Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the deterioration of articular cartilage. The progression of OA leads to an increase in inflammatory mediators in the joints, thereby promoting the destruction of the cartilage matrix. Recent studies have reported on the anti-inflammatory and antioxidant properties of cardamonin, which also appears to interact with cellular targets, such as nuclear erythroid 2-related factor 2 (Nrf2), extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin (mTOR) during the progression of tumors. To date, few studies have investigated the effects of cardamonin on chondrocyte inflammation. In the current study, we determined that treating interleukin-1 beta (IL-1β-stimulated chondrocyte cells) with cardamonin significantly reduced the release of nitric oxide (NO) and prostaglandin E2 (PGE2) and significantly inhibited the expression of pro-inflammatory proteins, including inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Cardamonin was also shown to: (1) inhibit the activation and production of matrix metalloproteinases (MMPs), (2) suppress the nuclear factor-κB (NF-κB) signaling pathway, (3) suppress the expression of toll-like receptor proteins, (4) activate the Nrf2 signaling pathway, and (5) increase the levels of antioxidant proteins heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). The increase in antioxidant proteins led to corresponding antioxidant effects (which were abolished by Nrf2 siRNA). Our findings identify cardamonin as a candidate Nrf2 activator for the treatment and prevention of OA related to inflammation and oxidative stress.

P revious studies in patients with an impaired efferent baroreflex led us to discover that water ingestion induces a robust increase in blood pressure (BP) and vascular resistance.1,2 Initially, Jordan et al 1 demonstrated that ingesting 473 mL (16 oz) of water induces a profound increase in systolic BP averaging ≈40 mm Hg in patients with autonomic failure and also elevated BP by ≈11 mm Hg in elderly subjects. This effect appears within 10 minutes, is maximal at 25 to 40 minutes, and largely dissipates by 90 minutes after water ingestion.1 Although the pressor effect of water is greatest in individuals with impaired baroreflex buffering, water induces a maximal rise in peripheral vascular resistance at 25 minutes after ingestion without an associated increase in BP in young healthy subjects. [3][4][5] This prominent vascular response after water ingestion is termed the osmopressor response (OPR), reflecting that the stimulus setting of the response is hypo-osmolality rather than gastric distension. 6,7 The hypo-osmotic stimulus of water has been thought to act through the osmosensitive structures in portal and splanchnic circulation. 8 In animals, the osmopressor response seems to be mediated through transient receptor potential cation channel, subfamily V, member 4 (TRPV4) activation on osmosensitive hepatic spinal afferents, dorsal horn ganglia, and spinal cord. Aquaporin-1 (AQP1), the first discovered water channel protein, was found colocalized with portal osmosensor TRPV4 in the plasma membrane of axons and synaptic terminals in the superficial dorsal horn and the enteric plexus. 10 We supposed that the AQP1, driven by osmotic gradients, contributes to the osmopressor response by acting as an osmotic sensing input carried by circulating red blood cells (RBCs).Thus, we hypothesized water ingestion induces functional expression of the AQP1 in circulating RBC during the osmopressor response.11 The study presented here demonstrates that the hypo-osmotic stimulus of water increases AQP1 tyrosine phosphorylation simultaneously with the osmopressor response.Abstract-Studies in patients with an impaired efferent baroreflex led us to discover that ingesting water induces a robust increase in blood pressure and vascular resistance. This response was also present in healthy subjects with intact baroreflexes, described as osmopressor response. This study was to discover the physiology of the osmopressor response by determining functional activation of the aquaporin-1 water channel receptor on red blood cell membranes in young healthy subjects. In a randomized, controlled, crossover fashion, 22 young healthy subjects (age, 19-27 years) ingested either 500 or 50 mL of water. Heart rate, blood pressure, cardiac index, and total peripheral vascular resistance were measured using a Finometer hemodynamic monitor. Blood sampling was performed at 5 minutes before and at 25 and 50 minutes after either the water ingestion or control session. Immunoblotting for aquaporin-1 tyrosine phosphorylation was performed before and after ...

Objective:We aimed to determine whether high-dose nitroglycerin, a nitric oxide donor, preserves erythrocyte deformability during cardiopulmonary bypass and examines the signaling pathway of nitric oxide in erythrocytes. Methods:In a randomized and controlled fashion, forty-two patients undergoing cardiac surgery with hypothermic cardiopulmonary bypass were allocated to high-dose (N = 21) and low-dose groups (N = 21). During rewarming period, patients were given intravenous nitroglycerin with an infusion rate 5 and 1 µg·kg −1 ·min −1 in high-dose and low-dose groups, respectively. Tyrosine phosphorylation level of non-muscle myosin IIA in erythrocyte membrane was used as an index of erythrocyte deformability and analyzed using immunoblotting.Results: Tyrosine phosphorylation of non-muscle myosin IIA was significantly enhanced after bypass in high-dose group (3.729 ± 1.700 folds, P = .011) but not low-dose group (1.545 ± 0.595 folds, P = .076). Phosphorylation of aquaporin 1, vasodilator-stimulated phosphoprotein, and focal adhesion kinase in erythrocyte membrane was also upregulated in high-dose group after bypass. Besides, plasma nitric oxide level was highly correlated with fold change of non-muscle myosin IIA phosphorylation (Pearson's correlation coefficient .871). Conclusions: High-dose nitroglycerin administered during cardiopulmonary bypass improves erythrocyte deformability through activating phosphorylation of aquaporin 1, vasodilator-stimulated phosphoprotein, and focal adhesion kinase in erythrocytes. K E Y W O R D S aquaporin 1, focal adhesion kinase, nitric oxide, non-muscle myosin IIA, vasodilatorstimulated phosphoprotein S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section.

Glucose ingestion attenuates the water ingestion-induced increase in the total peripheral vascular resistance and orthostatic tolerance. We investigated the gastrointestinal physiology of glucose by examining the effect of glucose ingestion on the functional expression of focal adhesion kinase (FAK) in red blood cell (RBC) membrane. This study was performed in 24 young, healthy subjects. Blood samples were collected at 5 min before and 25 min and 50 min after an ingestion of 10% glucose water 500 mL, water 500 mL, or normal saline 500 mL. We determined glucose and osmolality in plasma, and phosphorylation of aquaporin 1 (AQP1), glucose transporter 1 (Glut1), and FAK in RBC membrane. Our results showed that glucose ingestion reduced the rise of peripheral vascular resistance after water ingestion and upregulated the serine phosphorylation of Glut1. It also lowered both the serine phosphorylation of FAK and tyrosine phosphorylation of AQP1, compared with the ingestion of either water or saline. In an ex vivo experiment, glucose activated the Glut1 receptor and subsequently reduced the expression of FAK compared with 0.8% saline alone. We concluded that glucose activates Glut1 and subsequently lowers the functional expression of FAK, a cytoskeleton protein of RBCs. The functional change in the RBC membrane proteins in connection with the attenuation of osmopressor response may elucidate the pathophysiology of glucose in postprandial hypotension.