TAZ stimulates liver regeneration through IL-6-induced hepatocyte proliferation and inhibition of cell death after liver injury.-Kim, A. R., Park, J. I., Oh, H. T., Kim, K. M., Hwang, J.-H., Jeong, M. G., Kim, E.-H., Hwang, E. S., Hong, J.-H. TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury.

Contribution of actin filaments and microtubules to cell elongation and alignment depends on the grating depth of microgratings.

BACKGROUND: It has been reported that both chemical and physical surface patterns influence cellular behaviors, such as cell alignment and elongation. However, it still remains unclear how actin filament and microtubules (MTs) differentially respond to these patterns. RESULTS: We examined the effects of chemical and physical patterns on cell elongation and alignment by observing actin filament and MTs of retinal pigment epithelium-1(RPE-1) cells, which were cultured on either fibronectin (FN)-line pattern (line width and spacing: 1 µm) or FN-coated 1 µm gratings with two different depths (0.35 or 1 µm). On the surface with either FN-line pattern or micrograting structure, the cell aspect ratios were at least two times higher than those on the surface with no pattern. Cell elongation on the gratings depended on the depth of the gratings. Cell elongation and alignment on both FN-line pattern and 1 µm gratings with 0.35 µm depth were perturbed either by inhibition of actin polymerization or MT depletion, while cell elongation and alignment on 1 µm gratings with 1 µm depth were perturbed only by MT depletion. CONCLUSIONS: Our results suggest that the contribution of actin filaments and MTs to the elongation and alignment of epithelial cells on microgratings depends on the groove depth of these gratings.